EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 12, 2013

Teaching Physicians to Care Amid Chaos

Allan S. Detsky, M.D., Ph.D., of the University of Toronto, and Donald M. Berwick, M.D., of Harvard Medical School, Boston, examine the changes that have taken place in patient care in recent decades. “In 2013, inpatient medical care in teaching hospitals is different: far more complex, more intense, and, simply put, faster.” One of the results of these changes is that “inpatient care in teaching hospitals has become a relay race for the responsible physicians and consultants, and patients are the batons.”

In this Viewpoint, the authors offer suggestions on how to address the issues of rapid turnover and diffused responsibility among hospital staff.

“We are certain that today’s trainees are not a whit less dedicated to their professional mission than those of an earlier era were at their best, but we cannot help wonder whether the very definition of caring changes in undesirable and unintended ways when responsibility becomes a rapidly revolving door. If that risk exists, it warrants conversation.”

(JAMA. 2013;309[10]:987-988. Available pre-embargo to the media at https://media.jamanetwork.com)

Putting Health IT on the Path to Success

William A. Yasnoff, M.D., Ph.D., of NHII Advisors, Arlington, Va., and colleagues discuss the problems with the current approach to health information technology (HIT), and suggest an alternative that is “simpler, scalable, less expensive, and more secure and can provide lifetime records: patient-centric community health record banks (HRBs).”

“The idea of HRBs is not new. What is new is appreciating how HRBs can help achieve the HIT vision while most current health information exchange (HIE) pursuits cannot. It is time for physicians to insist that HIT be pursued with realistic, achievable, and measurable goals that will produce readily available, comprehensive electronic records that can actually improve patient care. To do so requires implementation of model health record banks and then refinement of those models to allow them to achieve the sustainability and scalability that have prevented the success of distributed HIEs. Otherwise, HIT may become its own sociopolitical, legal, and economic disease.”

(JAMA. 2013;309[10]:989-990. Available pre-embargo to the media at https://media.jamanetwork.com)

Improving the Electronic Health Record— Are Clinicians Getting What They Wished For?

James J. Cimino, M.D., of the Laboratory for Informatics Development, National Institutes of Health Clinical Center, Bethesda, Md., examines the “promise and perils” regarding the increase in adoption of electronic health records (EHRs).

“EHRs had to start someplace, and they have delivered the wishes of many. Rather than complain about the challenges they have introduced, clinicians should recognize that current EHRs are illuminating the opportunities for the next generation of systems that will support clinicians as active partners across the spectrum of health care settings and tasks. The resulting improvements in documentation will, in turn, support patients, administrators, and researchers as we move towards a true learning health system.”

(JAMA. 2013;309[10]:991-992. Available pre-embargo to the media at https://media.jamanetwork.com)

Helping Smokers Quit Around the Time of Surgery

In this Viewpoint, Dhruv Khullar, B.A., of the Yale University School of Medicine, New Haven, Conn., and colleagues discuss the reasons many physicians do not routinely counsel patients to stop smoking before an operation or do not refer them to appropriate cessation services.

“As accrediting agencies and public and private payers search more intensely for value in health care, surgeons must aim to improve postoperative outcomes. An effective strategy will be to encourage patients to stop smoking preoperatively, thereby potentially reducing postoperative complications and length of hospital stay. Collaborations with primary care physicians, anesthesiologists, nurses, and others can facilitate smoking cessation and the delivery of better surgical care.”

(JAMA. 2013;309[10]:993-994. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the articles 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, MARCH 12, 2013

Media Advisory: To contact Adnan K. Chhatriwalla, M.D., call Kerry A. O’Connor at 816-932-8646 or email koconnor@saint-lukes.org.

CHICAGO – In a study that included 3.3 million percutaneous coronary intervention (PCI; procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries) procedures, major bleeding after PCI was associated with significantly increased in-hospital mortality, with an estimated 12 percent of deaths after PCI related to bleeding complications, according to a study appearing in the March 13 issue of JAMA.

“Bleeding represents the most common noncardiac complication of PCI. Postprocedural bleeding is associated with short- and long-term death, nonfatal myocardial infarction, stroke, blood transfusion, prolonged hospital stay, rehospitalization, and increased hospital costs. Post-PCI bleeding is predictable, using tools such as the bleeding risk algorithm derived from the CathPCI Registry. Bleeding risk is modifiable through the use of established bleeding avoidance strategies such as bivalirudin anticoagulation, arterial closure devices, and radial artery access,” according to background information in the article. “The incidence of bleeding-related mortality after PCI has not been described in a nationally representative population. Furthermore, the relationships among bleeding risk, bleeding site, and mortality are unclear.”

Adnan K. Chhatriwalla, M.D., of Saint Luke’s Mid America Heart Institute, Kansas City, Mo., and colleagues conducted a study to estimate the adjusted population attributable risk of bleeding-related mortality in the U.S. PCI population. The study included data from 3,386,688 procedures in the CathPCI Registry performed in the United States between 2004 and 2011. The population attributable risk was calculated after adjustment for baseline demographic, clinical, and procedural variables. Also, the number needed to harm (NNH) for bleeding-related mortality was calculated.

In the total study population, there were 57,246 major bleeding events (1.7 percent) and 22,165 in-hospital deaths (0.65 percent). The adjusted population attributable risk of in-hospital mortality related to major bleeding was 12.1 percent. The propensity-matched population consisted of 56,078 procedures with major bleeding and 224,312 matched controls. The researchers found that patients with major bleeding had significantly higher in-hospital mortality relative to patients without bleeding (5.3 percent vs. 1.9 percent). Both access-site and non-access-site bleeding were associated with increased in-hospital mortality (2.7 percent vs. 1.9 percent; and 8.3 percent vs. 1.9 percent, respectively). The association between major bleeding and in-hospital mortality was observed in all levels of bleeding risk (low-, intermediate-, and high-risk groups).

The researchers conducted an analysis regarding the number of major bleeding events associated with 1 in-hospital mortality (NNH) in selected subgroups. “The NNH varied between 16 and 117, depending on bleeding risk and bleeding site, and was lowest in patients at high risk for bleeding (NNH = 21) or with non-access-site bleeding (NNH=16). NNH values were lowest in the following patient subgroups: age 75 years or older, ST-segment elevation myocardial infarction [a certain pattern on an electrocardiogram following a heart attack], or low glomerular filtration rate.”

“In this study of more than 3.3 million PCI procedures, we found that major bleeding was associated with significantly increased in-hospital mortality after PCI. The novel findings are that adjusted population attributable risk estimates for an unselected and nationally representative U.S. PCI population suggest that 12.1 percent of all in-hospital mortality after PCI may be related to bleeding complications and may therefore be modifiable…”, the authors write.

(JAMA. 2013;309(10):1022-1029; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR). 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, MARCH 12, 2013

Media Advisory: To contact co-author R. Doug McEvoy, M.D., email doug.mcevoy@health.sa.gov.au.

CHICAGO – Among patients who were identified as likely having moderate to severe obstructive sleep apnea, treatment based in primary care was not clinically inferior to treatment at a specialist sleep center for improvement in daytime sleepiness scores, according to a study appearing in the March 13 issue of JAMA.

“Obstructive sleep apnea with accompanying daytime sleepiness was estimated during the early 1990s to affect between 2 percent and 4 percent of middle-aged adults. With growing awareness of the public health implications of untreated disease and rising obesity rates that have increased the prevalence of obstructive sleep apnea, there has been a steady demand for sleep service provision in specialist centers and growing waiting lists for sleep physician consultation and laboratory-based polysomnography (PSG),” according to background information in the article. “One-third of primary care patients report symptoms suggestive of obstructive sleep apnea. With appropriate training and simplified management tools, primary care physicians and practice nurses might be ideally positioned to take on a greater role in diagnosis and management.” However, whether an ambulatory approach would be noninferior (outcome not worse than treatment compared to) in a primary care setting is unknown.

Ching Li Chai-Coetzer, M.B.B.S., Ph.D., of the Adelaide Institute for Sleep Health, Repatriation General Hospital, Daw Park, South Australia, and colleagues conducted a study to compare the clinical efficacy and within-trial costs of a simplified model of diagnosis and care in primary care relative to that in specialist sleep centers. The randomized, controlled, noninferiority study included 155 patients with obstructive sleep apnea who were treated at primary care practices (n = 81) in metropolitan Adelaide, three rural regions of South Australia or at a university hospital sleep medicine center in Adelaide, Australia (n = 74), between September 2008 and June 2010. Both interventions (primary care management vs. usual care in a specialist sleep center) included continuous positive airway pressure, mandibular (lower jaw) advancement splints, or conservative measures only. The primary outcome measure was 6-month change in scores on the Epworth Sleepiness Scale (ESS). Secondary outcomes included disease-specific and general quality of life measures, obstructive sleep apnea symptoms, adherence to using continuous positive airway pressure, patient satisfaction, and health care costs.

The researchers found that there were significant improvements in ESS scores from baseline to 6 months in both groups. “The mean [average] ESS for the entire study population was 12.6. The mean ESS scores in the primary care group improved from 12.8 at baseline to 7.0 at 6 months, for an adjusted mean difference of 5.8 and in the specialist group from a baseline mean of 12.5 to 7.0 at 6 months, for an adjusted mean difference of 5.4. After controlling for baseline ESS score and region, the adjusted difference in the mean change in the ESS score was -0.13.” The results the support noninferiority of primary care management.

There were no differences in secondary outcome measures between groups. Seventeen patients (21 percent) withdrew from the study in the primary care group vs. 6 patients (8 percent) in the specialist group. Adherence to CPAP use among those using it at 6 months was no different between the 2 groups.

Analysis of within-trial sleep-related diagnostic and treatment costs revealed that primary care management of obstructive sleep apnea was approximately 40 percent less expensive than specialist care. The equivalent total average costs per patient were estimated at U.S. $1,819 in the primary care group and U.S. $3,068 in the specialist group. Sleep study costs, sleep physician consultations, and travel costs appeared to be the main contributors to the increased within-trial costs in the specialist group.

“In conclusion, in this randomized controlled study, a simplified management strategy for obstructive sleep apnea based in primary care was not clinically inferior to standard care in a specialist sleep center. It possibly could be delivered at a lower cost. Thus, with adequate training of primary care physicians and practice nurses and with appropriate funding models to support an ambulatory strategy, primary care management of obstructive sleep apnea has the potential to improve patient access to sleep services. This would be particularly beneficial for rural and remote regions, as well as developing nations, where access to specialist services can be limited,” the authors write.

(JAMA. 2013;309(10):997-1004; 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, MARCH 12, 2013

Media Advisory: To contact Richard M. Martin, Ph.D., email richard.martin@bristol.ac.uk.

CHICAGO – In research that included nearly 14,000 healthy infants in Belarus, an intervention that succeeded in improving the duration and exclusivity of breastfeeding during infancy did not result in a lower risk of overweight or obesity among the children at age 11.5 years, according to a study appearing in the March 13 issue of JAMA.

Observational studies suggest that greater duration and exclusivity of having been breastfed reduces child obesity risk. “However, breastfeeding and growth are socially patterned in many settings,” and observed associations between these variables are at least partly explained by confounding factors, according to background information in the article.

Richard M. Martin, Ph.D., of the University of Bristol, England, and colleagues investigated the effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity (body fat) and circulating insulin-like growth factor 1 (IGF-1), which regulates growth. The randomized controlled trial was conducted in 31 Belarusian maternity hospitals and their affiliated clinics. Participants were randomized into 1 of 2 groups: breastfeeding promotion intervention or usual practices. Participants were 17,046 breastfeeding mother-infant pairs enrolled in 1996 and 1997, of whom 13,879 (81.4 percent) were followed up between January 2008 and December 2010 at a median (midpoint) age of 11.5 years. The breastfeeding promotion intervention was modeled on the WHO/UNICEF Baby-Friendly Hospital Initiative (World Health Organization/United Nations Children’s Fund). The main outcome measures were body mass index (BMI), fat and fat-free mass indices (FMI and FFMI), percent body fat, waist circumference, triceps and subscapular skinfold thicknesses, overweight and obesity, and whole-blood IGF-1.

As previously reported, the researchers found that infants in the intervention group had substantially increased breastfeeding duration and exclusivity vs. the control group: at 3 months, exclusively (43.3 percent vs. 6.4 percent) and predominantly (51.9 vs. 28.3 percent) breastfed; at 6 months, both exclusive (7.9 percent vs. 0.6 percent) and predominant breastfeeding (10.6 percent vs. 1.6) were lower, but more common in the intervention group; and at 12 months, 19.7 percent (intervention) vs. 11.4 percent (control), were still breastfeeding to any degree.

At followup, when children were a median 11.5 years age, there were no significant differences between the experimental vs. control groups for the main outcomes, with the cluster-adjusted mean [average] differences of 0.19 (95 percent CI, -0.09 to 0.46) for BMI; 0.12 for FMI; 0.04 for FFMI; 0.47 percent for percent body fat; 0.30 cm for waist circumference; -0.07 mm for triceps and -0.02 mm for subscapular skinfold thicknesses; and -0.02 standard deviations for IGF-1.

The cluster-adjusted odds ratio for overweight/obesity (BMI ≥85th vs. <85th percentile) was 1.18 (95 percent CI, 1.01 to 1.39) and for obesity (BMI ≥95th vs. <85th percentile) was 1.17 (95 percent CI, 0.97 to 1.41).

“Among healthy term infants in Belarus, an intervention to improve the duration and exclusivity of infant breastfeeding did not prevent overweight or obesity, nor did it affect IGF-1 levels among these children when they were aged 11.5 years. Nevertheless, breastfeeding has many health advantages for the offspring, including beneficial effects demonstrated by our PROBIT trial on gastrointestinal infections and atopic eczema in infancy and improved cognitive development at age 6.5 years. Although breastfeeding is unlikely to stem the current obesity epidemic, its other advantages are amply sufficient to justify continued public health efforts to promote, protect, and support it,” the researchers conclude.

(JAMA. 2013;309(10):1005-1013; 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, MARCH 12, 2013

Media Advisory: To contact corresponding author Carole Clair, M.D., M.Sc., email carole.willi@gmail.com. To contact co-author James B. Meigs, M.D., M.P.H., call Ryan Donovan at 617-724-6433 or email rcdonovan@partners.org. To contact editorial co-author Michael C. Fiore, M.D., M.P.H., M.B.A., call Christopher Hollenback at 608-262-3902 or email ch3@ctri.wisc.edu.

CHICAGO – Among adults without diabetes, quitting smoking, compared with continuing smoking, was associated with a lower risk of cardiovascular disease despite subsequent weight gain, according to a study appearing in the March 13 issue of JAMA.

“Cigarette smoking is the leading cause of preventable mortality in the United States and a major risk factor for cardiovascular disease (CVD). Smoking cessation substantially reduces the risks of CVD; however, quitting smoking is associated with a small number of adverse health consequences, weight gain being one of smokers’ major concerns,” according to background information in the article. The average postcessation weight gain varies between 6.6 lbs. and 13.2 lbs. in North America, happens within 6 months after smoking cessation, and persists over time. Obesity is also a risk factor for CVD. Weight gain following smoking cessation therefore might lessen the benefits of quitting smoking on CVD outcomes. In addition, among people with type 2 diabetes, weight gain following smoking cessation has potential to be of greater concern because it is a risk factor for poor diabetes control and increased risk of illness and death. “The effect on CVD of potential weight gain following smoking cessation is not well understood,” the authors write.

Carole Clair, M.D., M.Sc., of the University of Lausanne, Switzerland, and colleagues conducted a study to assess the association between 4-year weight gain following smoking cessation and CVD event rate among adults with and without diabetes. The study included data from the Framingham Offspring Study collected from 1984 through 2011. At each 4-year examination, self-reported smoking status was assessed and categorized as smoker, recent quitter (≤ 4 years), long-term quitter (>4 years), and nonsmoker. Models were used to estimate the association between quitting smoking and 6-year CVD events and to test whether 4-year change in weight following smoking cessation modified the association between smoking cessation and CVD events. The primary outcome measure was the incidence over 6 years of total CVD events, comprising coronary heart disease, cerebrovascular events, peripheral artery disease, and congestive heart failure.

Weight gain occurred over 4 years in participants without and with diabetes. Among participants without diabetes, recent quitters gained significantly more weight (median [midpoint], 5.9 lbs.) than long-term quitters (1.9 lbs.), smokers (1.9 lbs.), and nonsmokers (3 lbs.). Among patients with diabetes, recent quitters also gained significantly more weight (7.9 lbs.) than smokers (1.9 lbs.), long-term quitters (0.0 lbs., and nonsmokers (1.1 lbs.).

After an average follow-up of 25 years, 631 CVD events occurred among 3,251 participants. The researchers found that among participants without diabetes, the age- and sex-adjusted CVD incidence rates were lower for nonsmokers, recent quitters, and long-term quitters, compared with smokers.

After adjustment for CVD risk factors, compared with smokers, recent quitters had a 53 percent lower risk for CVD and long-term quitters had a 54 percent lower risk for CVD; these associations had only a minimal change after further adjustment for weight change. “Among participants with diabetes, there were similar point estimates that did not reach statistical significance,” the authors write.

The researchers observed similar benefits associated with smoking cessation for total CVD and for fatal and non-fatal coronary heart disease, with the cessation benefits not offset by weight gain.

“In conclusion, among adults without diabetes, quitting smoking was associated with a lower risk of CVD compared with continuing smoking. There were qualitatively similar lower risks among participants with diabetes that did not reach statistical significance, possibly because of limited study power. Weight gain that occurred following smoking cessation was not associated with a reduction in the benefits of quitting smoking on CVD risk among adults without diabetes. This supports a net cardiovascular benefit of smoking cessation, despite subsequent weight gain,” the authors write.

(JAMA. 2013;309(10):1014-1021; 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, March 12 at this link.

Editorial: Should Clinicians Encourage Smoking Cessation for Every Patient Who Smokes?

In an accompanying editorial, Michael C. Fiore, M.D., M.P.H., M.B.A., and Timothy B. Baker, Ph.D., of the University of Wisconsin School of Medicine and Public Health, Madison, suggest ways in which the findings of this study can be used by physicians.

“First, data from the study by Clair et al can be used to reassure patients concerned about the health effects of cessation-related weight gain. About 50 percent of female smokers and about 25 percent of male smokers are ‘weight concerned,’ which may discourage quit attempts and quitting success. Although such reassurance may not assuage concerns about the effects of weight gain on appearance, it may nevertheless be helpful. Furthermore, even though no treatments have been shown to reliably prevent cessation-related weight gain, exercise regimens may be beneficial, and use of nicotine replacement medications can suppress weight gain during their use. Second, physicians should use this information to reinforce their commitment to provide or arrange evidence based treatment for all of their patients who smoke.”

(JAMA. 2013;309(10):1032-1033; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This Editorial was supported by grants from the National Cancer Institute and National Heart, Lung, and Blood Institute. Dr. Fiore reported institutional support from Pfizer for a phase 4 study of varenicline. Dr. Baker reported no disclosures.

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EMBARGOED FOR EARLY RELEASE: 1:15 P.M. (CT) MONDAY, MARCH 11, 2013

Media Advisory: To contact Mihai Gheorghiade, M.D., call Erin White at 847-491-4888 or email ewhite@northwestern.edu.

CHICAGO – Among patients hospitalized for heart failure (HF) with reduced left ventricular ejection fraction (LVEF; a measure of how well the left ventricle of the heart pumps with each contraction), initiation of the medication aliskiren in addition to standard therapy did not reduce cardiovascular death or HF rehospitalization at 6 or 12 months after discharge, according to a study published online by JAMA. The study is being released early to coincide with its presentation at the American College of Cardiology’s annual Scientific Sessions.

“Inhibition of the renin-angiotensin-aldosterone system [RAAS; the regulation of sodium balance, fluid volume, and blood pressure by secretion of renin in response to reduced perfusion of the kidney] has long been recognized as a life-prolonging therapy for patients with chronic heart failure with reduced LVEF, and angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) are recommended by all major national guidelines. However, although the benefits of these treatments are undisputed, these agents induce a compensatory increase in renin [an enzyme secreted by the kidneys] and downstream RAAS intermediaries that may partially offset RAAS blocking effects,” according to background information in the article.

The direct renin inhibitors (DRIs) represent another pharmacologically distinct method for RAAS blockade. Aliskiren, an orally active DRI, has demonstrated a favorable hemodynamic and neurohormonal profile in patients with HF. “Despite current evidence-based therapies, patients with hospitalization for HF (HHF) face postdischarge mortality and rehospitalization rates as high as 15 percent and 30 percent, respectively, within 60 to 90 days. Incomplete suppression of the RAAS may contribute to the exceptionally high postdischarge event rate,” the authors write.

Mihai Gheorghiade, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, and colleagues conducted a study (the ASTRONAUT randomized trial) to examine whether the addition of a DRI (aliskiren) to standard therapy would improve long-term outcomes in HHF patients. The study included hemodynamically stable HHF patients a median (midpoint) 5 days after admission who met certain criteria. Patients were recruited from 316 sites across North and South America, Europe, and Asia between May 2009 and December 2011. The follow-up period ended in July 2012.

All patients received 150 mg (increased to 300 mg as tolerated) of aliskiren or placebo daily, in addition to standard therapy. The study drug was continued after discharge for a median 11.3 months.

The final group for efficacy analyses included 1,615 patients (808 assigned to aliskiren, 807 assigned to placebo). At randomization, patients were receiving diuretics (95.9 percent), beta-blockers (82.5 percent), ACE inhibitors or ARBs (84.2 percent), and MRAs (57.0 percent).There were no major differences between the 2 treatment groups at the time of randomization. The average age was 65 years.

“In total, 24.9 percent of patients receiving aliskiren (77 cardiovascular [CV] deaths, 153 HF hospitalizations) and 26.5 percent of patients receiving placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point [cardiovascular death or HF rehospitalization] at 6 months. At 12 months, the event rates were 35.0 percent for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3 percent for the placebo group (137 CV deaths, 224 HF rehospitalizations),” the authors write.

During the overall follow-up period (ranging from 0.1 to 31.2 months), the total hospitalization rates (i.e., percentage of patients hospitalized for any reason) in the aliskiren and placebo groups were 48.1 percent and 49.1 percent, respectively. The HF hospitalization rates within 12 months were 26.2 percent in the aliskiren group and 27.8 percent in the placebo group.

The researchers also found that the rates of hyperkalemia (higher than normal levels of potassium in the circulating blood), hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo.

“The results of the ASTRONAUT study do not support the routine administration of aliskiren, in addition to evidence-based therapy, to patients hospitalized for worsening chronic HF. Subgroup analysis is consistent with previous reports of poor outcomes with the use of aliskiren in patients with diabetes mellitus [DM] already taking RAAS inhibitors. Further investigations are needed to evaluate the effects of renin inhibition in a large cohort of HHF patients that excludes patients with DM,” the authors conclude.

(doi:10.1001/jama.2013.1954; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The ASTRONAUT study is funded by Novartis Pharma AG, Basel, Switzerland, under the guidance of the ASTRONAUT Executive Committee. 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: 1:30 P.M. (CT) MONDAY, MARCH 11, 2013

Media Advisory: To contact Margaret M. Redfield, M.D., call Traci Klein at 507-990-1182 or email klein.traci@mayo.edu.

CHICAGO – Among patients with heart failure with preserved ejection fraction (a measure of heart function), administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status, according to a study published online by JAMA. Some studies have suggested that phosphodiesterase-5 inhibitors (a class of drugs that includes sildenafil) may improve cardiovascular function. The study is being released early to coincide with its presentation at the American College of Cardiology’s annual Scientific Sessions.

Heart failure with preserved ejection fraction (HFPEF) or diastolic heart failure is a common condition with a high level of illness. “Clinical trials of renin-angiotensin system antagonists have not demonstrated improvement in outcomes or clinical status in HFPEF, and effective therapies are needed,” according to background information in the article. “Preclinical studies suggest that inhibition of phosphodiesterase-5 (PDE-5) reverses adverse cardiac structural and functional remodeling and enhances vascular, neuroendocrine, and renal function. In clinical studies, PDE-5 inhibitor therapy improved exercise tolerance and clinical status in patients with idiopathic pulmonary arterial hypertension and in patients with heart failure and reduced ejection fraction.”

Margaret M. Redfield, M.D., of the Mayo Clinic, Rochester, Minn., and colleagues conducted a study to test the hypothesis that, compared with placebo, therapy with the PDE-5 inhibitor sildenafil would improve exercise capacity in HFPEF after 24 weeks of therapy, assessed by the change in peak oxygen consumption. The multicenter, randomized clinical trial included 216 stable outpatients with heart failure, reduced exercise capacity and other certain criteria. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Sildenafil (n = 113) or placebo (n = 103) was administered orally at 20 mg 3 times daily for 12 weeks, followed by 60 mg 3 times daily for 12 weeks. Follow-up was through August 2012.

The primary end point for the study was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. The median (midpoint) age was 69 years, and 48 percent of patients were women.

The researchers found that at 24 weeks, the median change in peak oxygen consumption from the beginning of the study was not significantly different in patients treated with placebo and patients treated with sildenafil. Also, there were no significant differences in the clinical rank score, change in 6-minute walk distance at 24 weeks, or change in peak oxygen consumption or 6-minute walk distance at 12 weeks between treatment groups .

Adverse events occurred in 78 patients (76 percent) who received placebo and 90 patients (80 percent) who received sildenafil. Serious adverse events occurred in 16 patients (16 percent) who received placebo and 25 patients (22 percent) who received sildenafil.

“To our knowledge, [this] trial is the first multicenter study to investigate the effect of PDE-5 inhibition in HFPEF. Contrary to our hypothesis, long-term PDE-5 inhibition in HFPEF had no effect on maximal or submaximal exercise capacity, clinical status, quality of life, left ventricular remodeling, diastolic function parameters, or pulmonary artery systolic pressure. Renal function worsened more and NT-proBNP, endothelin-1, and uric acid levels increased more in patients treated with sildenafil. Furthermore, there were more (but not significantly more) patients in the sildenafil group who withdrew consent, died, or were too ill to perform the cardiopulmonary exercise test, and patients treated with sildenafil had a higher incidence of vascular adverse events. These findings do not suggest that therapy with the PDE-5 inhibitor sildenafil provides clinical benefit in the general HFPEF population,” the authors write.

(doi:10.1001/jama.2013.2024; 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: 10 A.M. (CT) THURSDAY, MARCH 7, 2013

Media Advisory: To contact Jared M. O’Leary, M.D., call Jessica Maki at 617-534-1603 or email jmaki3@partners.org.

CHICAGO – Jared M. O’Leary, M.D., of Brigham and Women’s Hospital, Boston, and colleagues analyzed U.S. hospitalizations from 1998 through 2010 for children and adults with congenital heart disease. “There are more than 787,000 adults with congenital heart disease in the United States. Adults with congenital heart disease remain at risk for frequent hospitalizations,” the authors write in a Research Letter published online by JAMA to coincide with its presentation at the American College of Cardiology’s annual Scientific Sessions.

The researchers identified congenital heart disease admissions to acute care hospitals from 1998 through 2010 using the Nationwide Inpatient Sample, a stratified 20 percent sample of hospitalizations, including approximately 8 million admissions annually from approximately 1,000 hospitals. The primary outcome was the change in number of admissions for all congenital heart disease diagnoses for pediatric (less than 18 years of age) vs. adult patients. To minimize the effect of year-to-year variability, the number of hospitalizations were compared between the first and second halves of the study (January 1998 through June 2004; July 2004 through December 2010).

The authors found that the frequency of hospitalizations for adults with congenital heart disease has grown at a rate more than twice that for children. Adult admission volume was 87.8 percent higher during the second half of the study (n = 622,084) compared with the first half (n = 331,162), while pediatric admissions grew 32.8 percent (1,082,540 vs. 815,471). Adults accounted for 36.5 percent of congenital heart disease admissions in the latter era, up from 28.9 percent.

“The observed trend is likely due to a number of independent forces including better congenital heart disease survival, an aging population, and accumulating comorbidities. Limited availability of quality outpatient services may also contribute,” the researchers write. “Adult congenital heart disease admissions will have an increasing impact on resource utilization. Further research and focus on optimizing health care delivery is warranted to effectively care for adults with congenital heart disease.”

(doi:10.1001/jama.2013.564; 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, MARCH 5, 2013

Index May Help Predict 10-Year Mortality Among Older Adults

“Recent guidelines recommend considering patients’ life expectancy when deciding whether to pursue preventive interventions with long lag times to benefit (≥ 7 years) such as colorectal cancer screening and intensive glycemic control for diabetes. However, most mortality indices have focused on short-term risk (≤ 5 years),” writes Marisa Cruz, M.D., of the University of California, San Francisco, and colleagues. The researchers examined whether their previously developed 4-year mortality index accurately predicted 10-year mortality.

As reported in a Research Letter, this analysis used 1998 data from the Health and Retirement Study (HRS), a nationally representative cohort of community-dwelling U.S. adults older than 50 years. The primary predictor was a 12-item mortality index, and participants received points depending on answers to the following: age; sex; current tobacco use; body mass index; diabetes; nonskin cancers; chronic lung disease; heart failure; difficulty bathing; difficulty managing finances; difficulty walking several blocks; and difficulty pushing/pulling large objects. The primary outcome was death through 2008 (10-year mortality). A risk score was calculated for each participant by summing the points for each risk factor present.

The researchers found that in the development cohort, 10-year mortality rates ranged from 2.5 percent (n=12/486) for participants with 0 points to 96 percent (n=298/310) for participants with 14 or more points. In the validation cohort, 10-year mortality rates ranged from 2.3 percent (n=8/354) to 93 percent (n= 239/257).

“We validated a mortality index that accurately stratified older adults into groups at varying risk for 10-year mortality,” the authors write. “Patients identified by this index as having a high risk of 10-year mortality may be more likely to be harmed by preventive interventions with long lag times to benefit, whereas patients identified as having a low risk of 10-year mortality may be good candidates for such interventions.”

(JAMA. 2013;309[9]:874-876. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Issue of JAMA

Keeping an Eye on Distracted Driving

In 2003, cell phone use while driving was estimated to cause 333,000 total injuries, 12,000 serious to critical injuries, and 2,600 fatalities annually. From 2005 to 2009, fatalities associated with driver distraction increased by 22 percent. Jeffrey H. Coben, M.D., and Motao Zhu, M.D., Ph.D., of West Virginia University, Morgantown, write that new technological and regulatory approaches are needed to reduce handheld phone use and texting while driving.

“Strong and courageous action is needed to effectively deal with the problem of cell phone use while driving. Education, legislation, and voluntary guidelines are insufficient. The federal government should enact stringent new safety standards that require all handheld devices to be rendered inoperable when the motor vehicle is in motion. Failure to act in this manner will result in the continued loss of thousands of lives each year to this preventable public safety hazard. In this era of smartphones and smart cars, it is time to be smarter about keeping them apart from one another.

(JAMA. 2013;309[9]:877-878. Available pre-embargo to the media at https://media.jamanetwork.com)

Please Note: An author podcast on this study will be available post-embargo on the JAMA website.

Improving Opioid Prescribing – The New York City Recommendations

“On January 10, 2013, New York City Mayor Michael Bloomberg announced new guidelines for the prescribing of opioid analgesics to patients being discharged from the city’s emergency departments. The guidelines were developed by a panel of emergency physicians and are intended to reduce opioid addiction and overdose deaths while preserving access to opioids for patients in whom the benefits are expected to exceed the harms,” writes David N. Juurlink, M.D., Ph.D., of the University of Toronto, and colleagues.

In this Viewpoint, the authors examine “why such guidelines are necessary and what complementary actions physicians, patients, and health authorities should take to address the increasing problem of opioid-related harm.”

(JAMA. 2013;309[9]:879-880. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the articles 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, MARCH 5, 2013

Media Advisory: To contact corresponding author Raymond J. Kim, M.D., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu. To contact editorial co-author Marc A. Pfeffer, M.D., Ph.D., call Jessica Maki at 617-534-1603 or email jmaki3@partners.org.

CHICAGO – Among patients with coronary artery disease referred for cardiovascular magnetic resonance  and found to have regional myocardial wall thinning (of the heart muscle), limited scar burden was associated with improved contraction of the heart and reversal of wall thinning after revascularization, suggesting that myocardial thinning is potentially reversible, according to a study appearing in the March 6 issue of JAMA.

Regional myocardial wall thinning is thought to represent chronic myocardial infarction. “However, recent case reports incorporating the use of delayed-enhancement cardiovascular magnetic resonance (CMR) imaging raise the possibility that this viewpoint is incorrect. These single-patient reports indicate that myocardial regions with severe wall thinning do not necessarily consist entirely of scar tissue but instead may have minimal or no scarring. Thus, some areas of myocardial thinning may represent viable myocardium and have the potential for recovery of function,” according to background information in the article.

Dipan J. Shah, M.D., of Duke University Medical Center, Durham, N.C., and colleagues conducted a study to evaluate patients with regional myocardial wall thinning and to determine scar burden and potential for functional improvement. The study, conducted from August 2000 through January 2008, included 1,055 patients with known coronary artery disease (CAD) who underwent CMR imaging.

“Of 201 patients [19 percent] identified by CMR as having wall thinning, most had significant left ventricular dysfunction, multivessel CAD, and thinning of a substantial portion of the left ventricle. Among this cohort, 18 percent of thinned regions had limited or no scarring observed using delayed-enhancement CMR. Because the lack of scarring was associated with significant contractile improvement and reverse remodeling with resolution of wall thinning following revascularization, we believe the data indicate that myocardial thinning is potentially reversible and therefore should not be considered a permanent state,” the authors write.

“… we believe our study provides new insights into the pathophysiology of thinned myocardium and more broadly the process of reversible ischemic injury. The data show that thinned myocardium may consist of limited scar tissue and can recover function— concepts that are both inconsistent with current views.

“The findings provide rationale for future experimental studies on reversible ischemic injury as well as for clinical studies prospectively testing whether CMR guidance for coronary revascularization decisions can improve patient outcome,” the researchers conclude.

(JAMA. 2013;309(9):909-918; 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: Cardiovascular Imaging in Clinical Practice

In an accompanying editorial, Deepak K. Gupta, M.D., of Brigham and Women’s Hospital, Boston, and colleagues write that the two cardiovascular imaging studies in this issue of JAMA “address the important issue of how supplemental noninvasive imaging studies can assist the cardiovascular specialist.”

“Together these reports provide a consistent message that detailed assessments of tissue composition, in particular fibrosis by late gadolinium enhancement (LGE), may provide superior information than morphologic parameters, in both ischemic and nonischemic cardiomyopathies. Collectively, these and other studies demonstrate that CMR with LGE imaging adds to the practitioner’s armamentarium for assessment of cardiac structure and function and augments diagnostic and prognostic capabilities.”

“However, the clinical challenge remains in deciding which patients to evaluate with CMR and LGE and what to do with the findings. Nevertheless, whether CMR with LGE imaging would provide better assessment for nonischemic or ischemic heart disease for guiding decisions regarding revascularization or implantable cardioverter defibrillator placement and the subsequent influence on prognosis remain intriguing and warrant further study. At this point, for the practicing physician, the incremental information gained from CMR with LGE imaging from these 2 studies, albeit novel and supportive, is not yet sufficient to alter clinical practice guidelines.”

(JAMA. 2013;309(9):929-930; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 5, 2013

Media Advisory: To contact corresponding author Sanjay K. Prasad, M.D., email s.prasad@rbht.nhs.uk.

CHICAGO – Detection of midwall fibrosis (the presence of scar tissue in the middle of the heart muscle wall) via magnetic resonance imaging among patients with nonischemic dilated cardiomyopathy (a condition affecting the heart muscle) was associated with an increased likelihood of death, according to a study appearing in the March 6 issue of JAMA.

Nonischemic dilated cardiomyopathy is associated with significant illness and death due to progressive heart failure (HF) and sudden cardiac death (SCD). Despite therapeutic advances, 5-year mortality remains as high as 20 percent. “Risk stratification of patients with nonischemic dilated cardiomyopathy is primarily based on left ventricular ejection fraction [LVEF; a measure of how well the left ventricle of the heart pumps with each contraction]. Superior prognostic factors may improve patient selection for implantable cardioverter-defibrillators (ICDs) and other management decisions,” according to background information in the article.  Attention has recently focused on whether detection of myocardial replacement fibrosis (scarring of the heart muscle) may assist with risk stratification in dilated cardiomyopathy. Fibrosis is associated with contractile impairment.

Ankur Gulati, M.D., of Royal Brompton Hospital, London, and colleagues evaluated whether midwall fibrosis (detected by late gadolinium enhancement cardiovascular magnetic resonance [LGE-CMR] imaging) predicts risk of death, independently of LVEF and other established prognostic factors in dilated cardiomyopathy. The study included 472 patients with dilated cardiomyopathy referred to a U.K. center for CMR imaging between November 2000 and December 2008 after presence and extent of midwall replacement fibrosis (scarring of the heart muscle present in the middle of the heart muscle wall) were determined. Patients were followed up through December 2011.

During a median (midpoint) follow-up of 5.3 years, there were 73 deaths. Overall, 38 of 142 patients with midwall fibrosis (26.8 percent) died compared with 35 of 330 patients without midwall fibrosis (10.6 percent). After analysis, both the presence and percentage extent of midwall fibrosis were significant independent predictors of all-cause mortality. The arrhythmic composite end point (SCD or aborted SCD) occurred in 65 patients (14 percent). Analysis indicated that patients with midwall fibrosis were more than 5 times more likely to experience SCD or aborted SCD compared with patients without midwall fibrosis (29.6 percent vs. 7.0 percent).

“After adjustment for LVEF and other conventional prognostic factors, both the presence of fibrosis and the extent were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation, SCD or aborted SCD, and the HF composite [HF death, HF hospitalization, or cardiac transplantation],” the authors write.

Also, the addition of fibrosis to LVEF significantly improved risk reclassification for all-cause mortality and the SCD composite.

“Our findings suggest that detection and quantification of midwall fibrosis by LGE-CMR may represent useful markers for the risk stratification of death, ventricular arrhythmia, and HF for patients with dilated cardiomyopathy,” the researchers write.

(JAMA. 2013;309(9):896-908; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by the National Institute for Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, England. 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, MARCH 5, 2013

Media Advisory: To contact Kevin L. Winthrop, M.D., M.P.H., call Mirabai Vogt at 503-494-7986 or email vogtmi@ohsu.edu.

CHICAGO – Although patients with rheumatoid arthritis (RA) have a disproportionately higher incidence of herpes zoster (shingles), an analysis that included nearly 60,000 patients with RA and other inflammatory diseases found that those who initiated anti-tumor necrosis factor therapies were not at higher risk of herpes zoster compared with patients who initiated nonbiologic treatment regimens, according to a study appearing in the March 6 issue of JAMA.

“For patients with rheumatoid arthritis, the risk of herpes zoster is elevated an additional 2- to 3-fold. The contribution of widely used biologic immunosuppressive therapy to this increased risk is not well understood. These therapies, including tumor necrosis factor (TNF) antagonists, are commonly used to treat RA and a variety of other immune-mediated inflammatory diseases and have clearly been associated with an increased risk of tuberculosis and other opportunistic infections,” according to background information in the article. “It is unclear whether anti-tumor necrosis factor (anti-TNF) therapy elevates herpes zoster risk.”

Kevin L. Winthrop, M.D., M.P.H., of Oregon Health and Science University, Portland, Ore., and colleagues conducted a study to determine whether initiation of anti-TNF therapy compared with non-biologic comparators is associated with increased herpes zoster risk. The researchers identified new users of anti-TNF therapy among groups of patients with RA, inflammatory bowel disease, and psoriasis, psoriatic arthritis, or ankylosing spondylitis from 1998 through 2007 within a large U.S. multi-institutional collaboration. The authors compared herpes zoster incidence between new anti-TNF users (n = 33,324) and patients initiating nonbiologic disease-modifying antirheumatic drugs (DMARDs) (n = 25,742) within each inflammatory disease cohort (last participant follow-up December 31, 2007).

Across all disease indications, there were 310 herpes zoster cases among anti-TNF and 160 among nonbiologic DMARD users. For patients with RA, the researchers found that adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators and comparable between all 3 anti-TNF therapies studied. Baseline use of corticosteroids of 10 mg/d or greater among all disease indications was associated with elevated risk compared with no baseline use.

After adjustment for various factors, no significant difference in herpes zoster rates was observed within any disease indication between patients initiating anti-TNF therapy and those initiating new DMARD regimens.

Within the RA group, herpes zoster risk was associated with increasing age, female sex, overall health status, and higher-dose corticosteroid use.

“In summary, among patients with RA and other select inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk of herpes zoster compared with patients who initiated nonbiologic treatment regimens,” the authors write.

(JAMA. 2013;309(9):887-895; 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, March 5 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 26, 2013

Why the Ethics of Parsimonious Medicine Is Not the Ethics of Rationing

In this Viewpoint, Jon C. Tilburt, M.D., of the Mayo Clinic, Rochester, Minn., and Christine K. Cassel, M.D., of the American Board of Internal Medicine, Philadelphia, discuss the ethical differences between parsimonious medicine (limiting the use of wasteful tests and treatments) and rationing health care resources.

“Both parsimonious medicine and rationing aim to reduce resource use. Nevertheless, the ethical difference between the two is clear. Rationing requires principles of distributive justice, which is good and important in circumstances of resource scarcity; parsimonious medicine rests squarely on the principles of doing no harm and attending to the good of patients in need. This is an essential attribute of professionalism.”

(JAMA. 2013;309[8]:773-774. Available pre-embargo to the media at https://media.jamanetwork.com)

The Value of Low-Value Lists

 “An international groundswell of activity is seeking to identify and reduce the use of health care services that provide little or no benefit— whether through overuse or misuse,” writes Adam G. Elshaug, Ph.D., M.P.H., of Harvard Medical School, Boston, and colleagues.

A major challenge faced by initiatives to address this issue has been how to identify and prioritize candidate services for consideration in a reasoned and transparent manner. “Today, several lists compiled by prominent organizations have identified numerous services as potentially low value in certain clinical circumstances. The challenge facing payers and health care service providers such as physicians and hospitals is to develop and implement strategies to reduce the use of services that are identified in these lists, many of which are discretionary, if not potentially harmful.”

(JAMA. 2013;309[8]:775-776. Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: Please see the articles 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, FEBRUARY 26, 2013

Media Advisory: To contact corresponding author Burkert Pieske, M.D., email burkert.pieske@medunigraz.at. To contact editorial co-author John G. F. Cleland, M.D., Ph.D., F.R.C.P., email J.G.Cleland@hull.ac.uk.

CHICAGO – Among patients with heart failure with preserved ejection fraction, long-term treatment with the medication spironolactone improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life, according to a study appearing in the February 27 issue of JAMA.

“Heart failure (HF) with preserved ejection fraction [EF; the percentage of blood that is pumped out of a filled ventricle as a result of a heartbeat is 50 percent or greater] accounts for more than 50 percent of the total HF population,” according to background information in the article.  There is not an established therapy for this condition, and aldosterone (a hormone) stimulation may contribute to its progression.

Frank Edelmann, M.D., of the University of Gottingen, Germany, and colleagues conducted a study to examine the long-term effects of spironolactone, an aldosterone receptor blocker, on diastolic function and exercise capacity in patients with HF with preserved EF. The Aldo-DHF trial, a randomized, placebo-controlled trial, was conducted between March 2007 and April 2012 at 10 sites in Germany and Austria. The study included 422 patients (average age, 67 years) with chronic New York Heart Association class II or III heart failure, preserved left ventricular ejection fraction of 50 percent or greater, and evidence of diastolic dysfunction. Patients were randomly assigned to receive 25 mg of spironolactone once daily (n = 213) or matching placebo (n = 209) with 12 months of follow-up. The primary outcomes measured were changes in diastolic function (E/e’) on echocardiography and maximal exercise capacity (peak VO₂) on cardiopulmonary exercise testing.

The researchers found that spironolactone improved some measures (left ventricular end-diastolic filling, left ventricular remodeling, and neurohumoral activation). Maximal exercise capacity did not significantly change with spironolactone vs. placebo, and spironolactone did not improve heart failure symptoms or quality of life and slightly reduced 6-minute walking distance. “Spironolactone also modestly increased serum potassium levels and decreased estimated glomerular filtration rate without affecting hospitalizations.”

The authors conclude that the “lack of accepted minimal clinically important differences in E/e’ or peak VO₂ in HF with preserved EF warrants additional prospective, randomized, adequately powered studies to further evaluate the effect of improving diastolic function on symptomatic, functional, and clinical end points.”

(JAMA. 2013;309(8):781-791; 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: Defining Diastolic Heart Failure and Identifying Effective Therapies

“Ultimately, Aldo-DHF trial provides valuable new information but is not particularly reassuring in terms of either the efficacy or safety of mineralocorticoid antagonists (MRAs) for patients with heart failure with preserved ejection fraction (HFpEF),”writes John G. F. Cleland, M.D., Ph.D., F.R.C.P., and Pierpaolo Pellicori, M.D., of the University of Hull, Kingston-upon-Hull, England, in an accompanying editorial.

“In the meantime, MRAs appear useful for managing congestion and preventing diuretic-induced hypokalemia [abnormally low level of potassium in the circulating blood] with the attendant risk of sudden arrhythmic death. It is likely that these benefits are independent of cardiac phenotype but might be more prominent in those with impaired aldosterone degradation due to hepatic congestion. Whether MRAs exert important benefits for patients with HFpEF through other mechanisms such as reducing fibrosis, inflammation, and adrenergic activity may take longer to unravel.”

(JAMA. 2013;309(8):825-826; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 26, 2013

Media Advisory: To contact Simon G. Thompson, D.Sc., email sgt27@medschl.cam.ac.uk.

CHICAGO – In contrast to the commonly adopted surveillance intervals in current abdominal aortic aneurysm (AAA) screening programs, surveillance intervals of several years may be clinically acceptable for the majority of patients with small AAA, as the smallest AAAs often do not appear to change significantly over many years, according to a meta-analysis of previous studies reported in the February 27 issue of JAMA.

“The survival rate following rupture of an abdominal aortic aneurysm is only 20 percent, making AAAs an important cause of mortality,” according to background information in the article. “In patients with small AAA (diameter <5.5 cm), the risk of rupture is lower than the risk of surgery and surveillance is indicated. The majority of small AAAs grow slowly, but there is substantial variation in growth rates between different individuals. The intervals between ultrasound surveillance examinations used in randomized trials of screening depend on aneurysm size. However, no consensus exists regarding the optimal time intervals between ultrasounds.”

To better guide AAA surveillance efforts, Simon G. Thompson, D.Sc., of the University of Cambridge, England, and colleagues conducted a study to determine the rates at which small AAAs progress to reach the surgery threshold diameter of 5.5 cm and the risk of AAA rupture over time. Via a meta-analysis, the authors assessed individual patient data from studies of small AAA growth and rupture. A total of 18 studies containing records from 15,471 individual patients (13,728 men and 1,743 women) under surveillance for small AAAs were included in the analyses. Most studies used 5.5 cm as the threshold for surgical intervention, used only ultrasound scans, and recorded external aortic diameters.

The researchers found that AAA growth and rupture rates varied considerably across studies. Each 0.5-cm increase in baseline AAA diameter resulted in a 0.59-mm per year increase in average aortic growth rate. Rupture rates in men increased by a factor of 1.9 for every 0.5-cm increase in baseline AAA diameter. For men with a 3.0-cm AAA, the estimated average time taken to have a 10 percent chance of reaching the surgery threshold diameter 5.5 cm was 7.4 years. The corresponding average times for 4.0 cm- and 5.0 cm-AAAs were 3.2 years and 8 months, respectively.

To control the risk of rupture in men to below 1 percent, the corresponding estimated surveillance intervals are 8.5 years for a 3.0 cm and 17 months for a 5.0-cm AAA.

While absolute growth rates were similar for women and men (particularly for larger baseline AAA diameters), there were marked differences in the absolute risks of rupture. Women had a 4-fold greater rupture risk for all AAA sizes and reached a rupture risk of greater than 1 percent in a much shorter time than men.

“Current recommendations for surveillance intervals vary widely although the intervals usually decrease with increasing AAA diameter (for example, 1 year for AAAs measuring 3.0-4.4 cm and 3 months for those measuring 4.5-5.4 cm in the current screening program in England),” the authors write. The findings of this study indicate that for men “these surveillance intervals could be extended to 3 years for AAAs measuring 3.0 to 3.9 cm, 2 years for 4.0 to 4.4 cm, and yearly for 4.5 to 5.4 cm; the risk of rupture would be maintained at less than 1 percent. For a U.S. patient with a 3.0-cm AAA detected by screening, this would reduce the average number of surveillance scans from approximately 15 to 7.”

“There is a need for more research regarding women with aneurysms in the diameter range of 4.5 to 5.4 cm. Since national rates of AAA rupture are declining, recommended surveillance intervals may need to be reassessed. There is also a need to establish the cost effectiveness of different surveillance policies. Decreasing surveillance frequency would reduce surveillance costs. However, it may also slightly increase rupture rates and increase patient anxiety. This would decrease overall life expectancy and quality of life in AAA patients under surveillance and increase costs attributable to emergency surgery,” the researchers conclude.

(JAMA. 2013;309(8):806-813; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was supported by the UK NIHR Health Technology Assessment Programme. 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, FEBRUARY 26, 2013

Media Advisory: To contact Justin B. Dimick, M.D., M.P.H., call Shantell Kirkendoll at 734-764-2220 or email smkirk@umich.edu. To contact Caprice C. Greenberg, M.D., M.P.H., call Susan Lampert Smith at 608-890-5643 or email SSmith5@uwhealth.org.

CHICAGO – In an analysis of data on patients who underwent bariatric surgery 2004-2009, there was no significant difference in the rates of complications and reoperation for Medicare patients before vs. after a 2006 Centers for Medicare & Medicaid Services policy that restricted coverage of bariatric surgery to centers of excellence, according to a study appearing in the February 27 issue of JAMA.

“Prompted by concerns about perioperative safety with bariatric surgery, the Centers for Medicare & Medicaid Services (CMS) issued a national coverage decision in 2006 that limited coverage of weight loss surgery to centers of excellence (COEs),” according to background information in the article. These COEs were accredited by a surgical professional organization. “In addition to other structural measures and processes of care, the accreditation was based on a hospital volume threshold (>125 cases/year). Whether the CMS restriction of bariatric surgery to COEs is associated with improved outcomes remains uncertain.”

Justin B. Dimick, M.D., M.P.H., of the University of Michigan, Ann Arbor, and colleagues compared outcomes in Medicare patients before and after implementation of the CMS policy to determine whether the policy was associated with improved outcomes (rate of complications, reoperations). The study included 2004-2009 hospital discharge data from 12 states (n = 321,464 patients) and analyzed changes in outcomes in Medicare patients undergoing bariatric surgery (n = 6,723 before and n = 15,854 after implementation of the policy). A difference-in-differences analytic approach was used to evaluate whether the national coverage decision was associated with improved outcomes in Medicare patients above and beyond existing time trends in non-Medicare patients (n = 95,558 before and n = 155,117 after implementation of the policy).

The researchers found that bariatric surgery outcomes improved during the study period in both Medicare and non-Medicare patients; however, this change was already underway prior to the CMS coverage decision. “After accounting for patient factors, changes in procedure type and pre-existing trends toward improved outcomes, there were no measurable improvements in outcomes after (vs. before) implementation of the CMS national coverage decision for any complication (8.0 percent after vs. 7.0 percent before the policy), serious complications (3.3 percent vs. 3.6 percent), and reoperation (1.0 percent vs. 1.1 percent).”

In a direct comparison of outcomes at COEs (n = 179) vs. non-COEs (n = 519), COEs did not result in better outcomes than non-COEs. “After accounting for patient factors, procedure type, and the year of operation, patients undergoing bariatric surgery at hospitals with the COE designation (vs. hospitals without the COE designation) did not have significantly different rates for any complication (5.5 percent vs. 6.0 percent), serious complications (2.2 percent vs. 2.5 percent), and reoperation (0.83 percent vs. 0.96 percent).”

Also, the authors found no relationship between hospital COE designation and adverse outcomes in a sensitivity analysis that evaluated Medicare and non-Medicare patients separately.

“Rather than the CMS policy restricting bariatric surgery to COEs, we found that the improvement in outcomes over time could be explained in part by the evolution away from higher risk toward lower risk procedures,” the researchers note. They add that procedure mix changed in 2 important ways: first, there was a general shift away from open to laparoscopic surgery, which is consistent with broader trends in surgery toward less invasive procedures with more favorable safety profiles; and second, there was a dramatic increase in the use of laparoscopic gastric banding, a safer but less effective procedure.

The authors write that the “CMS policy restricting coverage to COEs has not been associated with improved outcomes for bariatric surgery, but may have had the unintended consequence of reducing access to care [because of potentially increased travel distance to undergo the procedure]. These findings suggest that the CMS should reevaluate this policy.”

(JAMA. 2013;309(8):792-799; 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 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, February 26 at this link.

Editorial: Promoting Quality Surgical Care – The Next Steps

In an accompanying editorial, Caprice C. Greenberg, M.D., M.P.H., of the University of Wisconsin Hospitals and Clinics,  Madison, writes that because of the results of studies such as Dimick et al, the CMS is currently re-evaluating the need for bariatric surgery COEs.

Dr. Greenberg notes that COE accreditation relies on measures of structure and processes of care that duplicate accreditation functions of the Joint Commission. Measuring outcomes is difficult when relying on manual collection of information, delaying interventions when there is a need for improvement.

“As the CMS and the surgical societies re-examine the COE policy in bariatric surgery, there is an opportunity for them to be creative; to catapult surgical outcomes science forward through scalable approaches to data sharing, measurement, collaborative networks, and CER; and to design a program that can not only identify high-quality hospitals, but also provide a sustained mechanism for quality improvement.”

(JAMA. 2013;309(8):827-828; 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. Dr. Greenberg reported receiving an honorarium from the Michigan Bariatric Quality Collaborative to attend one of its collaboratives and discuss issues related to system performance and safety.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 26, 2013

Media Advisory: To contact Rebecca H. Johnson, M.D., call Alyse Bernal at 206-987-5213 or email alyse.bernal@seattlechildrens.org.

CHICAGO – An analysis of breast cancer trends in the U.S. finds a small but statistically significant increase in the incidence of advanced breast cancer for women 25 to 39 years of age, without a corresponding increase in older women, according to a study appearing in the February 27 issue of JAMA.

“In the United States, breast cancer is the most common malignant tumor in adolescent and young adult women 15 to 39 years of age, accounting for 14 percent of all cancer in men and women in the age group. The individual average risk of a woman developing breast cancer in the United States was 1 in 173 by the age of 40 years when assessed in 2008. Young women with breast cancer tend to experience more aggressive disease than older women and have lower survival rates. Given the effect of the disease in young people and a clinical impression that more young women are being diagnosed with advanced disease, we reviewed the national trends in breast cancer incidence in the United States,” the authors write.

Rebecca H. Johnson, M.D., of Seattle Children’s Hospital and University of Washington, Seattle, and colleagues conducted a study in which breast cancer incidence, incidence trends, and survival rates as a function of age and extent of disease at diagnosis were obtained from 3 U.S. National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registries. These registries provide data spanning 1973-2009, 1992-2009, and 2000-2009. SEER defines localized as disease confined to the breast, regional to contiguous and adjacent organ spread (e.g., lymph nodes, chest wall), and distant disease to remote metastases (bone, brain, lung, etc).

Since 1976, there has been a steady increase in the incidence of distant disease breast cancer in 25- to 39-year-old women, from 1.53 per 100,000 in 1976 to 2.90 per 100,000 in 2009. The researchers note that this is an absolute difference of 1.37 per 100,000, representing an average compounded increase of 2.07 percent per year over the 34-year interval, a relatively small increase, “but the trend shows no evidence for abatement and may indicate increasing epidemiologic and clinical significance.”

“The trajectory of the incidence trend predicts that an increasing number of young women in the United States will present with metastatic breast cancer in an age group that already has the worst prognosis, no recommended routine screening practice, the least health insurance, and the most potential years of life,” the authors write.

The researchers also found that the rate of increasing incidence of distant disease was inversely proportional to age at diagnosis. The greatest increase occurred in 25- to 34-year-old women. Progressively smaller increases occurred in older women by 5-year age intervals and no statistically significant incidence increase occurred in any group 55 years or older.

“For young women aged 25 to 39 years, the incidence of distant disease increased in all races/ethnicities assessed since at least 1992, when race/ethnicity became available in the SEER database,” the authors write. These increases occurred in both metropolitan and nonmetropolitan areas, and were statistically significant in African American and non-Hispanic white populations.

Incidence for women with estrogen receptor-positive subtypes increased more than for women with estrogen receptor-negative subtypes.

“Whatever the causes—and likely there are more than 1—the evidence we observed for the increasing incidence of advanced breast cancer in young women will require corroboration and may be best confirmed by data from other countries. If verified, the increase is particularly concerning, because young age itself is an independent adverse prognostic factor for breast cancer, and the lowest 5-year breast cancer survival rates as a function of age have been reported for 20- to 34-year-old women. The most recent national 5-year survival for distant disease for 25- to 39-year-old women is only 31 percent according to SEER data, compared with a 5-year survival rate of 87 percent for women with locoregional breast cancer,” the authors write.

(JAMA. 2013;309(8):800-805; 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, FEBRUARY 19, 2013

Opioid Analgesics Involved in Most Pharmaceutical Overdose Deaths

“Data recently released by the National Center for Health Statistics show drug overdose deaths increased for the 11th consecutive year in 2010. Pharmaceuticals, especially opioid analgesics, have driven this increase. Other pharmaceuticals are involved in opioid overdose deaths, but their involvement is less well characterized,” writes Christopher M. Jones, Pharm.D., of the Centers for Disease Control and Prevention, Atlanta, and colleagues.

As reported in a Research Letter, the authors used data from the National Vital Statistics System multiple cause-of-death file to examine the specific drugs involved in pharmaceutical and opioid-related overdose deaths. The researchers found that in 2010, there were 38,329 drug overdose deaths in the United States; most (22,134; 57.7 percent) involved pharmaceuticals; 9,429 (24.6 percent) involved only unspecified drugs. “Of the pharmaceutical-related overdose deaths, 16,451 (74.3 percent) were unintentional, 3,780 (17.1 percent) were suicides, and 1,868 (8.4 percent) were of undetermined intent. Opioids (16,651; 75.2 percent), benzodiazepines (6,497; 29.4 percent), antidepressants (3,889; 17.6 percent), and antiepileptic and anti-parkinsonism drugs (1,717; 7.8 percent) were the pharmaceuticals (alone or in combination with other drugs) most commonly involved in pharmaceutical overdose deaths.”

“This analysis confirms the predominant role opioid analgesics play in pharmaceutical overdose deaths, either alone or in combination with other drugs. It also, however, highlights the frequent involvement of drugs typically prescribed for mental health conditions such as benzodiazepines, antidepressants, and antipsychotics in overdose deaths. People with mental health disorders are at increased risk for heavy therapeutic use, nonmedical use, and overdose of opioids. Screening, identification, and appropriate management of such disorders is an important part of both behavioral health and chronic pain management. Tools such as prescription drug monitoring programs and electronic health records can help clinicians to identify risky medication use and inform treatment decisions, especially for opioids and benzodiazepines.”

(JAMA. 2013;309[7]:657-659. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Issue of JAMA

Reengineering U.S. Health Care

Ari Hoffman, M.D., of the University of California, San Francisco, and Ezekiel J. Emanuel, M.D., Ph.D., of the University of Pennsylvania, Philadelphia, write that “health reform requires fixing a chronically dysfunctional system. While it is tempting to try to identify a single solution to this complex problem, the cure will require a multimodality approach with a focus on reengineering the entire care delivery process.”

In this Viewpoint, the authors examine the issue of reengineering the U.S. health care system. “With a focus on reengineering, the nation may succeed not only in implementing systematic health care reform, but reform that actually improves the health of Americans while simultaneously controlling unsustainable costs.”

(JAMA. 2013;309[7]:661-662. Available pre-embargo to the media at https://media.jamanetwork.com)

Please Note: An author podcast on this article will be available post-embargo on the JAMA website.

Treatment of Atherosclerotic Renal Artery Stenosis

Peter W. de Leeuw, M.D., Ph.D., of the University Hospital Maastricht and Cardiovascular Research Institute Maastricht, the Netherlands, and colleagues discuss the diagnosis and treatment of atheroscle­rotic renal artery stenosis.

“From a scientific perspective, it is worthwhile to explore whether angioplasty added to optimal anti-atherosclerotic treatment will produce a better outcome in terms of renal function than medical treatment alone. This could be investigated in a clinical trial conducted among patients with hypertension and low-grade renal artery stenosis. On a broader scale, failure of trials to show an expected outcome should serve as motivation to reconsider the pathophysiological principles behind the treatment rather than abandon the treatment.”

(JAMA. 2013;309[7]:663-664. Available pre-embargo to the media at https://media.jamanetwork.com)

Policy Responses to Demand for Health Care Access

Katherine Diaz Vickery, M.D., of the University of Michigan, Ann Arbor, and colleagues write that the Emergency Medical Treatment and Active Labor Act (EMTALA), signed into law in 1986, was “intended by Congress to impart a social contract between the health care-seeking public and a U.S. health care system that the public progressively distrusted.”

“Examining where and how EMTALA fell short highlights how the Affordable Care Act can start to construct a system founded on shared societal obligations to health. The path forward in U.S. health care reform lies in recognizing the shared ethical standard that supersedes political differences.”

(JAMA. 2013;309[7]:665-666. Available pre-embargo to the media at https://media.jamanetwork.com)

Realigning Reimbursement Policy and Financial Incentives to Support Patient-Centered Out-of-Hospital Care

“… little consideration has been given to how fee-for-service reimbursement in out-of-hospital care limits the ability of emergency medical services (EMS) to provide more patient-centered care and reduce downstream health care costs,” writes Kevin Munjal, M.D., M.P.H., of the Mount Sinai Medical Center, New York, and Brendan Carr, M.D., M.S., of the University of Pennsylvania, Philadelphia.

“Current Medicare reimbursement policies for out-of-hospital care link payment to transport to an emergency department. This provides a disincentive for EMS agencies to work to reduce avoidable visits to emergency departments, limits the role of prehospital care in the U.S. health system, is not responsive to patients’ needs, and generates downstream health care costs. Financial and delivery model reforms that address EMS payment policy may allow out-of-hospital care systems to deliver higher-quality, patient-centered, coordinated health care that could improve the public health and lower costs.”

(JAMA. 2013;309[7]:667-668. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the articles 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, FEBRUARY 19, 2013

Media Advisory: To contact Ryan Zarychanski, M.D., M.Sc., call Ilana Simon at 204-789-3427 or email ilana.simon@med.umanitoba.ca. To contact editorial author Massimo Antonelli, M.D., email m.antonelli@rm.unicatt.it.

CHICAGO – In an analysis of studies that examined critically ill patients requiring an increase in blood fluid volume, intravenous use of the fluid hydroxyethyl starch, compared with other resuscitation solutions, was not associated with decreased mortality, according to an article appearing in the February 20 issue of JAMA. Moreover, after exclusion of 7 trials performed by an investigator whose research has been retracted because of scientific misconduct, the analysis of the remaining studies indicated that hydroxyethyl starch was associated with a significant increased risk of death and acute kidney injury.

“Fluids are a core element in the resuscitation of critically ill patients and the relative superiority and safety of different resuscitation solutions has been the focus of considerable debate,” according to background information in the article. “Hydroxyethyl starch is commonly used for volume resuscitation yet has been associated with serious adverse events, including acute kidney injury and death. Clinical trials of hydroxyethyl starch are conflicting. Moreover, multiple trials from one investigator have been retracted because of scientific misconduct.”

According to the article, “In 2011, 86 percent (88 of 102) of the research published by Joachim Boldt, M.D., since 1999 was retracted after a government investigation reported research misconduct reflecting failure to acquire ethical approval for research and fabrication of study data. The effect of these retractions has been far-reaching. All major systematic reviews and clinical guidelines are now being revised to account for the retracted data and permit sensitivity analyses on the remaining publications by Boldt et al.”

Ryan Zarychanski, M.D., M.Sc., of the University of Manitoba, Canada, and colleagues performed a systematic review and meta-analysis of randomized controlled trials comparing hydroxyethyl starch with other intravenous fluids (crystalloids, albumin, or gelatin) for acute fluid resuscitation in critically ill patients. The primary outcomes of interest were mortality and the incidence of acute kidney injury. Additionally, the researchers investigated the influence of the studies conducted by Boldt and colleagues on these outcomes.

After a review of the medical literature, the authors identified 38 trials that met criteria for inclusion in the analysis. Two reviewers independently extracted trial-level data including population characteristics, interventions, outcomes, and funding sources. Risk of bias and strength of evidence were assessed.

The researchers found that the majority of trials were categorized as having an unclear risk or high risk of bias. For the 10,880 patients in studies contributing mortality data, use of hydroxyethyl starch compared with other resuscitation solutions was not associated with a decrease in mortality. This summary effect measure included results from 7 trials performed by Boldt et al. When these 7 trials that involved 590 patients were excluded, hydroxyethyl starch was found to be associated with a significantly increased risk of mortality (among 10,290 patients), renal failure (among 8,725 patients), and increased use of renal replacement therapy (among 9,258 patients).

“Clinical use of hydroxyethyl starch for acute volume resuscitation is not warranted due to serious safety concerns,” the authors conclude.

(JAMA. 2013;309(7):678-688; 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: Hydroxyethyl Starch for Intravenous Volume Replacement – More Harm Than Benefit

Massimo Antonelli, M.D., and  Claudio Sandroni, M.D., of the Universita Cattolica del Sacro Cuore, Rome, comment on the findings of this study in an accompanying editorial.

“The importance of rigorous meta-analyses like that reported by Zarychanski et al appears fundamental for identifying bias in reporting results and preventing harm to patients. Moreover, in addition to confirming the potential nephrotoxic effect associated with hydroxyethyl starch, this meta-analysis is the first to demonstrate that use of hydroxyethyl starch for acute volume replacement is also associated with a significant risk of mortality.”

“This study also demonstrates the importance of revising and revisiting recommendations and guidelines in light of new systematic reviews and evidence.”

(JAMA. 2013;309(7):723-724; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 19, 2013

Media Advisory: To contact Sheldon Cohen, Ph.D., call Shilo Rea at 412-268-6094 or email shilo@cmu.edu.

CHICAGO – Among healthy adults who were administered a cold virus, those with shorter telomere length (a structure at the end of a chromosome) in certain cells were more likely to develop experimentally-induced upper respiratory infection than participants with longer telomeres, according to results of preliminary research published in the February 20 issue of JAMA.

Telomeres shorten with each cell division and function as protective caps to prevent erosion of genomic DNA during cell division. Telomere shortening in leukocytes (white blood cells) has implications for immunocompetence and is associated with poorer antibody response to vaccines. “Shorter leukocyte telomere length also is associated with aging-related illness and death from conditions with immune system involvement, including infectious diseases, cancer, and cardiovascular disease,” the authors write. It is not known whether leukocyte telomere length is related to acute disease in younger, healthy populations.

Sheldon Cohen, Ph.D., of Carnegie Mellon University, Pittsburgh, and colleagues conducted a study to determine whether shorter telomeres in leukocytes, especially CD8CD28- T cells, are associated with decreased resistance to upper respiratory infection and clinical illness in young to middle-aged adults. Between 2008 and 2011, telomere length was assessed in peripheral blood mononuclear cells (PBMCs) and T-cell subsets (CD4, CD8CD28+ , CD8CD28-) from 152 healthy 18- to 55-year-old residents of Pittsburgh. Participants were subsequently quarantined (single rooms), administered nasal drops containing a common cold virus (rhinovirus 39), and monitored for 5 days for development of infection and clinical illness.

Sixty-nine percent of participants (n = 105) developed respiratory infections; 22 percent of the entire sample (n = 33) developed a clinical illness (common cold).The researchers found that shorter telomere lengths in all 4 cell types were associated with increased odds of infection following exposure to RV39. However, CD8CD28- telomere length had the largest association with infection. The rate of infection in the CD8CD28- subset was 77 percent among participants in the group with the shortest telomeres and 50 percent for those in the group with the longest telomeres.

Analysis indicated that only telomere length in the CD8CD28- subset was associated with risk for clinical illness, with shorter telomere length associated with increased risk. Among participants with the shortest telomeres, 26 percent became clinically ill. The rate for clinical illness was 13 percent for those in the group with the longest telomeres.

Also, the magnitude of the association between CD8CD28- telomere length and infection increased with increasing age.

“In this study of healthy young and midlife adults, shorter CD8CD28- cell telomere length was associated with upper respiratory tract infection and clinical illness following experimental exposure to rhinovirus. Because these data are preliminary, their clinical implications are unknown,” the authors conclude.

(JAMA. 2013;309(7):699-705; 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, FEBRUARY 19, 2013

Media Advisory: To contact Jason D. Wright, M.D., call the Columbia University Medical Center Office of Communications at 212-305-3900 or email cumcnews@columbia.edu. To contact editorial co-author Joel S. Weissman, Ph.D., call Lori Schroth at 617-534-1604 or email ljschroth@partners.org.

CHICAGO –Between 2007 and 2010, the use of robotically-assisted hysterectomy for benign gynecologic disorders increased substantially, although, when compared with laparoscopic hysterectomy, the robotic procedure appears to offer little short-term benefit and is accompanied by significantly greater costs, according to a study appearing in the February 20 issue of JAMA.

“Hysterectomy for benign gynecologic disease is one of the most commonly performed procedures for women. Overall, 1 in 9 women in the United States will undergo the procedure during her lifetime. While hysterectomy has traditionally been performed abdominally via laparotomy, vaginally, or by laparoscopy, robotically assisted hysterectomy has been introduced as an alternative minimally invasive approach to hysterectomy. The robotic surgical platform received approval from the U.S. Food and Drug Administration in 2005 for the performance of gynecologic procedures and allows a surgeon to perform the procedure at a remote console,” according to background information in the article. “Proponents of robotic surgery have argued that robotic technology allows women who otherwise would undergo laparotomy to have a minimally invasive procedure. However, there is little to support these claims, and because both laparoscopic and robotic-assisted hysterectomy are associated with low complication rates, it is unclear what benefits robotically-assisted hysterectomy offers.”

The authors add that unlike other procedures such as prostatectomy for which robotic assistance is used more frequently than conventional laparoscopic approaches, laparoscopic hysterectomy is already widely available.

Jason D. Wright, M.D., of the Columbia University College of Physicians and Surgeons, New York, and colleagues examined the usage of robotic-assisted hysterectomy and assessed in-hospital outcomes and costs for robotically-assisted hysterectomy compared with laparoscopic and abdominal procedures. A total of 264,758 women were identified who underwent hysterectomy for benign gynecologic disorders at 441 hospitals across the United States from 2007 to 2010. The study group included 123,288 (46.6 percent) who underwent an abdominal hysterectomy, 54,912 (20.7 percent) who had a vaginal hysterectomy, 75,761 (28.6 percent) who had a laparoscopic procedure, and 10,797 (4.1 percent) who had a robotically-assisted hysterectomy.

The researchers found that robotically-assisted hysterectomy increased during the study period and accounted for 0.5 percent of the procedures in 2007 compared with 9.5 percent in 2010. The number of laparoscopic hysterectomies performed also increased; laparoscopic hysterectomy accounted for 24.3 percent of the procedures in the first quarter of 2007 compared with 30.5 percent in 2010.

After the introduction of robotically-assisted hysterectomy at a given hospital, use increased rapidly. “For example, at 3 years after the first robotic procedure in each hospital where robotics were used, robotic-assisted hysterectomy accounted for 22.4 percent of all hysterectomies. At these hospitals, use of vaginal, laparoscopic, and abdominal hysterectomy all declined,” the authors write. “In contrast, at hospitals where robotically assisted hysterectomy was not performed, abdominal and vaginal hysterectomy declined, while use of laparoscopic hysterectomy increased.”

Although patients who underwent a robotic-assisted hysterectomy were less likely to have a length of stay longer than 2 days (19.6 percent vs. 24.9 percent), overall complication rates were similar for robotic-assisted and laparoscopic hysterectomy (5.5 percent vs. 5.3 percent). Total costs associated with robotically assisted hysterectomy were $2,189 more per case than for laparoscopic hysterectomy, the researchers write.

“Our findings highlight the importance of developing rational strategies to implement new surgical technologies. Robotic surgery first gained prominence for prostatectomy as it essentially offered the only minimally invasive surgical approach for the procedure. Hysterectomy is unlike prostatectomy in that a number of alternatives to open surgery are available; laparoscopic hysterectomy is a well- accepted procedure and vaginal hysterectomy allows removal of the uterus without any abdominal incisions.”

“From a public health standpoint, defining subsets of patients with benign gynecologic disorders who derive benefit from robotic hysterectomy, reducing the cost of robotic instrumentation, and developing initiatives to promote laparoscopic hysterectomy are warranted,” the authors conclude.

(JAMA. 2013;309(7):689-698; 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, February 19 at this link.

Editorial: Comparative Effectiveness Research on Robotic Surgery

In an accompanying editorial, Joel S. Weissman, Ph.D., and Michael Zinner, M.D., of Brigham and Women’s Hospital, Boston, write that this study raises a number of questions.

“Would it be a better use of resources to train more surgeons in laparoscopic techniques than to spend the money on more robot machines? … A second issue is whether robotic surgery could be valuable for subgroups of patients with select comorbidities or anatomy. … A third issue involves the commercialization of this technology, which has raised eyebrows in the media and elsewhere,” the authors write. “… when the innovation being advertised is of questionable advantage, direct-to-consumer promotion may only fuel unnecessary utilization.”

“In the absence of additional research or decreases in price, the path taken by the medical and payer community should be one of caution. At a minimum, manufacturers might begin by voluntarily restricting their promotional activities.”

(JAMA. 2013;309(7):721-722; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Weissman reported having received a research grant from the National Pharmaceutical Council. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 12, 2013

Improving Access to Mental Health Services for Youth in the United States

“In the wake of the recent school shooting in Newtown, Connecticut, a public dialogue emerged about the accessibility of mental health care in the United States. Policy makers have called for a more critical examination of the mental health treatment system, and advocates are rallying around federal legislation that would strengthen community-based mental health services—especially for children and adolescents,” writes Janet R. Cummings, Ph.D., of Emory University, Atlanta, and colleagues.

In this Viewpoint, the authors examine the gaps in mental health facility infrastructure, including gaps in geographic accessibility for low-income youth.

“The national dialogue that emerged from the Connecticut school shooting has provided an opportunity to address these challenges and achieve meaningful improvements in the mental health system that serves children. Improving access to mental health services for this vulnerable population will require an ongoing national dialogue, sustained commitment from policy makers, and a comprehensive approach that addresses the complex array of barriers to treatment that exist in the current system.”

(JAMA. 2013;309[5]:553-554. Available pre-embargo to the media at https://media.jamanetwork.com)

Community Research Partnerships – Underappreciated Challenges, Unrealized Opportunities

“Thousands of physicians, predominantly in primary care and oncology, participate in community research networks sponsored by federal entities, industry, and academia. These numbers, however, are insufficient to achieve the goals of translational research or to realize the potential of ambitious new proposals to fully integrate research and clinical care,” writes Jennifer Kulynych, J.D., Ph.D., of the Johns Hopkins Hospital and Health System, Baltimore, and Kate Gallin Heffernan, J.D., of KGH Advisors LLC, Hingham, Mass.

The authors discuss in this Viewpoint the challenges and opportunities regarding academic medical centers and community research partnerships.

(JAMA. 2013;309[5]:555-556. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the articles 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, FEBRUARY 12, 2013

Media Advisory: To contact corresponding author Feiko O. ter Kuile, Ph.D., email terkuile@liv.ac.uk.

CHICAGO – Among pregnant women in sub-Saharan Africa, intermittent preventive therapy for malaria with 3 or more doses of the drug regimen sulfadoxine-pyrimethamine was associated with a higher birth weight and lower risk of low birth weight than the current standard 2-dose regimen, according to a review and meta-analysis of previous studies published in the February 13 issue of JAMA.

“Intermittent preventive therapy with sulfadoxine-pyrimethamine to control malaria during pregnancy is used in 37 countries in sub-Saharan Africa, and 31 of those countries use the standard 2-dose regimen. However, 2 doses may not provide protection during the last 4 to 10 weeks of pregnancy, a pivotal period for fetal weight gain,” according to background information in the article. “Furthermore, increasing sulfadoxine-pyrimethamine resistance, which results in a progressive decrease of the duration of the prophylactic effect, may also require more frequent dosing.”

Kassoum Kayentao, M.D., of the Liverpool School of Tropical Medicine, Liverpool, United Kingdom, and colleagues conducted a review and meta-analysis to evaluate whether 3 or more doses of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine are associated with higher birth weight or a lower risk of low birth weight (LBW; less than 5.5 lbs.) than a 2-dose regimen. After a review of the medical literature, the researchers identified 7 trials that met inclusion criteria. These trials included 6,281 pregnancies.

Analysis of the data indicated that women in the ≥ 3-dose group had a 20 percent lower  risk of having a LBW infant. The absolute risk reduction was 33 per 1,000 women, from a median (midpoint) risk of 167 per 1,000 in the 2-dose group to 134 per 1,000 in the ≥ 3-dose recipients (number needed to treat = 31). The median birth weight in the 2-dose group was 6.3 lbs., and on average 2 ounces higher in the ≥ 3-dose group.

“The association was consistent across a wide range of sulfadoxine-pyrimethamine resistance. There was no evidence of small-study bias. The ≥ 3-dose group had less placental malaria,” the authors write. “There were no differences in rates of serious adverse events.”

“These data provide support for the new World Health Organization (WHO) recommendation that intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine be provided at each scheduled focused antenatal-care [before birth] visit in the second and third trimesters in all settings in which intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine is recommended. Future research should focus on how best to implement the updated WHO guidelines for intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine and specifically their integration with focused antenatal care. Continued monitoring of the association between population-level sulfadoxine-pyrimethamine resistance and the effectiveness of intermittent preventive therapy during pregnancy is required,” the researchers conclude.

(JAMA. 2013;309(6):594-604; 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, FEBRUARY 12, 2013

Media Advisory: To contact Harlan M. Krumholz, M.D., S.M., call Karen Peart at 203-432-1326 or email karen.peart@yale.edu.

CHICAGO – In a study that included data on nearly 3 million hospital admissions for Medicare beneficiaries with heart attack, pneumonia or heart failure, researchers failed to find evidence that a hospital’s performance on the measure for 30-day mortality rates was strongly associated with performance on 30-day readmission rates, findings that may lessen concerns that hospitals with lower mortality rates will have higher readmission rates, according to a study appearing in the February 13 issue of JAMA.

“Measuring and improving hospital quality of care, particularly outcomes of care, is an important focus for clinicians and policy makers. The Centers for Medicare & Medicaid Services (CMS) began publicly reporting hospital 30-day, all-cause, risk-standardized mortality rates (RSMRs) for patients with acute myocardial infarction [AMI; heart attack] and heart failure (HF) in June 2007 and for pneumonia in 2008. In June 2009, the CMS expanded public reporting to include hospital 30-day, all-cause, risk-standardized-readmission rates (RSRRs) for patients hospitalized with these 3 conditions,” according to background information in the article. “The mortality and readmission measures have been proposed for use in federal programs to modify hospital payments based on performance.”

Some researchers have raised concerns that these rates might have an inverse relationship, such that hospitals with lower mortality rates are more likely to have higher readmission rates. “Interventions that improve mortality might also increase readmission rates by resulting in a higher-risk group being discharged from the hospital. Conversely, the measures could provide redundant information. … Limited information exists about this relationship, an understanding of which is critical to measurement of quality, and yet questions surrounding an inverse relationship have led to public concerns about the measures.”

Harlan M. Krumholz, M.D., S.M., of the Yale University School of Medicine,  New Haven, Conn., and colleagues investigated the relationship between hospital RSMRs and RSRRs overall and within subgroups defined by hospital characteristics. The study included Medicare fee-for-service beneficiaries discharged between July 2005 and June 2008. For AMI, the sample for final analysis consisted of 4,506 hospitals with 590,809 admissions for mortality and 586,027 readmissions; for HF, 4,767 hospitals with 1,161,179 admissions for mortality and 1,430,030 readmissions; and for pneumonia, 4,811 hospitals with 1,225,366 admissions for mortality and 1,297,031 readmissions.

The researchers found that average RSMRs and RSRRs, respectively, were 16.60 percent and 19.94 percent for heart attack, 11.17 percent and 24.56 percent for heart failure, and 11.64  percent and 18.22 percent for pneumonia. The correlations between RSMRs and RSRRs were 0.03 for acute myocardial infarction, -0.17 for heart failure, and 0.002 for pneumonia. In subgroup analyses, the correlations between RSMRs and RSRRs did not differ substantially in any of the subgroups of hospital types, including hospital region, safety net status, and urban/rural status.

“In a national study of the CMS publicly reported outcomes measures, we failed to find evidence that a hospital’s performance on the measure for 30-day RSMR is strongly associated with performance on 30-day RSRR,” the authors write. “For AMI and pneumonia, there was no discernible relationship, and for HF, the relationship was only modest and not throughout the entire range of performance.”

“Our findings indicate that many institutions do well on mortality and readmission and that performance on one does not dictate performance on the other.”

(JAMA. 2013;309(6):587-593; 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, FEBRUARY 12, 2013

Media Advisory: To contact Philippe Prokocimer, M.D., call Laura Kempke or Andrew Law at 781-684-0770 or email trius@mslgroup.com. To contact editorial co-author Helen W. Boucher, M.D., call Julie Jette at 617-636-3265 or email jjette@tuftsmedicalcenter.org.

CHICAGO – Treatment with a newer antibiotic, tedizolid phosphate, once daily for 6 days was statistically noninferior (no worse than) in efficacy to the antibiotic linezolid twice daily for 10 days for both early (at day 2 to 3) and sustained (at day 11) clinical responses in patients with acute bacterial skin and skin structure infections, according to a study appearing in the February 13 issue of JAMA.

“Antimicrobials available for treatment of complicated skin and skin structure infections (SSSIs) are generally efficacious, but antimicrobial resistance and adverse effects limit their use. Linezolid, an oxazolidinone [a class of antibiotics], is the only oral drug approved for complicated SSSI caused by methicillin-resistant Staphylococcus aureus (MRSA),” according to background information in the article. Sporadic outbreaks of linezolid-resistant strains of MRSA have been reported. Acute bacterial skin and skin structure infections (ABSSSIs) can be life-threatening and may require surgery and hospitalization. “Increasingly, ABSSSIs are associated with drug-resistant pathogens, and many antimicrobial agents have adverse effects restricting their use. Tedizolid phosphate is a novel oxazolidinone in development for the treatment of ABSSSIs.”

Philippe Prokocimer, M.D., of Trius Therapeutics Inc., San Diego, and colleagues conducted a study to establish the noninferiority of tedizolid phosphate vs. linezolid in treating ABSSSIs and compare the safety of the 2 agents. The phase 3, randomized trial was conducted from August 2010 through September 2011 at 81 study centers in North America, Latin America, and Europe. The intent-to-treat analysis set consisted of data from 667 adults ages 18 years or older with ABSSSIs treated with tedizolid phosphate (n = 332) or linezolid (n = 335). Patients were randomized to a 200 mg once daily dose of oral tedizolid phosphate for 6 days or 600 mg of oral linezolid every 12 hours for 10 days. The primary efficacy outcome was early clinical response at the 48- to 72-hour assessment (no increase in lesion surface area from baseline and oral temperature of 99.7°F or less, confirmed by a second temperature measurement within 24 hours). A 10 percent noninferiority margin was predefined.

The researchers found in the primary efficacy intent-to-treat (ITT) analysis, the response rates at the 48- to 72-hour assessment were 79.5 percent of 332 patients in the tedizolid phosphate group and 79.4 percent of 335 patients in the linezolid group.  Sustained clinical treatment response rates at the end of treatment (day 11) were similar in the tedizolid phosphate and linezolid groups in the ITT analysis set (69.3 percent vs. 71.9 percent, respectively). Investigator-assessed clinical treatment response at the post-therapy evaluation (PTE) visit was also similar in the tedizolid phosphate and linezolid groups in the ITT analysis set (85.5 percent vs. 86.0 percent, respectively).

“Of particular interest are the similar treatment response rates in the tedizolid phosphate group (78.0 percent) and in the linezolid group (76.1 percent) in the sensitivity analysis that was based on the Foundation for the National Institutes of Health recommended outcome (≥ 20 percent decrease in lesion area),” the authors write.

Also, the researchers found that the clinical response rate at the PTE (7 to 14 days after completing therapy) was high (85 percent) for 178 patients infected with MRSA and similar in both the tedizolid phosphate and linezolid treatment groups.

Treatment-emergent adverse events (mostly mild or moderate) occurred in 40.8 percent of patients in the tedizolid phosphate group and 43.3 percent of patients in the linezolid group. The overall incidence of serious adverse events was low and similar between groups.

“A short course of tedizolid phosphate was statistically noninferior to a 10-day course of linezolid for both early and sustained clinical responses in patients with ABSSSIs. Results were consistent for primary and sensitivity analyses, using either objective criteria or investigators’ assessments, and treatment response rates were concordant for early and late time points,” the authors conclude.

(JAMA. 2013;309(6):559-569; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Trius Therapeutics funded and conducted the trial. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Antibiotics for Skin Infections – New Study Design and a Step Toward Shorter Course Therapy

Shira Doron, M.D., and Helen W. Boucher, M.D., of Tufts Medical Center and Tufts University School of Medicine, Boston, comment on the findings of this study in an accompanying editorial.

“In the study by Prokocimer et al, only 2.4 percent of those who responded to treatment at the 48- to 72-hour assessment in the tedizolid group and 2 percent of those in the linezolid group experienced treatment failure at later time points, and only 7.2 percent and 8 percent, respectively, of the early nonresponders to treatment successfully responded to treatment at the later time point. This notable correlation between the early and late end points suggests that either is appropriate for noninferiority antibiotic trials. However, broad conclusions should not be drawn from this single study; future studies are needed to further enlighten the choice of end points.”

“Tedizolid is a new oral antibiotic that appears efficacious using a short course and may have a better safety profile than linezolid. The current study brings the Infectious Diseases Society of America’s 10 X 20 initiative 1 step closer to its goal of regulatory approval of 10 new antibacterial drugs with activity against drug-resistant bacteria by 2020. If approved, tedizolid will be the first oral drug in this initiative. [This study] also takes an important step toward validating the feasibility of implementing the new FDA end points for ABSSSI. Future studies should add to the understanding of which patients may be treated safely with shorter-course therapy and further explore the correlation between early and sustained response in ABSSSI.”

(JAMA. 2013;309(6):609-610; 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, FEBRUARY 12, 2013

Media Advisory: To contact Douglas R. Morgan, M.D., M.P.H., call Craig Boerner at 615- 322-4747 or email craig.boerner@vanderbilt.edu.

CHICAGO – In an analysis of the results of interventions to eradicate the bacterium Helicobacter pylori (a risk factor for gastric cancer) in seven diverse community populations in Latin America, researchers found that geographic site, demographic factors, adherence to initial therapy and infection recurrence may be as important as the choice of antibiotic regimen in H pylori eradication interventions, according to a study appearing in the February 13 issue of JAMA.

“Gastric adenocarcinoma is the second leading cause of cancer death worldwide. Although gastric cancer rates are declining in some areas, the number of deaths is expected to increase over the coming decades due to growing and aging populations in high-incidence regions such as Latin America and eastern Asia. Helicobacter pylori infects more than half of the world’s adult population, and chronic infection with this bacterium is the dominant risk factor for gastric cancer, accounting for an estimated two-thirds of all cases globally,” according to background information in the article. “The feasibility of large-scale programs is uncertain and success in specific populations will depend on the efficacy of the antibiotic regimen used and the risk of recurrent infection following eradication.”

Douglas R. Morgan, M.D., M.P.H., of Vanderbilt Medical Center, Nashville, Tenn., and colleagues estimated risk of H pylori recurrence and assessed factors associated with successful eradication 1 year after treatment with one of three regimens. The study included 1,463 participants, 21 to 65 years of age from 7 Latin American communities, who were treated for H pylori and observed between September 2009 and July 2011. Potential participants were selected using a census of households (Colombia, Costa Rica, Nicaragua), a large public clinic registry (Chile), or household recruitment (Honduras and 2 sites in Mexico). Participants were randomized to 1 of 3 treatment groups: 14-day lansoprazole, amoxicillin, and clarithromycin (triple therapy); 5-day lansoprazole and amoxicillin followed by 5-day lansoprazole, clarithromycin, and metronidazole (sequential); or 5-day lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant).

Of the 1,133 participants who were urea breath test (UBT; a diagnostic procedure used to identify the presence of H pylori) negative following initial treatment, 1,091 had a 1-year UBT result, of whom 125 had become UBT positive, a recurrence risk of 11.5 percent. The recurrence risk ranged from 6.8 percent in Costa Rica to 18.1 percent in Colombia. The researchers found that recurrence at 1 year was significantly associated with study site, number of children in the household, and nonadherence to therapy, but not with treatment assignment.

In the primary analysis of treatment effectiveness based on the 1,340 participants with definitive 1-year UBT results, the estimated 1-year eradication success rate was 80.4 percent for triple therapy, 79.8 percent for sequential therapy, and 77.8 percent for concomitant therapy. Overall effectiveness was 79.3 percent.

“In a single-treatment course analysis that ignored the effects of re-treatment, the percentage of UBT-negative results at 1 year was 72.4 percent and was significantly associated with study site, adherence to initial therapy, male sex, and age. One-year effectiveness among all 1,463 enrolled participants, considering all missing UBT results as positive, was 72.7 percent,” the authors write.

“In our current study, adherence, study site, sex, and age were significantly associated with the probability of a successful 1-year outcome. From the public health perspective, a ‘one size fits all’ intervention strategy may not be optimal.”

“Ongoing research initiatives are needed, given the expected increase in the gastric cancer burden in Latin America over the next 2 decades, evidence that H pylori infection is the dominant risk factor, and evidence that eradication reduces gastric cancer risk,” the researchers conclude.

(JAMA. 2013;309(6):578-586; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The Bill & Melinda Gates Foundation provided financial support for the trial, and the National Institutes of Health supported the SWOG (Southwest Oncology Group) administrative and statistical infrastructure. 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, FEBRUARY 12, 2013

Media Advisory: To contact Pal Surén, M.D., M.P.H., email pal.suren@fhi.no. To contact editorial co-author Robert J. Berry, M.D., M.P.H.T.M., call CDC Media Relations at 404-639-3286 or email media@cdc.gov.

CHICAGO – In a study that included approximately 85,000 Norwegian children, maternal use of supplemental folic acid from 4 weeks before to 8 weeks after the start of pregnancy was associated with a lower risk of autistic disorder in children, according to a study appearing in the February 13 issue of JAMA.

“Supplementation with folic acid around the time of conception reduces the risk of neural tube defects in children. This protective effect has led to mandatory fortification of flour with folic acid in several countries, and it is generally recommended that women planning to become pregnant take a daily supplement of folic acid starting 1 month before conception,” according to background information in the article. It has not been determined whether prenatal folic acid supplements protect against other neurodevelopmental disorders.

Pal Surén, M.D., M.P.H., of the Norwegian Institute of Public Health, Oslo, and colleagues investigated the association between the use of maternal folic acid supplements before and in early pregnancy and the subsequent risk of autism spectrum disorders (ASDs) (autistic disorder, Asperger syndrome, pervasive developmental disorder-not otherwise specified [PDD-NOS]) in children. The study sample of 85,176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002-2008; by the end of follow-up on March 31, 2012, the age range was 3.3 through 10.2 years (average age, 6.4 years). The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy, defined as the first day of the last menstrual period before conception. Analyses were adjusted for maternal education level, year of birth, and parity (the number of live-born children a woman has delivered).

A total of 270 children (0.32 percent) in the study sample have been diagnosed with ASDs: 114 (0.13 percent) with autistic disorder, 56 (0.07 percent) with Asperger syndrome, and 100 (0.12 percent) with PDD-NOS. The researchers found that there was an inverse association between folic acid use and subsequent risk of autistic disorder. Autistic disorder was present in 0.10 percent (64/61,042) of children whose mothers took folic acid, compared with 0.21 percent (50/24,134) in children whose mothers did not take folic acid, representing a 39 percent lower odds of autistic disorder in children of folic acid users.

Characteristics of women who used folic acid within the exposure interval included being more likely to have college- or university-level education, to have planned the pregnancy, to be nonsmokers, to have a pre-pregnancy body mass index below 25, and to be first-time mothers.

“No association was found with Asperger syndrome or PDD-NOS, but power was limited. Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use,” the authors write.

The researchers note that the inverse association found for folic acid use in early pregnancy was absent for folic acid use in mid pregnancy.

“Our main finding was that maternal use of folic acid supplements around the time of conception was associated with a lower risk of autistic disorder. This finding does not establish a causal relation between folic acid use and autistic disorder but provides a rationale for replicating the analyses in other study samples and further investigating genetic factors and other biological mechanisms that may explain the inverse association,” the authors conclude.

(JAMA. 2013;309(6):570-577; 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, February 12 at this link.

Editorial: Periconceptional Folic Acid and Risk of Autism Spectrum Disorders

“It is reassuring that the study by Surén et al found no association between folic acid supplementation and an increased risk for autistic disorder or ASDs,” write Robert J. Berry, M.D., M.P.H.T.M., and colleagues at the Centers for Disease Control and Prevention, Atlanta, in an accompanying editorial.

“This should ensure that folic acid intake can continue to serve as a tool for the prevention of neural tube birth defects. The potential for a nutritional supplement to reduce the risk of autistic disorder is provocative and should be confirmed in other populations.”

(JAMA. 2013;309(6):611-613; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This editorial was supported by the Centers for Disease Control and Prevention. 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, FEBRUARY 5, 2013

Study Examines Rate of Antipsychotic Use Among Nursing Home Residents

“The prescribing of antipsychotic medications persists at high levels in U.S. nursing homes (NHs) despite extensive data demonstrating marginal clinical benefits and serious adverse effects, including death. However, imprecise and outdated data have limited the understanding of the current state of antipsychotic medication prescribing in NHs,” writes Becky A. Briesacher, Ph.D., of the University of Massachusetts Medical School, Worcester, Mass., and colleagues.

As reported in a Research Letter, the authors conducted a study to assess the current level of antipsychotic use in NHs. The researchers analyzed September 2009 through August 2010 prescription dispensing data from a large, long-term care pharmacy that serves 48 states and half of all NH residents in the United States. Data elements included state location, patients’ sex, age, and enrollment dates, and national drug codes for all drugs dispensed regardless of payer (e.g., Medicare Part D, private insurance, and out of pocket). Overall and state-level annual prevalence of antipsychotic use was calculated as the percentage of NH residents receiving at least 1 antipsychotic drug.

“Of the overall sample of 1,402,039 NH residents, 308,449 (22.0 percent) received 1 or more prescriptions of antipsychotics. Prevalence of antipsychotic drug prescribing in NHs varied significantly, with the highest quintile [one of five groups] states (28.1 percent) located in the central south and the lowest quintile states (17.2 percent) located mostly in the west. Of 4,338,723 antipsychotic prescriptions in NHs, the majority (68.6 percent) were for the atypical agents quetiapine fumarate, risperidone, and olanzapine (n = 2,988,573).”

The authors note that their “finding that 22.0 percent of NH residents received antipsychotics in 2009-2010 is within the lower range of rates that were documented 25 years earlier before the passage of the Omnibus Budget Reconciliation Act of 1987, which instituted regulations on the appropriate use of antipsychotics in NHs.” They add that the extended duration of use (median duration, 30 to 77 days) raises “concerns about the care of frail elders residing in NHs.”

(JAMA. 2013;309[5]:440-442. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Issue of JAMA

Enhanced Tracking of Tissue for Transplantation

“The U.S. Food and Drug Administration (FDA) estimates that tissue banks provide 1.5 million tissue grafts annually, often supplying hospitals in several different states or even countries with tissue from a single donor. Tissue allografts have become a vitally important global industry. Nevertheless, tracking mechanisms that exist in other medical contexts have notable deficiencies with respect to tracking tissues,” writes John S. DePaolo, B.A., and James M. Barbeau, M.D., J.D., of the Louisiana State University School of Medicine, New Orleans.

In this Viewpoint, the authors discuss the deficiencies and provide suggestions for improving tracking of tissue.

(JAMA. 2013;309[5]:443-444. Available pre-embargo to the media at https://media.jamanetwork.com)

FDA Regulation of Off-label Drug Promotion Under Attack

Aaron S. Kesselheim, M.D., J.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues examine the issue of regulating off-label drug promotion, and cite a recent Court of Appeals decision that “signals that courts’ evolving views of protecting corporations’ commercial speech may prove incompatible with regulating drug promotion.”

“Courts’ seemingly inexorable drift toward greater protection of commercial speech at the expense of rigorous science directly threatens the FDA’s standing as the nation’s arbiter of which drugs are safe and effective. The existing approach to governing drug promotion, honed by enormous clinical and regulatory experience, is scientifically and legally justifiable and has benefitted patients and practitioners for decades. It should not be abandoned now.”

(JAMA. 2013;309[5]:445-446. Available pre-embargo to the media at https://media.jamanetwork.com)

The European Working Time Directive

“A large-scale, uncontrolled experiment in medical care and education is in progress in the European community with important implications for the quality of medical care and education. Working hours for physicians in training are now limited to 48 hours per week, a fact that—to our knowledge—is little known to most U.S. physicians,” writes Lloyd Axelrod, M.D., of the Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

In this Viewpoint, the authors discuss the European Working Time Directive that led to this reform, the effect of this directive on European medical care and education, and the important implications for graduate training reform in the United States.

(JAMA. 2013;309[5]:447-448. Available pre-embargo to the media at https://media.jamanetwork.com)

Improving Population Health in U.S. Cities

Nicholas W. Stine, M.D., of the New York City Health and Hospitals Corporation, New York, and colleagues describe in a Viewpoint the challenges and opportunities to improving population health in U.S. cities.

“While the diversity and fragmentation of services within cities pose formidable organizational challenges, there are several key attributes of urban settings, if harnessed strategically, that offer opportunities for potentially effective population health strategies.”

(JAMA. 2013;309[5]:449-450. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the articles 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, FEBRUARY 5, 2013

Media Advisory: To contact corresponding author Bill Vicenzino, Ph.D., email b.vicenzino@uq.edu.au.

CHICAGO – Among patients with chronic unilateral lateral epicondylalgia (“tennis elbow”), a single injection of corticosteroid medication was associated with poorer outcomes after one year and higher recurrence rates compared with placebo, while eight weeks of physiotherapy did not significantly improve long-term outcomes, according to a study appearing in the February 6 issue of JAMA.

“Use of corticosteroid injections to treat lateral epicondylalgia is increasingly discouraged, partly because evidence of long-term efficacy has not been found, and due to high recurrence rates,” according to background information in the article. Combining corticosteroid injection with physiotherapy to compensate for the poor long-term outcomes of corticosteroid injections has been evaluated in only 2 small studies, and the long-term effects of combining these therapies are not known.

Brooke K. Coombes, Ph.D., of the University of Queensland, St. Lucia, Australia, and colleagues conducted a study to evaluate the effectiveness of corticosteroid injection, multimodal physiotherapy, or both in 165 patients with unilateral lateral epicondylalgia of longer than 6 weeks’ duration. The patients were enrolled between July 2008 and May 2010; 1-year follow-up was completed in May 2011. Patients were randomized to either corticosteroid injection (n = 43), placebo injection (n = 41), corticosteroid injection plus physiotherapy (n = 40), or placebo injection plus physiotherapy (n = 41). The 2 primary outcomes were 1-year global rating of change scores for complete recovery or much improvement and 1-year recurrence (defined as complete recovery or much improvement at 4 or 8 weeks, but not later) analyzed on an intention-to-treat basis. Secondary outcomes included complete recovery or much improvement at 4 and 26 weeks.

The researchers found that corticosteroid injection demonstrated lower complete recovery or much improvement at 1 year compared with placebo injection (83 percent vs. 96 percent) and greater recurrence (54 percent vs. 12 percent). There were no differences between physiotherapy and no physiotherapy at 1 year for complete recovery or much improvement (91 percent vs. 88 percent) or recurrence (29 percent vs. 38 percent).

There were no significant interaction effects at 26 weeks. The corticosteroid injection demonstrated lower complete recovery or much improvement compared with the placebo injection (55 percent vs. 85 percent). Physiotherapy compared with no physiotherapy demonstrated no effects on the outcomes of complete recovery or much improvement (71 percent vs. 69 percent), and with no significant differences on measures of worst pain; resting pain; pain and disability; and quality of life.

“At 4 weeks, there was a significant interaction between corticosteroid injection and physiotherapy, whereby patients receiving the placebo injection plus physiotherapy had greater complete recovery or much improvement vs. no physiotherapy (39 percent vs. 10 percent, respectively). However, there was no difference between patients receiving the corticosteroid injection plus physiotherapy vs. corticosteroid alone (68 percent vs. 71 percent, respectively),” the authors write.

“Contrary to our hypothesis and to a generally held clinical view, we found that multimodal physiotherapy provided no beneficial long-term effect on complete recovery or much improvement, recurrence, pain, disability, or quality of life, thereby not supporting the hypothesis that the combined approach is superior. However, physiotherapy should not be dismissed altogether because in the absence of the corticosteroid, it provided short-term benefit across all outcomes, as well as the lowest recurrence rates (4.9 percent) and 100 percent complete recovery or much improvement at 1 year.”

(JAMA. 2013;309(5):461-469; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by the Australian National Health and Medical Research Council grant awarded to Drs. Bisset, Brooks, and Vicenzino. 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, FEBRUARY 5, 2013

Media Advisory: To contact Anna A. Ahimastos, Ph.D., email A.Ahimastos@alfred.org.au. To contact editorial author Mary McGrae McDermott, M.D., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu.

CHICAGO – Among patients with peripheral artery disease and intermittent claudication (pain in the calf that comes and goes, typically felt while walking), 24 weeks of treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril was associated with improvement in pain-free and maximum walking times and the physical health aspect of quality of life, according to a study appearing in the February 6 issue of JAMA.

“Approximately 27 million individuals in Europe and North America have peripheral artery disease (PAD). Intermittent claudication occurs in approximately one-third of patients with PAD and typically presents as pain within leg muscle groups that occurs during walking but is relieved by rest. Patients with intermittent claudication have significant impairment in ambulatory function, resulting in functional disability and significant lifestyle limitation. Treatment of these patients is aimed at reducing cardiovascular risk, increasing functional performance, and improving health-related quality of life,” according to background information in the article.  Current drug treatments to improve walking distance have limited efficacy. A pilot trial with ramipril showed promising results. However, that trial was small and the findings were restricted to a subset of patients who comprise approximately one-half of all patients with claudication.

Anna A. Ahimastos, Ph.D., of the Baker IDI Heart and Diabetes Institute, Melbourne, Australia, and colleagues conducted a study to examine the association of ramipril therapy on walking distance and health-related quality of life as compared with placebo in a larger, more general PAD population. The randomized, placebo-controlled trial included 212 patients with peripheral artery disease (average age, 65.5 years), initiated in May 2008 and completed in August 2011. Patients were randomized to receive 10 mg/d of ramipril (n = 106) or matching placebo (n = 106) for 24 weeks. The primary outcome measures for the study were maximum and pain-free walking times, as recorded during a standard treadmill test. The Walking Impairment Questionnaire (WIQ) and Short-Form 36 Health Survey (SF-36) were used to assess walking ability and quality of life, respectively.

The researchers found that relative to placebo, ramipril was associated with a 75-second increase in average pain-free walking time and a 255-second increase in maximum walking time (a 77 percent and 123 percent increase in pain-free and maximum walking times, respectively). Compared to placebo, ramipril was also associated with improvements in WIQ scores (median distance, speed score and stair climbing) and the overall SF-36 median Physical Component Summary score.

“The increase in WIQ scores suggests that ramipril improves patient-perceived ability to perform normal daily activities. Ramipril therapy was also associated with moderate improvement in the physical health component of the SF-36 score. Importantly, these associations were additional to those achieved with standard clinical management by a general practitioner or vascular specialist. Further benefits may be achieved by adherence to lifestyle recommendations including smoking cessation and regular exercise, as well as more aggressive medical management of cardiovascular risk factors,” the authors write.

“To our knowledge, this is the first adequately powered randomized trial demonstrating that treatment with ramipril is associated with improved treadmill walking performance in patients with PAD.”

(JAMA. 2013;309(5):453-460; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by the National Heart Foundation of Australia, the National Health and Medical Research Council of Australia, and the Operational Infrastructure Support Program of the Victorian State Government, Australia. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Please Note: An author podcast on this study will be available post-embargo on the JAMA website.

Editorial: Medications for Improving Walking Performance in Peripheral Artery Disease – Still Miles to Go

Mary McGrae McDermott, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, (also Contributing Editor, JAMA) comments on the results of this study in an accompanying editorial.

“A recent report from the Global Disease Burden study concluded that global disease burden continues to shift away from communicable to noncommunicable diseases and from premature death to greater years lived with disability. New therapies are needed to improve mobility and reduce disability among men and women living with PAD and other chronic diseases. Further study is needed to confirm the findings reported by Ahimastos et al and to determine whether ramipril therapy and other ACE inhibitors improve walking performance in ethnically diverse populations.”

(JAMA. 2013;309(5):487-488; 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. Dr. McDermott reported serving as a consultant for Ironwood Pharmaceuticals, a company that develops drugs used to treat peripheral artery disease (PAD), and serving as the medical editor for PAD for the Foundation for Informed Medical Decision Making.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 5, 2013

Media Advisory: To contact Joan M. Teno, M.D., M.S., call David Orenstein at 401-863-1862 or email david_orenstein@brown.edu. To contact editorial co-author Mary E. Tinetti, M.D., call Karen Peart at 203-432-1326 or email karen.peart@yale.edu.

CHICAGO – In a study that included data on more than 800,000 Medicare beneficiaries who died between 2000 – 2009, a lower proportion died in an acute care hospital in recent years, although both intensive care unit (ICU) use and the rate of health care transitions increased during the last month of life, according to a study appearing in the February 6 issue of JAMA.

“Site of death has been proposed as a quality measure for end-of-life care because, despite general population surveys indicating the majority of respondents and those with serious illness want to die at home, in actuality, most die in an institutional setting. One study found poorer quality of care in the institutional setting compared with care at home, especially with hospice services. The place of care and site of death have implications for the grief and posttraumatic stress disorders experienced by family members,” according to background information in the article.

Joan M. Teno, M.D., M.S., of the Warren Alpert Medical School of Brown University, Providence, R.I., and colleagues analyzed Medicare claims data to document places of care and health care transitions for Medicare decedents in the last months of life to assess end-of-life care. The study consisted of a random 20 percent sample of fee-for-service Medicare beneficiaries, 66 years of age and older, who died in 2000 (n = 270,202), 2005 (n = 291,819), or 2009 (n = 286,282). Based on billing data, patients were classified as having a medical diagnosis of cancer, chronic obstructive pulmonary disease, or dementia in the last 180 days of life. The main outcome measures for the study were site of death, place of care, rates of health care transitions, and potentially burdensome transitions (e.g., health care transitions in the last 3 days of life).

Among the findings of the researchers, the percentage of deaths that occurred in acute care hospitals decreased from 32.6 percent in 2000 to 24.6 percent in 2009. More decedents in 2009 than in 2000 had an ICU stay in the last month of life (from 24.3 percent to 29.2 percent). Hospice use at the time of death increased from 21.6 percent in 2000 to 42.2 percent in 2009.

“Short hospice stays increased from 22.2 percent in 2000 to 28.4 percent of hospice decedents using hospice for 3 days or less. Of these late hospice referrals in 2009, 40.3 percent were preceded by hospitalizations with an ICU stay,” the authors write.

Transitions in the last 3 days of life increased from 10.3 percent to 14.2 percent in 2009. The average rate of health care transitions in the last 90 days of life increased from 2.1 per decedent in 2000 to 3.1 per decedent in 2009, with an increase in 2 types of potentially burdensome transitions: transitions in the last 3 days of life and multiple hospitalizations in the last 90 days of life.

“Our findings of an increase in the number of short hospice stays following a hospitalization, often involving an ICU stay, suggest that increasing hospice use may not lead to a reduction in resource utilization. Short hospice lengths of stay raise concerns that hospice is an ‘add-on’ to a growing pattern of more utilization of intensive services at the end of life,” the researchers write.

(JAMA. 2013;309(5):470-477; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was funded by a National Institute on Aging grant and in part by the Robert Wood Johnson Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, February 5 at this link.

Editorial: Changes in End-of-Life Care Over the Past Decade – More Not Better

In an accompanying editorial, Grace Jenq, M.D., and Mary E. Tinetti, M.D., of the Yale School of Medicine, New Haven, Conn., write that “site of death has been proposed as a measure of the quality of end-of-life care, perhaps based on studies showing that the majority of people, including those with serious illness, want to die at home.”

“The study by Teno et al suggests that site of death is an insufficient metric given the many transitions endured, and intensive care services received, prior to the actual event of death. A more appropriate metric might be whether patients’ goals were elicited and care predicated on meeting those goals was instituted soon enough to make a difference in end-of-life care.”

(JAMA. 2013;309(5):489-490; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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