EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 11, 2012

Study Finds Association Between Weight of Pancreas and Potential Diabetes Biomarker

Autopsy and imaging studies suggest that among adults with type 1 diabetes (T1D), their pancreas is smaller and weighs less than the pancreas of adults without the disease. However, it is unknown when pancreatic atrophy begins in T1D. Martha Campbell-Thompson, D.V.M., Ph.D., of the University of Florida, Gainesville, and colleagues conducted a study to examine pancreas weight early in the natural history of T1D from at-risk individuals without diabetes but with disease-associated autoantibodies, obtained through the Network for Pancreatic Organ Donors with Diabetes program. All donors were identified by organ procurement organizations that coordinate organ and tissue donations for clinical transplantation or research.

As reported in a Research Letter, the final analysis included 51 donors (no diabetes, n = 23; positive for autoantibody only, n = 8; type 1 diabetes, n = 20). The authors found that the average weight of pancreata (plural form of pancreas) from those without diabetes (controls) was 81.4 g compared with 61.3 g from the group positive for a single autoantibody only and 44.9 g from the T1D group.

“In this study, the weight of pancreata in individuals without T1D, but with serum markers that potentially precede the clinical manifestations, as well as in individuals with T1D, was less than in controls. This suggests that early atrophy of the organ may be an important subclinical feature of T1D pathogenesis,” the authors write. “Future studies should include validation and analysis of the potential mechanisms underlying this observation to understand whether early pancreatic atrophy contributes to the pathogenesis of T1D.”

(JAMA. 2012;308[22]:2337-2339. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Lixivaptan for Hyponatremia – The Numbers Game

Ryan T. Borne, M.D., and Mori J. Krantz, M.D., of the Denver Health Hospital and Authority, examine the approval of the drug lixivaptan for the treatment of hyponatremia (abnormally low level of sodium in the blood) and the questions regarding the benefit of this class of drugs (vasopressin receptor antagonist).

“Sole reliance on laboratory surrogates can lead to widespread adoption of ineffective or harmful treatments. Regulators should create a landscape that supports evaluation of safety and efficacy across all phases of development and exhibit caution when making inferences based on predictive data from epidemiologic studies. Therapeutically modifying a given surrogate marker tightly linked in epidemiologic studies with improved outcomes cannot guarantee clinical efficacy,” they write. “… in the case of the vasopressin receptor antagonist class, it remains dubious that an increase in serum sodium levels will ultimately be demonstrated to improve outcomes in clinical trials given the myriad etiologies for hyponatremia. The manufacturers of lixivaptan sought approval for use in less severe hyponatremia and even among outpatients. The potential risks and benefits of lixivaptan and this expanded label are being carefully considered by the FDA.”

(JAMA. 2012;308[22]:2345-2346. 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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For More Information: contact The JAMA Network^® Media Relations Department at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 11, 2012

Media Advisory: To contact corresponding author David S. Friedman, M.D., M.P.H., Ph.D., call John Lazarou at 410-502-8902 or email jlazaro1@jhmi.edu. To contact editorial co-author David C. Musch, Ph.D., M.P.H., call Betsy Nisbet at 734-647-5586 or email bsnisbet@umich.edu.

CHICAGO – The prevalence of nonrefractive visual impairment (not due to need for glasses) in the U.S. has increased significantly in recent years, which may be partly related to a higher prevalence of diabetes, an associated risk factor, according to a study in the December 12 issue of JAMA.

“It is estimated that more than 14 million individuals in the United States aged 12 years and older are visually impaired (<20/40). Of these cases, 11 million are attributable to refractive error. In the United States, the most common causes of nonrefractive visual impairment are age-related macular degeneration, cataract, diabetic retinopathy, glaucoma, and other retinal disorders,” according to background information in the article. Previous studies have shown that visual impairment is common in persons with diabetes. “The prevalence of diagnosed diabetes has increased among adults in recent years, rising from 4.9 percent in 1990 to 6.5 percent in 1998, 7.9 percent in 2001, 10.7 percent in 2007, and 11.3 percent in 2010.”

Fang Ko, M.D., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues conducted a study to assess the prevalence of nonrefractive visual impairment and factors associated with risk of visual impairment. The study included data from the National Health and Nutrition Examination Survey (NHANES), a representative sample of the U.S. population. In 1999-2002 and 2005-2008, 9,471 and 10,480 participants 20 years of age or older received questionnaires, laboratory tests, and physical examinations. Visual acuity of less than 20/40 aided by autorefractor (a device for measuring a person’s refractive error) was classified as nonrefractive visual impairment.

The researchers found that prevalence of nonrefractive visual impairment increased 21 percent, from 1.4 percent in 1999-2002 to 1.7 percent in 2005-2008; and increased 40 percent among non-Hispanic whites 20-39 years of age, from 0.5 percent to 0.7 percent. In analysis among all participants, factors associated with nonrefractive visual impairment included older age, poverty, lower education level, and diabetes diagnosed 10 or more years ago. Among these risk factors, only the latter has increased in prevalence between the 2 time periods considered. Prevalence of diabetes with 10 or more years since diagnosis increased 22 percent overall from 2.8 percent to 3.6 percent; and 133 percent among non-Hispanic whites 20-39 years of age, from 0.3 percent to 0.7 percent.

“We report a previously unrecognized increase of visual impairment among U.S. adults that cannot be attributed to refractive error,” the authors write. “If the current finding becomes a persisting trend, it could result in increasing rates of disability in the U.S. population, including greater numbers of patients with end-organ diabetic damage who would require ophthalmic care. These results have important implications for resource allocation in the debate of distribution of limited medical services and funding. Continued monitoring of visual disability and diabetes, as well as additional research addressing causes, prevention, and treatment, is warranted.”

(JAMA. 2012;308(22):2361-2368; 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.

Please Note: For this study, there will be multimedia content available, 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, December 11 at this link.

Editorial: Diabetes and Nonrefractive Visual Impairment – The Young Have It

David C. Musch, Ph.D., M.P.H., and Thomas W. Gardner, M.D., M.S., of the University of Michigan, Ann Arbor, write in an accompanying editorial that the results of this study “are indeed meaningful, considering the cohort of young people for whom a milieu of sociodemographic and lifestyle factors have led to increased risk of type 2 diabetes and its consequences, which include nonrefractive visual impairment.”

“… this report should send an important message to pediatricians, family practitioners, internists, and ophthalmologists who already are seeing an increase of type 2 diabetes among their younger patients, and should alert public health planners, who need to prepare for the effects on the health care system. The findings of Ko et al should also stimulate funding for new and ongoing efforts to prevent the underlying causes that lead to diabetes and its complications such as obesity-prevention programs aimed at children and adolescents.”

(JAMA. 2012;308(22):2403-2404; 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, DECEMBER 11, 2012

Media Advisory: To contact corresponding author Konrad E. Bloch, M.D., email konrad.bloch@usz.ch.

CHICAGO – For individuals with obstructive sleep apnea traveling to higher altitudes (which may exacerbate symptoms), use of a combination therapy resulted in improvement in symptoms including  reduced insomnia and better control of sleep apnea, according to a preliminary study published in the December 12 issue of JAMA.

As travel to the mountains for professional and recreational activities is increasingly popular, involving millions of persons worldwide, the estimated number of patients with obstructive sleep apnea (OSA) among mountain tourists is also high, and may involve several hundred thousand persons each year, which may expose them to hypoxemia (abnormally low levels of oxygen in the blood) and exacerbation of sleep apnea. “The treatment in this setting is not established,” according to background information in the article.

Tsogyal D. Latshang, M.D., of the University of Zurich, Switzerland, and colleagues conducted a study to evaluate whether taking of the drug acetazolamide (a respiratory stimulant used to treat acute mountain sickness and high-altitude periodic breathing) combined with auto-adjusted continuous positive airway pressure (autoCPAP, computer-controlled continuous mask pressure adjustment) would provide better oxygenation and control of sleep-related breathing disturbances than autoCPAP alone in patients with OSA spending a few days at moderate altitude. The randomized trial included 51 patients with OSA living below an altitude of 800 meters (2,625 feet) and receiving CPAP therapy who underwent studies at a university hospital at 490 meters (1,608 feet) and resorts in Swiss mountain villages at 1,630 meters (5,348 feet) and 2,590 meters (8,497 feet) in the summer of 2009. Patients were studied during 2 stays of 3 days each in the mountain villages. At altitude, patients either took acetazolamide (750 mg/d) or placebo in addition to autoCPAP.

The researchers found that at 1,630 meters and 2,590 meters, combined acetazolamide and autoCPAP treatment was associated with higher oxygen saturation and a lower apnea/hypopnea index (AHI) compared with placebo and autoCPAP. AutoCPAP and acetazolamide increased the median [midpoint] nocturnal oxygen saturation by 1.0 percent at 1,630 meters and by 2.0 percent at 2,590 meters. Also, acetazolamide and autoCPAP resulted in better control of sleep apnea at these altitudes than placebo and autoCPAP: median apnea/ hypopnea index was 5.8 events per hour (5.8/h) and 6.8/h vs. 10.7/h and 19.3/h, respectively; median reduction was 3.2/h and 9.2/h. Median night-time spent with oxygen saturation less than 90 percent at 2,590 meters was 13 percent vs. 57 percent.

“The current randomized, placebo-controlled, double-blind trial provides several novel findings that are clinically relevant for patients with OSA traveling to altitude. First, the data show that combined therapy with acetazolamide and autoCPAP provides a better oxygenation during sleep and wakefulness, prevents an exacerbation of sleep apnea at altitude, and reduces the time spent awake during nights compared with autoCPAP alone. Second, the results demonstrate that autoCPAP alone is an effective therapy for obstructive apneas/hypopneas even at altitude where central apneas/hypopneas emerge,” the authors write.

“Our study provides important information for patients with OSA planning a stay at altitude because they can continue using their CPAP in autoadjusting mode during altitude travel and enhance this treatment with acetazolamide if they want to spend less time awake at night, to achieve a higher arterial oxygen saturation and an optimal control of sleep apnea.”

(JAMA. 2012;308(22):2390-2398; 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, December 4, 2012

Overcoming the Obstacles to Research During Residency – What Does It Take?

Michael B. Rothberg, M.D., M.P.H., of the Cleveland Clinic, writes that “although most physicians work as clinicians and never perform research, the Accreditation Council for Graduate Medical Education requires that residents ‘participate in scholarly activity’ and that programs ‘allocate adequate educational resources to facilitate resident involvement in scholarly activities.’” Dr. Rothberg notes that conducting research in residency is challenging, and insufficient scholarly activity remains a common reason for residency program citation.  In this Viewpoint, the author provides suggestions for overcoming the challenges presented.

“In conclusion, the requirement for resident research holds substantial promise for improving the practice of medicine, enhancing quality, and decreasing cost, but for research to become widespread, residency training programs must overcome a number of substantial obstacles. Successful implementation requires an intentional approach that addresses specific barriers, beginning with a commitment to change the underlying culture of the institution to create an atmosphere of inquiry and the financial investment to build the necessary infrastructure to facilitate rapid turnaround of small projects.”

(JAMA. 2012;308[21]:2191-2192. Available pre-embargo to the media at https://media.jamanetwork.com)

Residency Training and International Medical Graduates – Coming to America No More

Giovanni Traverso, M.B., B.Chir., Ph.D., of Massachusetts General Hospital, and Graham T. McMahon, M.D., M.M.Sc., of Brigham and Women’s Hospital, Boston, discuss the expected decrease in the number of international medical graduates (IMGs) who train in the United States, and the possible adverse effects.

“The rapidly increasing number of medical school graduates coupled with a constrained graduate medical education system is likely to have a substantial effect on the number of IMG recruits to U.S. programs. These trends threaten to reduce the diversity of the physician community and could meaningfully affect primary care delivery in the United States and even health care quality abroad. Despite the proven value of IMGs to the U.S. health care system, coming to America is likely to prove increasingly challenging for future IMGs.”

(JAMA. 2012;308[21]:2193-2194. Available pre-embargo to the media at https://media.jamanetwork.com)

Professionalism in the Era of Duty Hours – Time for a Shift Change?

Vineet M. Arora, M.D., M.A.P.P., of the University of Chicago, and colleagues write that “concerns have been raised that the implementation of shorter duty hours for residents may erode the professional allegiance of these physicians to their patients. Those who trained before duty hour regulations often dismiss current physicians in training as lifestyle oriented and not committed to the profession.”

In this Viewpoint, the authors examine how the conflict between nostalgic definitions of professionalism and the new model of medical training can be reconciled.

“To make the transition from a nostalgic to a new type of professionalism, the system of residency training must fully adopt a team-based care model in which patient ownership is not relegated to an individual, but shared among a group of team members. As shift work is adopted, such a structure can promote professionalism by preventing a ‘that’s not my patient’ sentiment by covering physicians,” they write. “It is the responsibility of educators and leaders to search for creative solutions to facilitate adoption of new professionalism. After all, now is the time for a shift change.”

(JAMA. 2012;308[21]:2195-2196. 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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For More Information: contact The JAMA Network® Media Relations Department at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact corresponding author Deborah Korenstein, M.D., call Kevin Orozovich at 212-241-9200 or email newsmedia@mssm.edu.

Azalea Kim, M.P.A., of the Mount Sinai School of Medicine, New York, and colleagues studied the association between routine conflicts of interest (COI) disclosure with preclinical medical students and students’ attitudes toward disclosure and industry interactions. In September 2010, the Mount Sinai School of Medicine began mandating COI disclosure by lecturers to preclinical medical students.

“Disclosure of potential COI from relationships with the pharmaceutical and device industries is recommended in publishing, research, and education of residents, faculty, and students. Disclosure in education may foster critical evaluation of information and assessment for potential bias, but its effect is unclear.”

As reported in a Research Letter, the authors adapted a published survey to assess student attitudes toward COI disclosure and the appropriateness of industry gifts to physicians, industry-sponsored education, and industry-faculty relationships. All year 1 (n = 143) and year 2 (n = 141) students were eligible to participate; results from the two classes were pooled. Participants were surveyed during class meetings at the beginning and end of the 2010-2011 academic year, comparing attitudes before and after policy implementation.

The researchers found that nearly all students (>97.0 percent) favored disclosure in both surveys. “Attitudes toward academic-industry relationships changed after policy implementation. Agreement increased over whether schools should limit industry meetings with students. Agreement decreased over whether industry should fund medical school programs. Attitudes did not change regarding the influence of COI on educators or educational content. Few students believed that educational content or quality were influenced by educator relationships with industry.”

“Our findings suggest that a COI disclosure policy to students is feasible and may influence student attitudes toward industry prescribing but not education.”

(JAMA. 2012;308[21]:2187-2189. Available pre-embargo to the media at https://media.jamanetwork.com)

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Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact Peter Yeates, M.B.B.S., M.Clin.Ed., email peter.yeates@manchester.ac.uk.

Peter Yeates, M.B.B.S., M.Clin.Ed., of the University of Manchester, United Kingdom, and colleagues conducted a study to examine whether observations of the performance of postgraduate year 1 physicians influence raters’ scores of subsequent performances.

“The usefulness of performance assessments within medical education is limited by high interrater score variability, which neither rater training nor changes in scale format have successfully ameliorated. Several factors may explain raters’ score variability, including a tendency of raters to make assessments by comparing against other recently viewed learners, rather than by using an absolute standard of competence. This has the potential to result in biased judgments,” according to background information in the article.

The study consisted of an internet-based randomized experiment using videos of Mini Clinical Evaluation Exercise (Mini-CEX) assessments of postgraduate year 1 trainees interviewing new internal medicine patients. Participants were 41 attending physicians from England and Wales experienced with the Mini-CEX, with 20 watching and scoring 3 good trainee performances and 21 watching and scoring 3 poor performances. All then watched and scored the same 3 borderline video performances. The study was completed between July and November 2011.

The researchers found that attending physicians exposed to videos of good medical trainee performances rated subsequent borderline performances lower than those who had been exposed to poor performances, consistent with a contrast bias. The implication is that a rater of a trainee’s performance may be unconsciously influenced by the previous trainee, rather than objectively assessing the individual in isolation.

“With the movement toward competency-based models of education, assessment has largely shifted to a system that relies on judgments of performance compared with a fixed standard at which competence is achieved (criterion referencing). Although this makes conceptual sense (with its inherent ability to reassure both the profession and the public that an acceptable standard has been reached), the findings in this study, which are consistent with contrast bias, suggest that raters may not be capable of reliably judging in this way.”

(JAMA. 2012;308[21]:2226-2232. Available pre-embargo to the media at https://media.jamanetwork.com)

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Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact Kevin W. Eva, Ph.D., call Brian Kladko at 604-827-3301 or email brian.kladko@ubc.ca.

Kevin W. Eva, Ph.D., of the University of British Columbia, Vancouver, and colleagues conducted a study to determine whether students deemed acceptable through a revised admissions protocol using a 12-station multiple mini-interview (MMI) would outperform rejected medical students when they later took the Canadian national licensing examinations after completing medical school. The MMI process requires candidates to rotate through brief sequential interviews with structured tasks and independent assessment within each interview.

“Modern conceptions of medical practice demand more of practitioners than a strong knowledge base. By emphasizing compassionate care, professionalism, and interpersonal skill, the Accreditation Council for Graduate Medical Education core competencies indicate that physicians are expected to possess strong personal qualities distinct from academic achievement. There is evidence of a link between these aspects of practice and quality of care,” according to background information in the article. “There has been difficulty designing medical school admissions processes that provide valid measurement of candidates’ nonacademic qualities.”

The study included potential medical students who were interviewed at McMaster University in Hamilton, Canada, using an MMI in 2004 or 2005 and accepted (whether or not they matriculated [enrolled] at McMaster) with those who were interviewed and rejected but gained entry elsewhere.

The computer-based Medical Council of Canada Qualifying Examination (MCCQE) part I (aimed at assessing medical knowledge and clinical decision making) can be taken on graduation from medical school; MCCQE part II (involving simulated patient interactions testing various aspects of practice) is based on the objective structured clinical examination and typically completed 16 months into postgraduate training. Interviews were granted to 1,071 candidates, and those who gained entry could feasibly complete both parts of their licensure examination between May 2007 and March 2011. Scores could be matched on the examinations for 751 (part I) and 623 (part II) interviewees. Admissions decisions were made with use of scores assigned to autobiographical essays, grade point average (GPA), and MMI performance. Academic and nonacademic measures contributed equally to the final ranking.

The researchers found that compared with students who were rejected by an admission process that used MMI assessment, students who were accepted scored higher on Canadian national licensing examinations, whether they had attended McMaster or another school.

“In conclusion, there appears to be a complementary relationship between GPA and the MMI process, with the former related to more knowledge-oriented outcome measures and the latter to more clinical/ethical/interpersonal skill-oriented outcomes. Our study demonstrates that at McMaster, a GPA plus MMI approach has yielded better outcomes than were achieved by the historical use of GPA plus panel-style interview/simulated tutorial.”

(JAMA. 2012;308[21]:2233-2240. Available pre-embargo to the media at https://media.jamanetwork.com)

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Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact corresponding author Khalid S. Khan, M.B.B.S., M.Sc., email k.s.khan@qmul.ac.uk.

Regina Kulier, M.D., of the World Health Organization, Geneva, Switzerland, and colleagues conducted a study to evaluate the effects of a clinically integrated e-learning evidence-based medicine (EBM) course on knowledge, skills, and educational environment in comparison with traditional EBM teaching in a group of low-middle-income countries.

“Evidence-based medicine encourages assimilation and implementation of new, valid, and relevant scientific knowledge by health care professionals as part of their daily clinical work. To be effective at achieving this, EBM curricula need to be clinically integrated,” according to background information in the article. “In low-middle-income countries (LMICs) there is a scarcity of EBM-trained clinical tutors, lack of protected time for teaching EBM, and poor access to relevant databases in languages other than English.”

The randomized trial was conducted between April 2009 and November 2010 among postgraduate trainees in obstetrics-gynecology in 7 LMICs (Argentina, Brazil, Democratic Republic of the Congo, India, Philippines, South Africa, Thailand). Each training unit was randomized to an experimental clinically integrated course consisting of e-modules using the World Health Organization Reproductive Health Library (RHL) for learning activities and trainee assessments (31 clusters, 123 participants) or to a control self-directed EBM course incorporating the RHL (29 clusters, 81 participants). A facilitator with EBM teaching experience was available at all teaching units. Courses were administered for 8 weeks, with assessments at baseline and 4 weeks after course completion. The study was completed in 24 experimental clusters (98 participants) and 22 control clusters (68 participants).

After the trial, the experimental group had higher average scores in knowledge and skills. Although there was no difference in improvement for the overall score for educational environment, there was an associated average improvement in the domains of general relationships and support and EBM application opportunities.

“The associated improvements in educational environment suggest that EBM principles that are learned may become culturally embedded in the workplace,” the authors write.

(JAMA. 2012;308[21]:2218-2225. Available pre-embargo to the media at https://media.jamanetwork.com)

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Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact Kevin G. Volpp, M.D., Ph.D., call Jessica Mikulski at 215-349-8369 or email jessica.mikulski@uphs.upenn.edu

Kevin G. Volpp, M.D., Ph.D., of the Philadelphia Veterans Affairs Medical Center and University of Pennsylvania, Philadelphia, and colleagues conducted a study to determine whether a protected sleep period of 5 hours is feasible and effective in increasing the time slept by interns on extended duty overnight shifts.

In 2009, the Institute of Medicine (IOM) published a report on resident work hours and work schedules to improve patient safety that recommended a protected sleep period of 5 hours during any work shift longer than 16 hours to reduce the risk of fatigue-related errors when residents are in the hospital for prolonged duty periods of up to 30 hours. “The IOM report acknowledged that there was a paucity of data on optimizing duty hours for physicians in training but argued that the evidence on the hazards of fatigue-related performance errors in other professions likely extended to medicine,” according to background information in the article.

For the study, two randomized controlled trials were conducted in parallel: one at the Philadelphia Veterans Affairs Medical Center, the other at the Hospital of the University of Pennsylvania (2009-2010). Of the 106 interns and senior medical students who consented, 3 were not scheduled on any study rotations. Among the others, 44 worked at the VA center, 16 at the university hospital, and 43 at both. Twelve 4-week blocks were randomly assigned to either a standard intern schedule (extended duty overnight shifts of up to 30 hours; equivalent to 1,200 overnight intern shifts at each site), or a protected sleep period (protected time from 12:30 a.m. to 5:30 a.m. with handover of work cell phone; equivalent to 1,200 overnight intern shifts at each site). Participants were asked to wear wrist actigraphs (monitors changes in physical activity) and complete sleep diaries.

The researchers found that at the VA center, participants with protected sleep had an average 2.86 hours of sleep vs. 1.98 hours among those who did not have protected hours of sleep. At the university hospital, participants with protected sleep had an average 3.04 hours of sleep compared to 2.04 hours among those who did not have protected sleep. Participants with protected sleep were significantly less likely to have call nights with no sleep: 5.8 percent vs. 18.6 percent at the VA center and 5.9 percent vs. 14.2 percent at the university hospital. As gauged by a sleepiness scale, participants felt less sleepy after on-call nights in the intervention group.

“Although there is evidence that obtaining sleep (relative to no sleep) during prolonged duty helps reduce fatigue and that the amount of fatigue reduction increases with the amount of sleep, from this study we do not have evidence that this is also associated with improvements in patient outcomes. A rigorous comparative effectiveness analysis of protected sleep times vs. 16-hour shifts in improving intern alertness and cognitive function and patient outcomes could have a significant effect on policy. To the extent that protected sleep periods are feasible and improve alertness, they may provide a reasonable alternative to mandated shorter shifts,” the authors conclude.

(JAMA. 2012;308[21]:2208-2217. Available pre-embargo to the media at https://media.jamanetwork.com)

Please Note: For this study, there will be multimedia content available, 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, December 4 at this link.

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Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact Brian P. Lucas, M.D., M.S., call Nancy Di Fiore at 312-942-5159 or email Nancy_DiFiore@rush.edu.

Brian P. Lucas, M.D., M.S., of the Cook County Health and Hospitals System and Rush Medical College, Chicago, and colleagues conducted a study to compare the effects of 2- vs. 4-week inpatient attending physician rotations on unplanned patient revisits (a measure to assess the effect on patients), attending evaluations by trainees, and attending propensity for burnout.

“Trainees learn inpatient medicine on the job, providing clinical care to patients as members of ward teams led by attending physicians. Although the structures of these ward teams vary by local educational heritage and hospital policy, a prevailing trait is that attending physicians are assigned to them for only 2 continuous weeks—a duration that is half of the previous standard,” according to background information in the article. Data are sparse on the effect of varying the duration of rotations.

The study included 62 attending physicians who staffed at least 6 weeks of inpatient service (8,892 patients whom they discharged), and the 147 house staff and 229 medical students who evaluated their performance. Participants were assigned to random sequences of 2- and 4-week rotations at a university-affiliated teaching hospital in academic year 2009.

Among the 8,892 patients, there were 2,437 unplanned revisits. The percentage of 30-day unplanned revisits for patients of attending physicians on 2-week rotations was 21.2 percent compared with 21.5 percent for 4-week rotations. Average length of hospital stay was not significantly different for the rotations. “Attending physicians were more likely to score lower in their ability to evaluate trainees after 2- vs. 4-week rotations by both house staff and medical students. They were less likely to report higher scores of both burnout severity (16 percent vs. 35 percent) and emotional exhaustion (19 percent vs. 37 percent) after 2- vs. 4-week rotations,” the authors write.

(JAMA. 2012;308[21]:2199-2207. Available pre-embargo to the media at https://media.jamanetwork.com)

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 4, 2012

Media Advisory: To contact Colin P. West, M.D., Ph.D., call Alyson Fleming at 507-284-5005 or email newsbureau@mayo.edu.

Colin P. West, M.D., Ph.D., and Denise M. Dupras, M.D., Ph.D., of Mayo Clinic, Rochester, Minn., conducted a study to evaluate career plans of internal medicine residents.

“General internists provide comprehensive and coordinated care for both acute and chronic diseases. General internists are expected to play an increasingly critical role in health care provision as the population ages, the burden of chronic disease grows, and health care reform targets coverage of tens of millions of currently uninsured patients,” according to background information in the article. “Current medical training models in the United States are unlikely to produce sufficient numbers of general internists and primary care physicians. Differences in general internal medicine (GIM) career plans between internal medicine residency program types and across resident demographics are not well understood.”

The researchers used an annual survey linked to the Internal Medicine In-Training Examination taken in October of 2009-2011 to evaluate career plans by training program, sex, and medical school location. Of 67,207 U.S. eligible categorical and primary care internal medicine residents, 57,087 (84.9 percent) completed and returned the survey. Demographic data provided by the National Board of Medical Examiners were available for 52,035 (77.4 percent) of these residents, of whom 51,390 (76.5 percent) responded to all survey items and an additional 645 (1.0 percent) responded to at least 1 survey item. Data were analyzed from the 16,781 third-year residents (32.2 percent) in this sample.

The authors found that a GIM career plan was reported by 3,605 graduating residents (21.5 percent). A total of 562 primary care program (39.6 percent) and 3,043 categorical (19.9 percent) residents reported GIM as their ultimate career plan. “Conversely, 10,008 categorical (65.3 percent) and 745 primary care program (52.5 percent) residents reported a subspecialty career plan. GIM career plans were reported more frequently by women than men. U.S. medical graduates were slightly more likely to report GIM career plans than international medical graduates. Within primary care programs, U.S. medical graduates were much more likely to report GIM career plans than international medical graduates.”

“This study of a large national sample of internal medicine residents confirms that general medicine remains a less common career plan overall than subspecialty medicine. Combined with the fact that only a small minority of medical students express interest in general medicine and primary care careers, the small number of internal medicine residents reporting plans for generalist careers means a very limited number of generalists can be expected to enter practice each year.”

(JAMA. 2012;308[21]:2241-2247. 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.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 27, 2012

Earnings of U.S. Physicians Grow Less Than Other Health Professionals  

“Understanding trends in physician earnings is important given health care cost growth and proposed Medicare physician fee reductions,” writes Seth A. Seabury, Ph.D., of the RAND Corporation, Santa Monica, Calif., and colleagues. National surveys find that annual physician incomes decreased between 1995 and 2003. Other surveys suggest that physician incomes increased only slightly since 2004. “However, little is known about how growth in physician earnings compares with other health professionals. Comparing physicians and other health professionals is necessary to assess whether physician labor earnings have outpaced or lagged behind earnings growth of other workers in the health care sector.”

As reported in a Research Letter, the authors estimated annual earnings and hourly wages of physicians and other health professionals from the Current Population Survey (CPS), a nationally representative monthly survey of approximately 60,000 households, and examined growth rates from 1987-1990 to 1996-2000 and from 1996-2000 to 2006-2010. This sample included 30,556 respondents across all years who reported working as health professionals, including 6,258 physicians (20.5 percent).

The researchers found that physician earnings fluctuated over the study period. During 1987-1990, median (midpoint) earnings for physicians were $143,963 compared with $157,751 during 2006-2010 ($13,788 increase or growth of 9.6 percent). Other health professionals experienced larger growth in earnings from 1987-1990 to 2006-2010 (e.g., pharmacists earnings increased by $30,938 or 44.0 percent). From 1996-2000 to 2006-2010, there was no significant growth in adjusted earnings for physicians (-1.6 percent). Adjusted earnings continued to increase for other health professionals from 1996-2000 to 2006-2010 (e.g., pharmacists, 34.4 percent). Similar patterns were noted for wages.

“Despite attention paid to higher earnings of physicians in the United States compared with other countries, physician earnings grew less than those of other health professionals in the last 15 years. Possible explanations include managed care growth, Medicaid payment cuts, sluggish Medicare payment growth, or bargaining by insurance companies. Despite lack of recent growth, physician earnings remain higher than other occupations.”

(JAMA. 2012;308[20]:2083-2085. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Medical Documentation in the Electronic Era

C. Jason Wang, M.D., Ph.D., of Stanford University, Stanford, Calif., examines the challenges presented by the implementation and use of electronic health records for patient-centered care.

“The current era of electronic communication has both benefits and perils. Electronic health records can serve as a platform with personal health records for coordinated patient-centered care by allowing clinicians to communicate quickly with one another and providing patients critical information about their own health. To fully realize these benefits, ‘search’ and ‘retrieval’ mechanisms must be supported by simple, unambiguous, standardized language. Electronic health records also must include mechanisms to promote synthesis of clinical data to avoid information overload. However, by relying on the GPS (global positioning system) mentality that ‘the computer will help me find it,’ clinicians will gradually be relegated to technicians.”

(JAMA. 2012;308[20]:2091-2092. Available pre-embargo to the media at https://media.jamanetwork.com)

Toward a Harmonized and Centralized Conflict of Interest Disclosure – Progress From an IOM Initiative

In this Viewpoint, Allen S. Lichter, M.D., of the American Society of Clinical Oncology, Alexandria, Va., and Ross McKinney, M.D., of Duke University School of Medicine, Durham, N.C., discuss the need and development of a “harmonized, centralized [conflict of interest] disclosure system to be created for the benefit of everyone who must produce or receive disclosure information.”

“Such a system can be designed and implemented as one element in a process to help ensure that research can progress in a trusted, transparent fashion, thereby increasing trust among the public and health care professionals in new medical products that are brought to the benefit of patients.”

(JAMA. 2012;308[20]:2093-2094. 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, NOVEMBER 27, 2012

Media Advisory: To contact Charlotte Merie, M.D., email c.merie@mail.dk. To contact editorial co-author Shamir R. Mehta, M.D., M.Sc., call Veronica McGuire at 905-525-9140, ext. 22169, or email vmcguir@mcmaster.ca.

CHICAGO – Although current guidelines recommend 3 months of anticoagulation treatment after bioprosthetic aortic valve replacement surgery, a study that included more than 4,000 patients found that patients who had warfarin therapy continued between 3 and 6 months after surgery had a lower rate of cardiovascular death, according to a study in the November 28 issue of JAMA.

“Biological prostheses are preferred to mechanical valves for aortic valve replacement (AVR) surgery in elderly patients older than 65 years because of shorter life expectancy and lack of a need to use anticoagulation treatment in the long-term. Especially in these patients, the tradeoff between thromboembolic complications due to the valve implant and bleeding events as adverse effects from anticoagulation therapy must be balanced. Nevertheless, appropriate duration of anticoagulation treatment postoperatively is yet to be established because the risk of complications when the treatment is discontinued is unknown,” according to background information in the article. The current recommendation of 3 months of warfarin treatment after bioprosthetic AVR surgery is primarily based on results from 1 retrospective study with a limited number of events.

Charlotte Merie, M.D., of the Copenhagen University Hospital Gentofte, Copenhagen, Denmark and colleagues investigated whether discontinuation of warfarin treatment within prespecified periods after bioprosthetic AVR surgery was associated with increased risk of thromboembolic complications, cardiovascular death, and bleeding incidents. Through a search in the Danish National Patient Registry, 4,075 patients were identified who had bioprosthetic AVR surgery performed between January 1997 and December 2009. The researchers determined the incidence rate ratios (IRRs) of strokes, thromboembolic events, cardiovascular deaths, and bleeding incidents by discontinuing warfarin as opposed to continued treatment at 30 to 89 days, 90 to 179 days, 180 to 364 days, 365 to 729 days, and at least 730 days after surgery. Average age of the patients was 75 years; 41 percent were women.

Overall, 361 patients (8.9 percent) experienced a stroke, 615 (15.1 percent) had a thromboembolic event, and 364 (8.9 percent) encountered a bleeding incident after the date of surgery. During the observation period, 1,156 patients (28.4 percent) died, with 879 (76.0 percent) of these deaths related to cardiovascular disease. The IRRs for patients not treated with warfarin compared with those treated with warfarin were 2.46 for stroke; 2.93 for thromboembolic events; 2.32 for bleeding incidents; and 7.61for cardiovascular deaths within 30 to 89 days after surgery; and 3.51 for cardiovascular deaths within 90 to 179 days after surgery.

“Our study demonstrates that discontinuing warfarin therapy within the first 3 months after surgery is associated with a significant increase in the risk of stroke, thromboembolic complications, and cardiovascular death. The novelty of our study is the finding that discontinuing warfarin therapy within 90 to 179 days after surgery is associated with a significant increase in the risk of cardiovascular death,” the authors write.

“International guidelines on anticoagulation after a bioprosthetic AVR have been written with limited data on the appropriate duration of warfarin treatment after surgery. Consequently, our study challenges current guidelines on the duration of antithrombotic treatment after AVR surgery with biological valves by presenting results suggesting that these patients will gain from an additional 3 months of warfarin treatment in terms of reduced cardiovascular death without risking a significant increase in bleeding events.”

(JAMA. 2012;308(20):2097-2107; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by the Research Fund of the Department of Cardiology at Copenhagen University Hospital Gentofte, Gentofte, Denmark. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Warfarin After Bioprosthetic Aortic Valve Implantation

Shamir R. Mehta, M.D., M.Sc., and Jeffrey I. Weitz, M.D., of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, comment on the findings of this study in an accompanying editorial.

“Will the results of this study change practice in patients undergoing bioprosthetic aortic valve replacement? Should all of these patients receive warfarin for 3 months, or even for 6 months, as the authors suggest? Although there are limitations to this study, the answer to both of these questions is yes. This study shows that the rates of stroke and thromboembolic events in the first 6 months after bioprosthetic aortic valve replacement are substantial among patients not treated with warfarin. Use of warfarin was associated with a reduction in this risk and a reduction in cardiovascular mortality; these benefits are difficult to ignore.”

(JAMA. 2012;308(20):2147-2148; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Mehta reported serving as a consultant for AstraZeneca, Eli Lilly, and Sanofi. Dr. Weitz reported serving as a consultant for Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 27, 2012

Media Advisory: To contact Lara K. Misegades, Ph.D., M.S., call Alison Patti at 404-639-3286 or email APatti@cdc.gov. To contact editorial co-author Eugene D. Shapiro, M.D., call Karen Peart at 203-432-1326 or email karen.peart@yale.edu.

CHICAGO – In an examination of cases of childhood pertussis in California, researchers found that children with pertussis had lower odds of having received all 5 doses of the diphtheria, tetanus, and acellular pertussis vaccine (DTaP) vaccine series; however the odds increased as the time since last DTaP dose lengthened, which is consistent with a progressive decrease in estimated vaccine effectiveness each year after the final dose of DTaP vaccine, according to a study in the November 28 issue of JAMA.

“Pertussis remains a poorly controlled vaccine-preventable disease in the United States, despite a well-established childhood vaccination program and high coverage. Although infants have substantially higher rates of pertussis compared with other age groups, data from the National Notifiable Diseases Surveillance System reflect a recent increase in the number of reported pertussis cases among children aged 7 to 10 years,” according to background information in the article. “Recent studies have demonstrated waning protection following the current 5-dose DTaP schedule, but no study, to our knowledge, has compared fully vaccinated with unvaccinated children to estimate the durability of protection afforded by the childhood series.”

Lara K. Misegades, Ph.D., M.S., of the Centers for Disease Control and Prevention, Atlanta, and colleagues conducted a study to evaluate the association between pertussis and receipt of 5 DTaP doses by time since the fifth DTaP dose in 15 California counties. Cases (n = 682) were all suspected, probable, and confirmed pertussis cases among children ages 4 to 10 years reported from January through December 14, 2010; controls (n = 2,016) were children in the same age group who received care from the clinicians reporting the cases. Three controls were selected per case. Vaccination histories were obtained from medical records and immunization registries.

Cases were more likely than controls to be unvaccinated (7.8 percent vs. 0.9 percent), female and older (the median [midpoint] ages of cases and controls were 9 and 7 years, respectively). Compared with controls, children with pertussis had a 89 percent lower odds of having received all 5 doses of DTaP. When children were categorized by time since completion of the series, using an unvaccinated reference group, children with pertussis compared with controls were less likely to have received their fifth dose within the prior 12 months (19 [2.8 percent] vs. 354 [17.6 percent]; estimated vaccine effectiveness [VE], 98.1 percent). This association was evident with longer time since vaccination, with odds ratios increasing with time since the fifth dose. At 60 months or longer (range, 60-83 months; n = 231 cases [33.9 percent] and n = 288 controls [14.3 percent]), the estimated VE was 71.2 percent. The estimated relative decline in VE was 27.4 percent from less than 12 months to 60 months or longer since fifth DTaP dose. Accordingly, the estimated VE declined each year after receipt of the fifth dose of DTaP.

“The increasing incidence of pertussis, changing epidemiology, and demonstrated decline in the estimated DTaP VE over time have raised concerns about the current U.S. pertussis vaccine program and may prompt consideration of alternative schedules,” the authors write. “Ultimately, improved control of pertussis may require a vaccine that provides longer duration of protection or differently affects transmission in the community.”

(JAMA. 2012;308(20):2126-2132; 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.

Please Note: For this study, there will be multimedia content available, 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, November 27 at this link.

Editorial: Acellular Vaccines and Resurgence of Pertussis

“Strategies to use the current vaccines to provide optimal benefit need to be implemented,” writes Eugene D. Shapiro, M.D., of the Yale University School of Medicine and Yale Graduate School of Arts and Sciences, New Haven, Conn., in an accompanying editorial.

“The most important consideration is to try to protect infants, who have the most morbidity and mortality from pertussis. The highest rates both of hospitalizations for and of deaths from pertussis occur in children younger than 2 months. Immunization of all pregnant women and of all household and day-care contacts (both adults and children) of children younger than 1 year is one important strategy that may help alleviate this problem. Public health authorities will need to assess the feasibility and safety of different schedules for administering currently available vaccines, including the possibility of shorter periods between primary and booster doses (more frequent administration of tetanus toxoid may be associated with more severe local adverse reactions).”

(JAMA. 2012;308(20):2149-2150; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This publication was made possible in part by support from CTSA grants from the National Center for Research Resources and the National Center for Advancing Translational Science, components of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 27, 2012

Media Advisory: To contact Adrian F. Hernandez, M.D., M.H.S., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu. To contact Lars H. Lund, M.D., Ph.D., email lars.lund@alumni.duke.edu. To contact editorial author James C. Fang, M.D., call Mike Ferrari at 216-844-7239 or email Mike.Ferrari@uhhospitals.org.

CHICAGO – An analysis of two heart failure therapies finds differing outcomes regarding improvement in survival, according to two studies appearing in the November 28 issue of JAMA.

In one study, Adrian F. Hernandez, M.D., M.H.S., of the Duke Clinical Research Institute, Durham, N.C., and colleagues examined the clinical effectiveness of aldosterone antagonist therapy and associations with long-term outcomes of older patients discharged from a hospitalization for heart failure.

“Aldosterone antagonist therapy [a diuretic drug] for heart failure and reduced ejection fraction [a measure of how well the left ventricle of the heart pumps with each contraction] has been highly efficacious in randomized trials. However, questions remain regarding the effectiveness and safety of the therapy in clinical practice,” according to background information in the article.

The researchers examined outcomes of eligible patients hospitalized with heart failure and reduced ejection fraction using clinical registry data linked to Medicare claims from 2005 through 2010. The primary outcomes measured for the study were all-cause mortality, cardiovascular readmission, and heart failure readmission at 3 years, and readmission associated with hyperkalemia (higher than normal levels of potassium in the circulating blood) at 30 days and 1 year.

Of the 5,887 patients (average age, 78 years) who met the inclusion criteria from 246 hospitals, 1,070 (18.2 percent) received a prescription for an aldosterone antagonist at hospital discharge. The researchers found that rates of all-cause mortality (49.9 percent vs. 51.2 percent) and cardiovascular readmission (63.8 percent vs. 63.9 percent) were similar between the treatment groups at 3 years. The cumulative incidence rates of arrhythmia (5.4 percent vs. 3.9 percent) and elective readmission for an arrhythmia control device (6.5 percent vs. 4.2 percent) were higher for the treated group. Analysis of the data indicated that there were no significant differences in mortality and cardiovascular readmission.

The authors also found that the cumulative incidence of the first heart failure readmission was significantly lower in the treated group (38.7 percent vs. 44.9 percent). The hyperkalemia readmission rates at 30 days (2.9 percent vs. 1.2 percent) and 1 year (8.9 percent vs. 6.3 percent) were higher in the treated group; however, hyperkalemia was seldom the primary diagnosis for these readmissions, and the absolute increase in hyperkalemia as a primary diagnosis was small.

The authors add that a potential explanation for their findings is that aldosterone antagonists have limited effectiveness regarding mortality in real-world settings among older patients. “One potential reason for limited effectiveness may be a lack of adherence to or persistence with therapy. … Our findings highlight the importance of conducting clinical trials that can be easily generalized to real-world practice and in which the most vulnerable patient groups are well represented.”

(JAMA. 2012;308(20):2097-2107; 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.

Use of ACE Inhibitors, ARB’s, Associated With Improved Survival Among Certain Patients With Heart Failure

In another study, Lars H. Lund, M.D., Ph.D., of the Karolinska Institutet, Stockholm, Sweden, and colleagues conducted a study to examine whether renin-angiotensin system (RAS) antagonists (i.e., angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs] are associated with reduced mortality in heart failure patients with preserved ejection fraction.

“Up to half of patients with heart failure have normal or near-normal ejection fraction, termed heart failure with preserved ejection fraction (HFPEF) or diastolic heart failure. The mortality in HFPEF may be as high as in heart failure with reduced ejection fraction (HFREF) or systolic heart failure, but there is no proven therapy,” according to background information in the article.

The study included 41,791 patients in the Swedish Heart Failure Registry, from 64 hospitals and 84 outpatient clinics between 2000 and 2011. Of these, 16,216 patients with HFPEF (ejection fraction of 40 percent or greater; average age, 75 years; 46 percent women) were either treated (n = 12,543) or not treated (n = 3,673) with RAS antagonists. Analyses was conducted of the data to determine the association between use of RAS antagonists and all-cause mortality, with use of a matched cohort. The researchers included 20,111 patients with ejection fraction of less than 40 percent for the HFREF consistency analysis.

In the overall HFPEF group, crude 1-year survival was 86 percent for patients receiving RAS antagonists vs. 69 percent for patients not receiving RAS antagonists; and 5-year survival was 55 percent vs. 32 percent, respectively. In the matched HFPEF cohort, 1-year survival was 77 percent for treated patients vs. 72 percent for untreated patients. Five-year survival was 36 percent vs. 34 percent, respectively.

“There is currently no consensus on the use of RAS antagonists in patients with HFPEF. In our study, use of RAS antagonists was associated with reduced all-cause mortality in a broad unselected population of patients with HFPEF. Our results together with the signal toward benefit in randomized controlled trials suggest that RAS antagonists may be beneficial in patients with HFPEF, but this should be confirmed in an appropriately powered randomized trial,” the authors conclude.

(JAMA. 2012;308(20):2108-2117; 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: Heart Failure Therapy – What Should Clinicians Believe?

In an accompanying editorial, James C. Fang, M.D., of University Hospitals Case Medical Center, Cleveland, examines the question of what physicians should conclude from these 2 observational studies that would appear to contradict the clinical trial evidence.

“If all of the evidence is carefully considered in its totality, it would be sound to conclude that (1) renin-angiotensin system antagonists are reasonable agents to control hypertension in heart failure with preserved ejection fraction, and (2) aldosterone antagonists are effective drugs in heart failure with reduced ejection fraction but should be used carefully and selectively. Although clinical trials should remain the gold standard for testing hypotheses, observational studies bridge the gap from the scientific rigor of clinical trials to real-world experience. Clinical trials are a reminder of the rigor of medicine as a science; observational studies are a reminder that medicine is still an art.”

(JAMA. 2012;308(20):2144-2146; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 20, 2012

Study Finds That Older Persons With Positive Age Stereotypes More Likely to Recover From Severe Disability

“Little research has been conducted on factors that account for why some older persons recover from disability and others do not. We considered a new culture-based explanatory factor: age stereotypes (defined as beliefs about old people as a category),” writes Becca R. Levy, Ph.D., of the Yale School of Public Health, New Haven, Conn., and colleagues. “Positive age stereotypes may promote recovery from disability through several pathways: limiting cardiovascular response to stress, improving physical balance, enhancing self-efficacy, and increasing engagement in healthy behaviors.” The researchers hypothesized that older persons with positive age stereotypes would be more likely to recover from disability than those with negative age stereotypes. Recovery was based on 4 essential activities of daily living (ADLs; bathing, dressing, transferring, and walking) that are strongly associated with use of health care services and longevity.

As reported in a Research Letter, the study participants were interviewed monthly for up to about 11 years, and completed home-based assessments every 18 months from March 1998 through December 2008. Participants were age of 70 years or older, community-living, nondisabled (i.e., independent in the 4 ADLs at the beginning of the study), responded to the baseline age-stereotype measure, and experienced at least 1 month of ADL disability during follow-up (117 participants remained nondisabled). The final sample consisted of 598 participants. Age stereotypes were assessed by asking, “When you think of old persons, what are the first 5 words or phrases that come to mind?” Responses (coded on a 5-item scale ranging from 1 = most negative [e.g., decrepit] to 5 = most positive [e.g., spry]) were averaged.

The researchers found that older persons with positive age stereotypes were 44 percent more likely to fully recover from severe disability than those with negative age stereotypes. The positive age-stereotype group showed an advantage in the associated absolute risk increase percentages and also had a significantly slower rate of ADL decline. “Further research is needed to determine whether interventions to promote positive age stereotypes could extend independent living in later life.”

(JAMA. 2012;308[19]:1972-1973. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Mentoring Translational Science Investigators

Michael Fleming, M.D., M.P.H., of the Northwestern University Feinberg School of Medicine, Chicago, and colleagues write that a primary mission of the National Institutes of Health is to train the next generation of clinical/translational scientists. In this Viewpoint, the authors summarize the findings and recommendations of a 4-year effort by the Mentor Working Group, which was established to develop a series of white papers and recommendations on the various programmatic elements of a comprehensive mentoring program.

“Effective mentoring is broadly recognized as an essential element of research training. However, given the paucity of empirical evidence for what works to enhance research mentoring, and the substantial investment required to train a new clinical/translational investigator, a research agenda and funding mechanisms for research are needed to strengthen the evidence base for effective mentoring practices and programs.”

(JAMA. 2012;308[19]:1981-1982. 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, NOVEMBER 20, 2012

Media Advisory: To contact Ross D. Zafonte, D.O., call Tim Sullivan at 617-573-2918 or email tsullivan11@partners.org. To contact editorial co-author Robert L. Ruff, M.D., Ph.D., call Jessica Studeny at 216-368-4692 or email jessica.studeny@case.edu.

CHICAGO – Although approved for use for treating traumatic brain injury (TBI) in nearly 60 countries, use of citicoline in a randomized trial that included more than 1,200 participants with TBI did not result in improvement in functional and cognitive status, according to a study appearing in the November 21 issue of JAMA.

“Despite considerable advances in emergency and critical care management of TBI as well as decades of research on potential agents for neuroprotection or enhanced recovery, no effective pharmacotherapy has yet been identified,” according to background information in the article. Citicoline, an endogenous (produced within the body) compound, offers potential neuroprotective properties as well as neurorepair post injury. Citicoline is widely available in the United States as a nutraceutical (product that reportedly provides health and medical benefits) and is used by patients with a range of neurologic disorders, yet it has not been evaluated in a large randomized clinical trial for TBI.

Ross D. Zafonte, D.O., of Harvard Medical School, Spaulding Rehabilitation and Massachusetts General Hospital, Boston, and colleagues conducted a study to evaluate the efficacy of citicoline for improving cognitive and functional status among patients with TBI. The Citicoline Brain Injury Treatment Trial (COBRIT), a phase 3, randomized clinical trial, was conducted between July 2007 and February 2011. The study, which included 1,213 patients at 8 U.S. level 1 trauma centers, examined the effects of 90 days of enteral or oral citicoline (2,000 mg) vs. placebo initiated within 24 hours of injury in patients with complicated mild, moderate, and severe TBI.

The researchers found that the citicoline and placebo groups did not differ significantly at the 90-day evaluation on measures of cognitive and functional status. “Rates of favorable improvement for the Glasgow Outcome Scale-Extended were 35.4 percent in the citicoline group and 35.6 percent in the placebo group. For all other scales the rate of improvement ranged from 37.3 percent to 86.5 percent in the citicoline group and from 42.7 percent to 84.0 percent in the placebo group.”

There was no significant treatment effect in the two severity subgroups (moderate/severe and complicated mild TBI). In patients with moderate/severe TBI, no statistically significant difference was observed between treatment groups at the 180-day evaluation.

The overall proportion of patients reporting serious adverse events was similar between the placebo and citicoline groups.

“The COBRIT study indicates that citicoline was not superior to placebo as an acute and postacute therapy among participants with a broad range of severity of TBI. The worldwide use of citicoline for TBI should now be questioned.”

(JAMA. 2012;308(19):1993-2000; 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: Effective Treatment of Traumatic Brain Injury – Learning From Experience

In an accompanying editorial, Robert L. Ruff, M.D., Ph.D., and Ronald G. Riechers II, M.D., of the Cleveland VA Medical Center, and Case Western Reserve University (Dr. Ruff), write that the primary importance reported by this trial “is that it conclusively demonstrated the lack of efficacy of citicoline monotherapy for TBI.”

“It is unlikely that this finding can be accounted for by limitations in the study design or conduct. The broader implication of the COBRIT study may be that no single therapeutic agent is likely to be sufficient to improve functional outcomes for patients with TBI. The diverse and complex nature of the pathological mechanisms activated by TBI suggests that multimodal treatment interventions may be needed to improve recovery. Future studies of TBI treatment should be designed to incorporate multiple treatment interventions and comprehensive TBI rehabilitation strategies, either as components of the intervention or standardized across study treatment groups.”

(JAMA. 2012;308(19):2032-2033; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 20, 2012

Media Advisory: To contact Ted E. Palen, M.D., Ph.D., M.S.P.H., call Amy Whited at 303-344-7518 or email Amy.L.Whited@kp.org. To contact editorial co-author David W. Bates, M.D., M.Sc., call Lori Schroth at 617-534-1604 or email Ljshanks@partners.org.

CHICAGO – Patients with online access to their medical records and secure e-mail communication with clinicians had increased use of clinical services, including office visits and telephone encounters, compared to patients who did not have online access, according to a study appearing in the November 21 issue of JAMA.

“Using health information technology to foster efficient health care delivery is an important component of health care reform,” according to background information in the article. “Prior studies suggest that providing patients with online access to health records and e-mail communication with physicians may substitute for traditional health care services.” The presumption is if patients could look up health information online such as their test results, request prescription refills, schedule appointments, or send secure e-mail to clinicians, their use of clinical in-person and telephone calls may decrease. “Many previous studies involved small numbers of patients and were conducted early in the implementation of patient online access.”

Ted E. Palen, M.D., Ph.D., M.S.P.H., of the Institute for Health Research, Kaiser Permanente Colorado, Denver, and colleagues investigated the association between patient online access and use of clinical services. The study examined the use of health care services by group members (18 years of age or older) who were continuously enrolled for at least 24 months during the study period March 2005 through June 2010 in Kaiser Permanente Colorado, a group model, integrated health care delivery system. Utilization rates were calculated for both users and nonusers of My Health Manager (MHM), a patient online access system. Member use of online access steadily increased from about 25 percent at the end of 2007 to 54 percent by June 2009 (n = 375,620). More than 45 percent of members with MHM access used at least 1 MHM function. The refined groups each contained 44,321 matched members.

The researchers found that when they compared the use of clinical services before and after the index date between MHM users and nonusers, they saw a significant increase in the per-member rates of office visits (0.7 per member per year) and telephone encounters (0.3 per member per year). “There was also a significant increase in per-1,000-member rates of after-hours clinic visits (18.7 per 1,000 members per year), emergency department encounters (11.2 per 1,000 members per year), and hospitalizations (19.9 per 1,000 members per year) for MHM users compared with nonusers. This utilization pattern was seen for members both younger and older than 50 years.” More variability was found in rates of utilization by MHM users with chronic illnesses.

The authors suggest several possible explanations for these findings. “Online access to care may have led to an increase in use of in-person services because of additional health concerns identified through online access. Members might have activated their online access in anticipation of health needs. Members who are already more likely to use services may selectively sign up for online access and then use this technology to gain even more frequent access rather than view it as a substitute for contact with the health care system.”

“If these findings are evident in other systems, health care delivery planners and administrators will need to consider how to allocate resources to deal with increased use of clinical services. As online applications become more widespread, health care delivery systems will need to develop methodologies that effectively integrate health information technologies with in-person care.”

(JAMA. 2012;308(19):2012-2019; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by the Kaiser Permanente Colorado Regional Initiative Committee Fund. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Palen is employed by the Colorado Permanente Medical Group. Ms. Ross, Mr. Powers, and Dr. Xu are all employees of the Kaiser Permanente Health Plan of Colorado. No other disclosures were repotted.

Please Note: For this study, there will be multimedia content available, 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, November 20 at this link.

Editorial: Personal Health Records and Health Care Utilization

David W. Bates, M.D., M.Sc., and Susan Wells, M.B. Ch.B., of Brigham and Women’s Hospital, Boston, write in an accompanying editorial that these findings may be disappointing for patient portal enthusiasts, but should not discourage organizations from increasing the use of electronic health portals by patients.

“Personal health records (PHR) are here to stay, and the tethered architecture appears to offer the most benefits. The data on utilization are uncertain and PHRs may not decrease health care utilization. However, electronic access to PHRs represents an extremely powerful tool from a variety of perspectives and can help empower and engage patients. More data on how to use them and on what specific modules and applications will be beneficial are clearly needed.”

(JAMA. 2012;308(19):2034-2036; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Both authors completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Wells reported receiving the 2012/13 Harkness Fellowship in Health Policy and Practice from The Commonwealth Fund. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 13, 2012

Study Examines Brain White Matter Changes in Soccer Players

“Soccer is the most popular sport in the world, with more than 250 million active players. It is the only sport in which the unprotected head is a primary point of contact when heading the ball. In other contact sports, the deleterious [harmful] long-term effects of repetitive traumatic brain injury (TBI), such as impaired white matter integrity, are well recognized. However, whether frequent subconcussive blows to the head lead to TBI remains controversial, although evidence suggests impaired neuropsychological function in soccer players,” writes Inga K. Koerte, M.D., of Harvard Medical School, Boston, and colleagues. The researchers evaluated soccer players who had not experienced a concussion using high-resolution diffusion tensor imaging (DTI), which is highly sensitive for detecting alterations in the integrity of white matter.

As reported in a Research Letter, the study included 12 male soccer players from 2 training groups of an elite-level soccer club in Germany. A comparison group of 11 swimmers, who participate in a sport with low exposure to repetitive brain trauma, were recruited from competitive clubs. The researchers found differences in white matter integrity of the soccer players compared with the swimmers. “Although only participants without previous symptomatic concussion were included, advanced DTI revealed widespread increase in radial diffusivity [a certain pattern seen on magnetic resonance imaging suggesting alterations in white matter architecture] in soccer players, consistent with findings observed in patients with mild TBI, and suggesting possible demyelination [nerve disorder],” they write. “The etiology of the findings, however, is not clear. One explanation maybe the effect of frequent subconcussive brain trauma, although differences in head injury rates, sudden accelerations, or even lifestyle could contribute.” The authors add that future studies are needed to confirm the results and elucidate the cause and effects of white matter alterations in soccer players.

(JAMA. 2012;308[18]:1859-1861. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Inga K. Koerte, M.D., call Lori Schroth at 617-534-1604 or email ljschroth@partners.org.

Viewpoints in This Week’s JAMA

Prevention of Fatal Opioid Overdose

Leo Beletsky, J.D., M.P.H., of the Northeastern University School of Law and Bouve College of Health Sciences, Boston, and colleagues suggest various steps to support a more comprehensive approach to reducing opioid overdose deaths in the U.S., which account for at least 16,000 deaths annually. “To date, federal government response has focused primarily on monitoring and securing the drug supply.”

“Federal agencies are uniquely situated to address national public health crises through increasing awareness, funding, and coordinated action. Community-based organizations, state and local health departments, and professional societies have taken the lead in developing, implementing, and publicizing overdose education and naloxone distribution as a component in a comprehensive response to this veritable epidemic. The federal government should actively support research and programmatic action on overdose education and naloxone access.”

(JAMA. 2012;308[18]:1863-1864. Available pre-embargo to the media at https://media.jamanetwork.com)

Rethinking Opioid Prescribing to Protect Patient Safety and Public Health

G. Caleb Alexander, M.D., M.S., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues write that “prescription drugs, including amphetamines, opioids, and benzodiazepines, provide therapeutic value to millions of Americans. At the same time, there are increasing concerns about the skyrocketing rates of prescription abuse and overdose deaths.” The annual number of fatal drug overdoses in the United States now surpasses the annual number of motor vehicle deaths, and overdose deaths attributable to prescription opioids exceed those attributable to cocaine and heroin combined.

“Advocates of greater recognition and treatment of chronic pain have argued for a ‘principle of balance,’ stressing the need to balance the judicious availability of opioids with the need to prevent their misuse and abuse. Although prescribing practices vary widely, there is little evidence to suggest that physicians have curtailed their practice of prescribing opioids in response to exponential increases in addiction and overdose deaths. Broader clinical and public health research should examine the comparative effectiveness of different approaches to pain treatment concurrent with assessments that examine the effects and cost-effectiveness of opioid prescribing practices on community health and safety.”

(JAMA. 2012;308[18]:1865-1866. 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, NOVEMBER 13, 2012

Media Advisory: To contact Gregory P. Levin, Ph.D., call Leila Gray at 206-685-0381 or email leilag@u.washington.edu.

CHICAGO – Findings from a study suggest that certain variations in vitamin D metabolism genes may modify the association of low serum 25-hydroxyvitamin D concentrations with health outcomes such as hip fracture, heart attack, cancer, and death, according to a study appearing in the November 14 issue of JAMA.

Vitamin D status is defined by the circulating concentration of 25-hydroxyvitamin D. Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases, prompting ongoing clinical trials to test whether vitamin D supplementation can reduce the risk of disease development. Certain complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D, according to background information in the article.

Gregory P. Levin, Ph.D., of the University of Washington, Seattle, and colleagues conducted a study to investigate whether known relationships between serum 25-hydroxyvitamin D and certain diseases would differ according to common variation in 25-hydroxyvitamin D metabolism genes. The study consisted of an examination of 141 single-nucleotide polymorphisms (SNPs) in a group of 1,514 white participants from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median (midpoint) of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based U.S. Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.

The researchers found a SNP within the vitamin D receptor (VDR) gene that significantly modified associations of low serum 25-hydroxyvitamin D concentration with major health outcomes of hip fracture, heart attack, cancer, and death over long-term follow-up. “Findings were observed within a large community-based study of older adults in the United States and were consistent in magnitude and direction across individual disease outcomes, and replicated in a meta-analysis of 3 large independent cohorts. An additional vitamin D receptor SNP significantly modified the low 25-hydroxyvitamin D-disease association in a meta-analysis that included results from the discovery and replication cohorts. The discovered SNPs, which are common in European populations, identified subsets of individuals for whom associations between low 25-hydroxyvitamin D concentration and disease outcomes were either strongly positive vs. null. These results suggest that individuals with specific 25-hydroxyvitamin D metabolism genotypes maybe particularly susceptible to, or protected from, the potential adverse health effects of low vitamin D.”

The authors add that “these findings represent a first step toward identifying what may be clinically relevant effects of 25-hydroxyvitamin D metabolism genes and may contribute to a better understanding of the biological impact of genetic variation within the vitamin D receptor. Further studies are needed to confirm these observed associations and to enhance knowledge of how variation in vitamin D metabolism genes may stratify individuals as to their susceptibility to vitamin D deficiency. Evaluating the identified interactions in randomized clinical trials of vitamin D supplementation, when available, would help to assess the validity of our results and pave the way toward identifying individual patients who may benefit most from vitamin D interventions.”

(JAMA. 2012;308(18):1898-1905; 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, NOVEMBER 13, 2012

Media Advisory: To contact corresponding author Mark C. Kruit, M.D., Ph.D., email m.c.kruit@lumc.nl. To contact editorial co-author Deborah I. Friedman, M.D., M.P.H., call Jeff Carlton at 214-648-2876 or email Jeffrey.Carlton@utsouthwestern.edu.

CHICAGO – After nearly 10 years of follow-up of study participants who experienced migraines and who had brain lesions indentified via magnetic resonance imaging, women with migraines had a higher prevalence and greater increase of deep white matter hyperintensities (brain lesions) than women without migraines, although the number, frequency, and severity of migraines were not associated with lesion progression, according to a study appearing in the November 14 issue of JAMA. Also, increase in deep white matter hyperintensity volume was not significantly associated with poorer cognitive performance at follow-up.

Migraine affects up to 15 percent of the general population. “A previous cross-sectional study showed an association of migraine with a higher prevalence of magnetic resonance imaging (MRI)-measured ischemic lesions in the brain,” according to background information in the article. White matter hyperintensities are associated with atherosclerotic disease risk factors, increased risk of ischemic stroke, and cognitive decline.

Inge H. Palm-Meinders, M.D., of the Leiden University Medical Center, the Netherlands, and colleagues conducted a study to determine whether women and men with migraine headaches have a higher incidence of brain lesions 9 years after initial MRI, whether migraine frequency was associated with progression of brain lesions, and whether progression of brain lesions was associated with cognitive decline. In a follow-up of the 2000 Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis cohort, which is a population-based observational study of Dutch participants with migraine and an age- and sex-matched control group, 203 of the 295 participants at the beginning of the study in the migraine group and 83 of 140 in the control group underwent MRI scan in 2009 to identify progression of MRI-measured brain lesions. Comparisons were adjusted for age, sex, hypertension, diabetes, and educational level. The participants in the migraine group were an average of 57 years of age, and 71 percent were women. Those in the control group had an average age of 55 years, and 69 percent were women.

The researchers found that of the 145 women in the migraine group, 112 (77 percent) vs. 33 of 55 women (60 percent) in the control group had progression of deep white matter hyperintensities. Among men, no association was found between migraine with progression of MRI-measured brain lesions. Although migraine was associated with a higher prevalence of infratentorial (an area of the brain) hyperintensities at follow-up, there were no significant associations of migraine with progression of infratentorial hyperintensities or posterior circulation territory infarctlike lesions among women.

“In addition, the number of migraines, frequency of migraines, migraine severity, type of migraine, and migraine therapy were not associated with lesion progression,” the authors write. “Increase in deep white matter hyperintensity volume was not significantly associated with poorer cognitive performance at follow-up.”

“In summary, in a community-based cohort followed up for 9 years, migraine was associated only with a higher incidence of deep white matter brain changes among women. There were no significant associations of migraine with progression of other brain lesions among women, and there were no associations of migraine headache with progression of any brain lesions among men. These findings raise questions about the role of migraine headaches with progression of cerebral vascular changes. The functional implications of MRI brain lesions in women with migraine and their possible relation with ischemia and ischemic stroke warrant further research.”

(JAMA. 2012;308(18):1889-1897; 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: White Matter Hyperintensities in Migraine – Reason for Optimism

In an accompanying editorial, Deborah I. Friedman, M.D., M.P.H., of the University of Texas Southwestern Medical Center, Dallas, and David W. Dodick, M.D., of the Mayo Clinic, Scottsdale, Ariz.,  examine the question of how the results of this study can help physicians advise patients with migraine.

“The findings imply that small white matter hyperintensities in most patients with migraine should not be a reason for alarm. However, given the relationship between migraine and several acquired and genetic vasculopathies, it is possible that certain subpopulations of patients with migraine with white matter hyperintensities may be at an increased genetic risk for significant white matter disease and neurological morbidity, including stroke, transient ischemic attack, cognitive impairment, and other neurologic outcomes. Addressing modifiable risk factors for stroke—such as obesity, smoking, hypertension, hypercholesterolemia, and physical inactivity—and avoiding high-dose combined oral contraceptives in women older than 35 years and in those with untreated or poorly controlled vascular risk factors seems prudent. Further research and advances in genetics will provide additional answers.”

(JAMA. 2012;308(18):1920-1921; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 2:45 P.M. (CT) MONDAY, NOVEMBER 12, 2012

Media Advisory: To contact Chun-Ying Wu, M.D., Ph.D., M.P.H., email chun@vghtc.gov.tw. To contact editorial author Anna S. F. Lok, M.D., call Nicole Fawcett at 734-764-2220 or email nfawcett@umich.edu.

CHICAGO – Patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC; liver cancer) who received nucleoside analogues (antiviral therapy) after cancer surgery had an associated lower risk of HCC recurrence compared to patients who did not receive antiviral therapy, according to a study appearing in the November 14 issue of JAMA. The study is being released early online to coincide with its presentation at the annual meeting of the American Association for the Study of Liver Diseases.

“Surgery is considered the standard curative treatment option for HCC. However, the rate of long-term disease-free survival after liver resection remains unsatisfactory due to persistent high incidences of HCC recurrence,” according to background information in the article. “Higher HBV viral load has been reported to be an independent risk factor for HCC recurrence in patients with HBV-related HCC. Nucleoside analogues are effective in suppressing HBV replication and in ameliorating [make better] HBV-related liver disease. They have been shown to be associated with a lower risk of HCC and other cirrhosis-related complications in those with chronic hepatitis and cirrhosis. However, studies on the effectiveness of nucleoside analogue use in HCC recurrence have been relatively limited and have yielded conflicting results.”

Chun-Ying Wu, M.D., Ph.D., M.P.H., of National Yang-Ming University, Taipei, Taiwan, and colleagues conducted a study to examine the association between use of nucleoside analogues and risk of HCC recurrence among patients with HBV-related HCC after curative liver resection. The study included data from the Taiwan National Health Insurance Research Database. Among 100,938 patients newly diagnosed with HCC, the researchers identified 4,569 patients with HBV-related HCC who received curative liver resection for HCC between October 2003 and September 2010. The primary outcome measure for the study was the risk of first tumor recurrence between patients not taking nucleoside analogues (untreated group, n = 4,051) and patients taking nucleoside analogues (treated group, n = 518).

The researchers found that the treated group had a higher prevalence of liver cirrhosis when compared with the untreated group (48.6 percent vs. 38.7 percent), but lower risk of HCC recurrence (n = 106 [20.5 percent] vs. n = 1,765 [43.6 percent]), and lower overall death (n = 55 [10.6 percent] vs. n = 1,145 [28.3 percent]). After adjusting for competing mortality, the risk of HCC recurrence was significantly lower for patients in the treated group (6-year cumulative incidence, 45.6 percent) than for patients in the untreated cohort (54.6 percent). The risk of overall mortality was significantly lower in patients in the treated vs. untreated group (6-year cumulative incidence, 29.0 percent vs. 42.4 percent, respectively).

After analysis, nucleoside analogue use was associated with a 33 percent reduced risk of HCC recurrence; statin use, a 32 percent reduced risk; and nonsteroidal anti-inflammatory drugs or aspirin use a 20 percent reduced risk of HCC recurrence. Further analyses verified the association in all subgroups of patients, including those who were noncirrhotic and diabetic.

“In conclusion, nucleoside analogue use was associated with a lower risk of HCC recurrence among patients with HBV-related HCC after liver resection,” the authors write.

(JAMA. 2012;308(18):1906-1913; 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: Does Antiviral Therapy Prevent Recurrence of Hepatitis B Virus-Related Hepatocellular Carcinoma After Curative Liver Resection?

Anna S. F. Lok, M.D., of the University of Michigan, Ann Arbor, Mich., writes in an accompanying editorial that “the results of this study support findings from multiple smaller studies but are by no means definitive enough to answer the question of whether antiviral therapy after curative resection of hepatitis B-related HCC will prevent disease recurrence.”

“Given the long interval between cell damage, malignant transformation, and tumor development, it is unrealistic to expect that administration of antiviral therapy for 1 to 2 years can prevent HCC recurrence, particularly because early recurrence is likely due to previously undiscovered metastasis from the primary tumor. However, nucleoside/nucleotide analogues may decrease short-term mortality after liver resection, particularly among patients with underlying cirrhosis, high levels of HBV replication, or active hepatic inflammation. For patients who do not experience early HCC recurrence, continued therapy with nucleoside/nucleotide analogues may prevent de novo primary tumors and further progression of liver disease, thereby decreasing late HCC recurrence and long-term mortality.”

(JAMA. 2012;308(18):1922-1924; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Lok has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reports having served as an advisor for Arrowhead, Bayer, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, and Roche; and having received research grants from Bristol-Myers Squibb, Gilead, and GlaxoSmithKline.

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FOR RELEASE: 2 P.M. (CT) MONDAY, NOVEMBER 5, 2012

Jay H. Traverse, M.D., of the Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, and colleagues investigated the influence of timing of cardiovascular cell delivery within the first week after a heart attack on improving left ventricular (LV) function following reperfusion.

“Cell therapy may eventually become a therapeutic option for patients following acute myocardial infarction [AMI; heart attack], potentially preventing the transition to end-stage heart failure where cardiac transplantation is currently the only curative procedure available,” the authors write. “However, despite a growing number of trials, many fundamental questions such as optimal timing of bone marrow mononuclear cell (BMC) delivery remain unanswered.”

Between July 2008 and November 2011, 120 patients were enrolled in the TIME trial, which included patients with LV dysfunction following successful primary percutaneous coronary intervention (PCI; procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries) of anterior ST-segment elevation myocardial infarction (STEMI; a certain pattern on an electrocardiogram following a heart attack). Patients received intracoronary infusion of BMCs or placebo, administered at day 3 or day 7 post-PCI. Patient average age was 57 years; 88 percent were male.

“To our knowledge, TIME is the first cardiovascular cell therapy trial that was specifically designed to determine whether the timing of BMC administration after primary PCI influences LV functional recovery. There was no overall effect of BMC treatment on this ongoing improvement at 6 months vs. placebo despite previous supportive clinical data.  Additionally, the day of cell delivery did not demonstrate an effect on the recovery of LV function or on LV volumes or infarct size [damaged area of heart],” the researchers conclude.

(doi:10.1001/jama. 2012.28726;. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: This study is being released early online to coincide with its presentation at the American Heart Association’s Scientific Sessions. To contact corresponding author Judy Bettencourt, M.P.H., call Deborah Mann Lake at 713-500-3304 or email Deborah.M.Lake@uth.tmc.edu.

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FOR RELEASE: 2 P.M. (CT) MONDAY, NOVEMBER 5, 2012

Joshua M. Hare, M.D., of the University of Miami Miller School of Medicine, and colleagues conducted a study to examine whether allogeneic (taken from a different individual) mesenchymal stem cells (MSCs) are as safe and effective as autologous (donor and recipient are the same person) MSCs in patients with left ventricular dysfunction due to ischemic cardiomyopathy.

“Mesenchymal stem cells are under evaluation as a therapy for ischemic cardiomyopathy (ICM),” according to background information in the article. Both autologous and allogeneic therapies are possible; however, their safety and efficacy have not been compared. “One potential advantage of allogeneic cells is the possibility of their use as an ‘off-the-shelf’ therapeutic agent, avoiding the need for bone marrow aspiration and tissue culture delays before treatment. It is also hypothesized that the function of autologous MSCs could be impaired in patients with comorbidities [other illnesses] or advanced age.”

The randomized study included a comparison of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2010 and September 2011, with 13-month follow-up. Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites.

The researchers found that in this early-stage study of patients with ICM, “transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent serious adverse events, including immunologic reactions” and that, “in aggregate, MSC injection favorably affected patient functional capacity, quality of life and ventricular modeling.”

(doi:10.1001/jama. 2012.25321;. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: This study is being released early online to coincide with its presentation at the American Heart Association’s Scientific Sessions. To contact Joshua M. Hare, M.D., call Lisa Worley at 305-243-5184 or email LWorley2@med.miami.edu.

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EMBARGOED FOR EARLY RELEASE: 12:45 P.M. (CT) MONDAY, NOVEMBER 5, 2012

David Sullivan, M.D., of the Royal Prince Alfred Hospital, Camperdown, Australia, and colleagues conducted a phase 2 study to assess the efficacy and safety of subcutaneous (under the skin) administration of a human monoclonal antibody to the protein PCSK9, (the product is designated AMG145), in patients with a documented history of muscle-related adverse effects with statins. In phase 1 studies, AMG145 was well tolerated and lowered low-density lipoprotein (LDL) cholesterol levels.

The 12-week randomized study was conducted at 33 international sites between July 2011 and May 2012 with statin-intolerant adult patients. AMG145 (of varying doses) or placebo was administered subcutaneously every 4 weeks. Of 236 patients screened, 160 were randomized (average age, 62 years; 64 percent female; average baseline LDL cholesterol, 193 mg/dL). The researchers found that “treatment with AMG145 produced LDL-C reductions of 41 percent to 63 percent, without significant muscle-related side effects, in patients predisposed to such side effects. These reductions are comparable to those achieved with maximal doses of the most efficacious statins.”

(doi:10.1001/jama. 2012.25790;. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: This study is being released early online to coincide with its presentation at the American Heart Association’s Scientific Sessions. To contact corresponding author Evan A. Stein, M.D., Ph.D., call 513-579-8811 or email esteinmrl@aol.com.

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EMBARGOED FOR EARLY RELEASE: 11 A.M. (CT) MONDAY, NOVEMBER 5, 2012

Media Advisory: To contact corresponding author Dariush Mozaffarian, M.D., Dr.P.H., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu. To contact corresponding author Roberto Marchioli, M.D., email marchioli@negrisud.it.
 

CHICAGO – Among patients undergoing cardiac surgery, supplementation with a n-3-polyunsaturated fatty acid (fish oil) before and after surgery did not reduce the risk of postoperative atrial fibrillation, according to a study appearing in JAMA. The study is being released early online to coincide with its presentation at the American Heart Association’s Scientific Sessions.

“Postoperative atrial fibrillation or flutter (AF) occurs in approximately 1 of 3 patients undergoing cardiac surgery, and rates of this complication remain unchanged, even with advances in surgical techniques, anesthetic procedures, and perioperative care,” according to background information in the article. Postoperative AF can cause symptoms requiring escalation of supportive therapies and renal and neurological complications.  The authors note that “new therapies are needed to prevent postoperative AF and its associated morbidity and health care costs.”

“Experimental evidence supports direct and indirect antiarrhythmic effects of long-chain n-3 polyunsaturated fatty acids (n-3-PUFAs) in fish oil, especially in the setting of acute ischemia. Yet effects of n-3-PUFAs on atrial arrhythmias such as postoperative AF remain uncertain.”

Dariush Mozaffarian, M.D., Dr.P.H., of the Harvard School of Public Health, Boston, and colleagues conducted a study to determine whether perioperative administration of oral n-3-PUFAs reduces postoperative AF in patients undergoing cardiac surgery. The study (Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation [OPERA]) was a randomized, placebo-controlled, multinational, clinical trial that included a total of 1,516 patients who were scheduled for cardiac surgery in the United States, Italy, and Argentina. Patients were enrolled between August 2010 and June 2012 and were randomized to receive fish oil (1-gram capsules containing 840 mg or more of n-3- PUFA as ethyl esters) or placebo, with preoperative loading of 10 grams over 3 to 5 days (or 8 grams  over 2 days) followed postoperatively by 2 grams/day until hospital discharge or postoperative day 10, whichever came first.

At the beginning of the study, the average age of the patients was 64 years; 1,094 patients (72.2 percent) were men, and cardiovascular risk factors were common. Fifty-two percent of patients had planned valvular surgery.

The researchers found that the primary end point (occurrence of postoperative AF lasting longer than 30 seconds) occurred in 233 patients (30.7 percent) in the placebo group and 227 (30.0 percent) in the n-3-PUFA group. “None of the secondary end points were significantly different between the placebo and fish oil groups, including postoperative AF that was sustained, symptomatic, or treated (231 [30.5 percent] vs. 224 [29.6 percent]) or number of postoperative AF episodes per patient (1 episode: 156 [20.6 percent] vs. 157 [20.7 percent]; 2 episodes: 59 [7.8 percent] vs. 49 [6.5 percent]; ≥3 episodes: 18 [2.4 percent] vs. 21 [2.8 percent]).”

The total number of days in the intensive care unit or coronary care unit, of telemetry monitoring, or of total hospital stay did not differ significantly between groups. Also, supplementation with n-3-PUFAs was generally well-tolerated, with no evidence for increased risk of bleeding or serious adverse events.

“This large, multinational, double-blind, placebo-controlled clinical trial found no evidence that perioperative n-3-PUFA supplementation reduced postoperative AF. Results were similar for various secondary end points, among different patient subgroups, and in various sensitivity analyses. Major strengths of OPERA include its large size and large numbers of events, which achieved anticipated statistical power. Our broad inclusion criteria and multinational enrollment support the generalizability of our findings,” the researchers conclude.

(doi:10.1001/jama. 2012.28733;. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The OPERA trial was an investigator-initiated, not-for-profit trial sponsored by the OPERA Investigators, who had full responsibility for study planning and conduct, curation of the study database, and discretion on data utilization, analysis, and publication. Financial support was provided by the National Heart, Lung, and Blood Institute, National Institutes of Health, GlaxoSmithKline, Sigma Tau, and Pronova BioPharma, which also provided the study drug. 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 EARLY RELEASE: 5:30 P.M. (CT) SUNDAY, NOVEMBER 4, 2012

Paul A. Gurbel, M.D., of the Sinai Center for Thrombosis Research, Baltimore, and colleagues conducted a study to examine the differences in platelet reactivity and clinical outcomes among patients with acute coronary syndromes (ACS) being treated by the antiplatelet agents clopidogrel or prasugrel.

From 2008 to 2011, patients with medically managed unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI; a certain pattern on an electrocardiogram following a heart attack) were enrolled in the TRILOGY ACS trial comparing clopidogrel vs. prasugrel. Of 9,326 participants, 27.5 percent were included in a platelet function substudy, including 1,286 who received prasugrel and 1,278 who received clopidogrel. Patients were randomized to receive aspirin with either prasugrel (10 or 5 mg/d) or clopidogrel (75 mg/d); those 75 years or older or younger than 75 years but who weighed less than 132 lbs. received a 5-mg prasugrel maintenance dose.

The researchers found that “among patients with ACS without ST-segment elevation and initially managed without revascularization, prasugrel was associated with lower platelet reactivity than clopidogrel, irrespective of age, weight, and dose. Among those in the platelet substudy, no significant differences existed between prasugrel vs. clopidogrel in the occurrence of the primary efficacy end point [composite of cardiovascular death, heart attack, or stroke] through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes.”

(doi:10.1001/jama. 2012.17312;. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: This study is being released early online to coincide with its presentation at the American Heart Association’s Scientific Sessions. To contact corresponding author Matthew T. Roe, M.D., M.H.S., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

Editorial:

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EMBARGOED FOR EARLY RELEASE: 11 A.M. (CT) MONDAY, NOVEMBER 5, 2012

Media Advisory: To contact Martha L. Daviglus, M.D., Ph.D., call Jeanne Galatzer-Levy at 312-996-1583 or email jgala@uic.edu.

CHICAGO – In a study that involved more than 16,000 Hispanic/Latino men and women living in the United States, the prevalence of major cardiovascular disease (CVD) risk factors was high and varied markedly across different background groups; and those born in the U.S. were more likely to report a history of coronary heart disease and stroke and to have multiple CVD risk factors, according to a study appearing in November 7 issue of JAMA, a theme issue on cardiovascular disease. The study is being released early online to coincide with the American Heart Association’s Scientific Sessions.

In the last decades, the U.S. Hispanic and Latino population has increased dramatically, now comprising the nation’s largest minority group. Cardiovascular diseases are leading causes of death among Hispanic/Latino individuals in the United States, and this relatively young ethnic group is at high risk of future CVD illness and death as it ages. “Risk for CVDs among Hispanic/Latino individuals has been reported to differ with acculturation and duration of residence in the United States,” according to background information in the article. “Comprehensive data are limited regarding the prevalence of CVD risk factors in this population and relations of these traits to socioeconomic status (SES) and acculturation.”

Martha L. Daviglus, M.D., Ph.D., of the University of Illinois at Chicago and Northwestern University Feinberg School of Medicine, and Gregory A. Talavera, M.D., M.P.H., of San Diego State University, and colleagues conducted a study to examine the prevalence of major CVD risk factors and CVD (coronary heart disease [CHD] and stroke) among U.S. Hispanic/Latino individuals of different backgrounds. The multicenter, population-based Hispanic Community Health Study/Study of Latinos included individuals of Cuban (n = 2,201), Dominican (n = 1,400), Mexican (n = 6,232), Puerto Rican (n = 2,590), Central American (n = 1,634), and South American backgrounds (n = 1,022), ages 18 to 74 years. The analyses involved 15,079 participants (5,979 men; 9,100 women) with complete data enrolled between March 2008 and June 2011. Seventy percent had lived in the United States for 10 or more years. The study included measurements of adverse CVD risk factors defined using national guidelines for hypercholesterolemia (high cholesterol), hypertension, obesity, diabetes, and smoking. Prevalence of CHD and stroke were determined from self-reported data.

The researchers found that large proportions of participants (80 percent of men, 71 percent of women) had at least one risk factor. Overall, 31 percent of men had an adverse level of any 1 major risk factor only (most commonly hypercholesterolemia); 28 percent and 21 percent had any 2 only or 3 or more risk factors. Prevalence of 3 or more risk factors was highest among Puerto Rican men and lowest among South American men. Among women, 30 percent had 1 risk factor only (most commonly obesity); 23 percent and 17 percent had any 2 or 3 or more risk factors. Prevalence of 3 or more risk factors was highest among Puerto Rican women and lowest among South American women.

The prevalence of 3 or more risk factors was significantly higher with lower education or income. “In general, participants with lower income or education had higher rates of smoking, diabetes, obesity, and hypercholesterolemia. Compared with those who were less acculturated (i.e., were foreign-born or first-generation immigrants, had lived in the United States <10 years, or for whom Spanish was the preferred language), more acculturated participants had higher prevalence of 3 or more risk factors.” In general, more acculturated participants had markedly higher rates of current smoking and obesity compared with others.

For the different risk factors, the overall prevalence of hypercholesterolemia was 52 percent among men and 37 percent among women; 25 percent of men and 24 percent of women had hypertension; about 37 percent of men and 43 percent of women were obese; 17 percent of men and women had diabetes; and about 26 percent of men, as well as 15 percent of women, were current smokers.

“Overall, self-reported CHD and stroke prevalence were low (4.2 percent and 2.0 percent in men; 2.4 percent and 1.2 percent in women, respectively). In multivariate-adjusted models, hypertension and smoking were directly associated with CHD in both sexes as were hypercholesterolemia and obesity in women and diabetes in men,” the authors write.

“In conclusion, findings from [this study] demonstrate the pervasive burden of CVD risk factors in all Hispanic/Latino groups in the United States and identify specific groups by origin, sociodemographic characteristics, and sociocultural backgrounds at particularly high risk of CVD. These data may enhance the impetus to implement interventions to lower the burden of CVD risk factors among Hispanic/Latino people overall and targeted at-risk groups, as well as develop strategies to prevent future development of adverse CVD risk factors starting at the youngest ages.”

(JAMA.2012;308[17]:1775-1784. 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: 11 A.M. (CT) MONDAY, NOVEMBER 5, 2012

Use of Corticosteroid During Cardiac Surgery Does Not Appear to Improve Outcomes

Jan M. Dieleman, M.D., of the University Medical Center, Utrecht, the Netherlands and colleagues conducted a randomized clinical trial to quantify the effect of a single intraoperative dose of the corticosteroid dexamethasone on the incidence of major adverse events in patients undergoing cardiac surgery.

“Prophylactic corticosteroids are often administered during cardiac surgery to attenuate [lessen] the inflammatory response to cardiopulmonary bypass and surgical trauma; however, evidence that routine corticosteroid use can prevent major adverse events is lacking,” according to background information in the article.

The study included 4,494 patients ages 18 years or older undergoing cardiac surgery with cardiopulmonary bypass at 8 cardiac surgical centers in the Netherlands, enrolled between April 2006 and November 2011. Patients were randomly assigned to receive a single intraoperative dose of dexamethasone (n = 2,239) or placebo (n = 2,255). The primary outcome measure for the study was a composite of death, heart attack, stroke, renal failure, or respiratory failure, within 30 days of randomization.

A total of 157 patients in the dexamethasone group (7.0 percent) and 191 patients in the placebo group (8.5 percent) reached the primary study end point (absolute risk reduction, -1.5  percent). “Our randomized study of 4,494 patients undergoing cardiac surgery failed to show a statistically significant benefit of intraoperative administration of dexamethasone on the incidence of the composite primary study end point of major adverse events,” the authors write.

(JAMA.2012;308[17]:1761-1767. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Jan M. Dieleman, M.D., email s.dieleman@umcutrecht.nl.

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Most High-Risk Cardiovascular Devices Approved Without Comparative Effectiveness Data

Connie E. Chen, M.D., of the Stanford Hospital and Clinics, Palo Alto, Calif., and colleagues conducted a study to examine the type of controls used by the Food and Drug Administration in evaluating comparative effectiveness during premarket approval of cardiovascular devices.

“Use of a comparator group is not required in studies used for approval of medical devices, in contrast to drugs, which require 2 randomized controlled trials. … Unlike drugs, device trials frequently use control data from previous trials (historical controls) and performance benchmarks imputed from prior studies (objective performance criteria; OPC) in evaluating outcomes. However, the lack of active controls raises concerns about selection bias and validity,” the authors write.

As reported in a Research Letter, data were extracted from publicly available FDA summaries of safety and effectiveness data. Summaries representing all high-risk cardiovascular devices approved by the FDA between January 1, 2000, and December 31, 2011, were analyzed. All primary end points were examined to determine the type of controls with which the device was compared. Comparative effectiveness research was defined as use of active controls in evaluating primary end points.

“The 121 summaries identified contained 203 supporting clinical studies. These studies used 353 primary end points, of which 40 percent (n = 140) were evaluated against an active control, 13 percent (n = 45) against a historical control, 26 percent (n = 90) against an OPC, and 22 percent (n = 78) against no control. Thirty-six percent (74/203) of studies included at least 1 primary end point evaluated against an active control; 48 percent (58/121) of devices had an active control in at least 1 supporting study, while 35 percent (42/121) of devices were approved without data from any control or OPC,” the authors write.

“It is hard to know if a new device is safe and more effective than alternative treatments unless it is compared with conventional treatment. While occasionally use of active controls may not be possible, such as ventricular assist devices, more frequent use of a comparator group may help to better inform clinical and regulatory decisions.”

(JAMA.2012;308[17]:1740-1742. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Transforming Clinical Trials in Cardiovascular Disease – Mission Critical for Health and Economic Well-being

Elliott M. Antman, M.D., of Brigham and Women’s Hospital, Boston, and Robert A. Harrington, M.D., of the Stanford University Department of Medicine, Stanford, Calif., discuss changes in design and quality of randomized controlled trials (RCTs) involving cardiovascular disease.

“These innovations to RCTs need to occur in concert with ongoing efforts by the Food and Drug Administration (FDA) to promote innovations in regulatory science. Academic and industry stakeholders need to collaborate with the FDA to establish common definitions of end points and case report form data elements and the appropriate use of biomarkers and genetic testing in RCTs. Researchers also need to learn how to deal with the regulatory challenges of establishing new approval methods when generic drugs used in managing cardiovascular disease are found to be effective for ‘off-label’ indications. Similarly, researchers and clinicians need to consider innovative approaches when observational data raise the hypothesis that approved drugs used broadly in the population may need to be re-evaluated in new RCTs to define appropriate use.”

(JAMA.2012;308[17]:1743-1744. Available pre-embargo to the media at https://media.jamanetwork.com)

Preventing and Controlling Hypertension in the Era of Genomic Innovation and Environmental Transformation

Donna K. Arnett, M.S.P.H., Ph.D., and Steven A. Claas, M.S., of the University of Alabama at Birmingham, examine how genomics has contributed to the understanding of hypertension, and the relationship of environmental factors with the occurrence of hypertension.

“The current understanding of hypertension genomics and the ability to create environments that are not at odds with the evolutionary legacy have never been greater, and gains on both of these fronts are likely. More importantly, the medical community has only just begun to illuminate how these 2 domains interact to create sustainable health. Today, there is an unprecedented opportunity to synergistically merge genomic knowledge and environmental acumen to prevent and control hypertension.”

(JAMA.2012;308[17]:1745-1746. Available pre-embargo to the media at https://media.jamanetwork.com)

The Future of Cardiovascular Clinical Research – Informatics, Clinical Investigators, and Community Engagement

Robert M. Califf, M.D., of Duke University Medical Center, Durham, N.C., and colleagues write that reductions in cardiovascular illness and death will depend on enhanced individual and community engagement with the research enterprise, and that informatics will play an important role.

“If all Americans have an electronic health record that supports individual care, and data are collected using common standards and housed in data warehouses jointly owned by health care delivery systems and local communities, this resource could be used to design and conduct health interventions; investigate the intersection of biology, culture, and environment; and provide a continuous learning environment. With a learning health care delivery system in place, when effect sizes for an intervention are less than an odds ratio or relative risk of 1.6 (in the range of most effective therapies), randomization could occur as an intrinsic element of an intervention at the individual or neighborhood scale, increasing the ability to generate high-level evidence by an order of magnitude at a much lower cost. That dream, described as an aspiration in the 2002 NIH Roadmap, is now within reach.”

(JAMA.2012;308[17]:1747-1748. 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 EARLY RELEASE: 11 A.M. (CT) MONDAY, NOVEMBER 5, 2012

Media Advisory: To contact Monika M. Safford, M.D., call Jennifer Park Lollar at 205-934-3888 or email jpark@uab.edu. To contact editorial author Michael S. Lauer, M.D., call the NHLBI Office of Communications at 301-496-4236 or email nhlbi_news@nhlbi.nih.gov.

CHICAGO – In an examination of the incidence of coronary heart disease (CHD) in the U.S. by race and sex, black men and women had twice the rate of fatal CHD compared with white men and women, with this increased risk associated with a greater prevalence of CHD risk factors, according to a study appearing in November 7 issue of JAMA, a theme issue on cardiovascular disease. The study is being released early online to coincide with the American Heart Association’s Scientific Sessions.

“Although mortality rates for acute myocardial infarction [MI; heart attack] and coronary heart disease have declined in the United States since the 1970s, both death certificate data and evidence from 4 U.S. communities suggest a steeper decline in acute CHD mortality between 2000 and 2008 for whites than for blacks, widening a long-standing disparity,” according to background information in the article. It is unknown whether disparities in the incidence of CHD among U.S. blacks and whites persist.

Monika M. Safford, M.D., of the University of Alabama at Birmingham, and colleagues conducted a study to examine racial and sex differences in incident total CHD, fatal CHD, and nonfatal CHD across race-sex groups. The study included 24,443 participants without CHD at the beginning of the study from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, who resided in the continental United States and were enrolled between 2003 and 2007 with follow-up through December 2009. Blacks and whites had a similar average age, but smoking, diabetes, and reduced estimated glomerular filtration rate (a measure of kidney function) were more prevalent, and systolic blood pressure and body mass index were higher among blacks than whites.

The average follow-up time was 4.2 years. There were 659 total incident CHD events through December 2009, including 153 events in black men, 254 in white men, 138 in black women, and 114 in white women. The researchers found that although the measured incidence rate of total CHD was similar among black men and white men, black men had higher incidence of fatal CHD and lower incidence of nonfatal CHD. Women had lower incidence rates than men within each racial group. However, black women had higher incidence rates for total CHD, for fatal CHD, and for nonfatal CHD, compared to white women. The increased risk of fatal CHD among blacks was associated with a higher prevalence of cardiovascular disease risk factors.

“Excess risk factor burden among black men and women continues to be a major public health challenge, along with their high risk for death as the presentation of CHD. Increased emphasis on optimizing well-established CHD risk factors among blacks could potentially reduce these disparities,” the authors conclude.

(JAMA.2012;308[17]:1768-1774. 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: Time for a Creative Transformation of Epidemiology in the United States

Michael S. Lauer, M.D., of the National Heart, Lung, and Blood Institute, Bethesda, Md., writes in an accompanying editorial that two studies in this issue of JAMA (by Safford et al and by Daviglus et al) “send a powerful and sobering message: despite 50 years of epidemiological knowledge and despite numerous therapeutic advances, risk factor burdens among minority populations are unacceptably high and consequential.”

“[These reports] demonstrate the ongoing power of epidemiology. These reports should stimulate results-based transformations of epidemiological science that, in consonance with digital revolution, are better, faster, cheaper, and more responsive to current needs. These transformations will occur if epidemiologists and their supporters join forces with many other stakeholders. This is already happening to some degree with the Million Hearts Initiative and the National Program to Reduce Cardiovascular Risk. These transformations will also ensure that epidemiology will have much to give, whether lately or later.”

(JAMA.2012;308[17]:1804-1805. 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. Lauer is a full-time employee of the National Heart, Lung, and Blood Institute, which provided partial funding support for the 2 articles that form the basis of this Editorial. He directs the division that includes 2 co-authors (M. Larissa Aviles-Santa and Paul D. Sorlie) of one of the articles.

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EMBARGOED FOR EARLY RELEASE: 11 A.M. (CT) MONDAY, NOVEMBER 5, 2012

Media Advisory: To contact Howard D. Sesso, Sc.D., M.P.H., call Tom Langford at 617-534-1605 or email tlangford@partners.org. To contact Eva M. Lonn, M.D., M.Sc., call Veronica McGuire at 905-525-9140, ext. 22169; or email vmcguir@mcmaster.ca.

CHICAGO – In a randomized study that included nearly 15,000 male physicians who were middle-aged or older, daily multivitamin use for more than 10 years of treatment and follow-up did not result in a reduction of major cardiovascular events, heart attack, stroke, or death from cardiovascular disease, according to a study appearing in November 7 issue of JAMA, a theme issue on cardiovascular disease. The study is being released early online to coincide with its presentation at the American Heart Association’s Scientific Sessions.

“Despite uncertainty regarding the long-term health benefits of vitamins, many U.S. adults take vitamin supplements to prevent chronic diseases or for general health and well-being,” according to background information in the article. Individuals who believe they are deriving benefits from supplements may be less likely to engage in other preventive health behaviors. “Although multivitamins are used prevent vitamin and mineral deficiency, there is a perception that multivitamins may prevent cardiovascular disease (CVD). Observational studies have shown inconsistent associations between regular multivitamin use and CVD, with no long-term clinical trials of multivitamin use.”

Howard D. Sesso, Sc.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues analyzed data regarding multivitamin use and major cardiovascular events from the Physicians’ Health Study (PHS) II, a large-scale trial testing the effects of long-term use of a common multivitamin on the risk of major cardiovascular events and cancer. The Physicians’ Health Study II is a randomized, placebo-controlled trial that began in 1997 with continued treatment and follow-up through June 1, 2011. A total of 14,641 male U.S. physicians initially 50 years of age or older (average, 64 years), including 754 men with a history of CVD at randomization, were enrolled. This analysis measured the composite end point of major cardiovascular events, including nonfatal myocardial infarction (MI; heart attack), nonfatal stroke, and death from CVD. Secondary outcomes included heart attack and stroke individually. Participants were randomized to multivitamin (n = 7,317) or placebo (n = 7,324).

During a median (midpoint) follow-up of 11.2 years, 1,732 men had major cardiovascular events, including 652 cases (first events) of heart attack and 643 cases of stroke, and 829 men had cardiovascular death, with some men experiencing multiple events. A total of 2,757 (18.8 percent) men died during follow-up (multivitamin, n = 1,345; placebo, n = 1,412). In an analysis of the rate of events for men in each group, the researchers found that there was no significant effect of a daily multivitamin on major cardiovascular events, or total MI or total stroke. Taking a daily multivitamin was not significantly associated with a reduction in CVD mortality. There were fewer total deaths among multivitamin users, but this difference was not statistically significant.

The authors also found no significant effect of a daily multivitamin on rates of congestive heart failure, angina, and coronary revascularization.  Also, the effect of a daily multivitamin on total MI, total stroke, and other cardiovascular end points did not differ between men with and without CVD at the beginning of the study.

“The PHS II represents to our knowledge the only large-scale, randomized, double-blind, placebo-controlled trial testing the long-term effects of a commonly available multivitamin in the prevention of chronic disease,” the authors write. “These data do not support multivitamin use to prevent CVD, demonstrating the importance of long-term clinical trials of commonly used nutritional supplements. Whether to take a daily multivitamin requires consideration of an individual’s nutritional status, because the aim of supplementation is to prevent vitamin and mineral deficiency, plus consideration of other potential effects, including a modest reduction in cancer and other important outcomes in PHS II that will be reported separately.”

(JAMA.2012;308[17]:1751-1760. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by grants from the NIH and an investigator-initiated grant from BASF Corporation. Study agents and packaging were provided by BASF Corporation and Pfizer (formerly Wyeth, American Home Products, and Lederle), and study packaging was provided by DSM Nutritional Products Inc. (formerly Roche Vitamins). Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Multivitamins in Prevention of Cardiovascular Disease

In an accompanying editorial, Eva M. Lonn, M.D., M.Sc., of McMaster University and Hamilton General Hospital, Hamilton, Ontario, Canada, writes that “robust data from multiple trials clearly confirm that CVD cannot be prevented or treated with vitamins.”

“Nonetheless, many people with heart disease risk factors or previous CVD events lead sedentary lifestyles, eat processed or fast foods, continue to smoke, and stop taking lifesaving prescribed medications, but purchase and regularly use vitamins and other dietary supplements, in the hope that this approach will prevent a future myocardial infarction or stroke. This distraction from effective CVD prevention is the main hazard of using vitamins and other unproven supplements. The message needs to remain simple and focused: CVD is largely preventable, and this can be achieved by eating healthy foods, exercising regularly, avoiding tobacco products, and, for those with high risk factor levels or previous CVD events, taking proven, safe, and effective medications.”

(JAMA.2012;308[17]:1802-1803. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported serving as a consultant to Merck and Servier; providing expert testimony for Merck; receiving grants or grants pending from AstraZeneca, GSK, and Hoffman Laroche; and receiving payment for lectures from Novartis and Merck.

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EMBARGOED FOR EARLY RELEASE: 11 A.M. (CT) MONDAY, NOVEMBER 5, 2012

Media Advisory: To contact John T. Wilkins, M.D., M.S., call Erin White at 847-491-4888 or email ewhite@northwestern.edu.

CHICAGO – Even in men and women with an optimal cardiovascular disease (CVD) risk factor profile, the lifetime risk estimate for CVD is greater than 30 percent, and is more than 50 percent for men and women overall, according to a study appearing in November 7 issue of JAMA, a theme issue on cardiovascular disease. The study is being released early online to coincide with the American Heart Association’s Scientific Sessions.

“To date, there have been no published data on the lifetime risk for total CVD (including coronary heart disease [CHD], atherosclerotic and hemorrhagic stroke, congestive heart failure [CHF], and other CVD death),” according to background information in the article. “Estimates of lifetime risk for total CVD may provide projections of the future population burden of CVD and may assist in clinician-patient risk communication.”

John T. Wilkins, M.D., M.S., of the Northwestern University Feinberg School of Medicine, Chicago, and colleagues conducted a study to estimate lifetime risk for total CVD in separate models for men and women overall and by aggregate risk factor burden at index ages of 45, 55, 65, and 75 years. The study consisted of a pooled survival analysis of data from 1964 through 2008 from five National Heart, Lung, and Blood Institute-funded community-based cohorts: Framingham Heart Study, Framingham Offspring Study, Atherosclerosis Risk in Communities Study, Chicago Heart Association Detection Project in Industry Study, and Cardiovascular Health Study. All participants were free of CVD at entry into the study with risk factor data (blood pressure [BP], total cholesterol [TC], diabetes, and smoking status) and total CVD outcome data. The primary outcome measure for the study was any total CVD event (including fatal and nonfatal coronary heart disease, all forms of stroke, congestive heart failure, and other CVD deaths).

Across all index ages, 1.7 percent to 7.9 percent of individuals were in the all optimal risk factor group. In contrast, more than 55 percent of individuals were in the 1 major or at least 2 major risk factor strata at all index ages. At some time during follow-up across all index age groups, approximately 30 percent to 35 percent of individuals experienced CVD events. The researchers found that at an index age of 45 years, overall lifetime risk estimates for total CVD through age 95 years were 60.3 percent for men, and 55.6 percent for women. Women had significantly lower lifetime risk estimates than men at all index ages.

At index ages 55 and 65 years, men and women with at least 1 elevated risk factor (BP, 140-149/90-99 mm Hg; or TC, 200-239 mg/dL; but no diabetes or smoking), 1 major risk factor, or at least 2 major risk factors (BP, 160/100 mm Hg or greater or receiving treatment; TC, 240 mg/dL or greater or receiving treatment; diabetes mellitus; or current smoking) had lifetime risk estimates to age 95 years that exceeded 50 percent. At an index age of 55 years, men with optimal risk factor profiles [BP, <120/80 mm Hg; TC, <180 mg/dL; and no smoking or diabetes] had remaining lifetime risks for total CVD that exceeded 40 percent and women had risks that approached 30 percent through 85 years of age.

Longer survival time free of total CVD was experienced by individuals with optimal risk factor levels when compared with participants with at least 2 major risk factors across all index ages. “For example, at an index age of 45 years, individuals with optimal risk factor profiles lived up to 14 years longer free of total CVD than individuals with at least 2 risk factors,” the authors write.

The researchers note that “lifetime risks for total CVD were high regardless of index age, indicating that achieving older age free of total CVD does not guarantee escape from remaining lifetime risk for total CVD.” They add that the finding of a substantial lifetime CVD risk even among individuals with an optimal risk factor profile highlights “the large public health burden and opportunities for prevention of total CVD.”

(JAMA.2012;308[17]:1795-1801. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: An author podcast for this study will be available on the journal website after the embargo lifts. 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: 2:00 P.M. (CT) TUESDAY, OCTOBER 30, 2012
Media Advisory: To contact corresponding author Josef Coresh, M.D., Ph.D., call Tim Parsons at 410-955-7619 or email tmparson@jhsph.edu. To contact editorial author Ian H. de Boer, M.D., M.S., call Clare LaFond at 206-685-1323 or email clareh@uw.edu.

CHICAGO – In a large, collaborative study that included more than 2 million individuals from around the world, two measures of poor kidney function, low estimated glomerular filtration rate and high albuminuria, were associated with risk of death and end-stage renal disease regardless of the age of the individuals, according to a study appearing in JAMA. The study is being release early online to coincide with its presentation at the American Society of Nephrology’s Kidney Week meeting.

“Chronic kidney disease (CKD) is defined by reduced glomerular filtration rate [GFR less than 60 mL/min/1.73 m2] or kidney damage (usually detected by high albuminuria; e.g., 30 mg or greater of albumin per 1 gram of creatinine). Chronic kidney disease affects 10 percent to 15 percent of adults in the United States, Europe, and Asia, and the prevalence increases dramatically with age (from 4 percent at age 20-39 to 47 percent at age ≥70 years in the United States). Recently, it has been suggested that the definition and staging of CKD and corresponding clinical risk should be determined by the combination of estimated GFR (eGFR) and albuminuria levels,” according to background information in the article. “However, controversy exists about whether age modifies their independent and combined association with clinical risk, partly because of different analytic approaches. The resulting uncertainty about the comprehensive effect of age on the CKD-risk relationship hampers optimal clinical practice and public health initiatives for this large patient group.”

Stein I. Hallan, M.D., Ph.D., of the Norwegian University of Science and Technology, Trondheim, Norway, and colleagues conducted a study to evaluate the possible effect of age on the association of eGFR and albuminuria with risk of death and end-stage renal disease (ESRD), examining both relative and absolute risks. The study included 2,051,244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD groups from Asia, Australasia, Europe, and North/South America, conducted from 1972-2011, with an average follow-up time of 5.8 years.

After meta-analysis of the data, the researchers found that mortality (112,325 deaths) and ESRD (8,411 events) risks were higher at lower eGFR and higher albuminuria in every age category. “We found that mortality risk associations were weaker on the relative scale but stronger on the absolute scale at older ages in general population and high-risk cohorts. In cohorts specifically selected for CKD, age did not modify the mortality associations. For ESRD risk, age did not significantly influence relative and absolute risk gradients. Thus, eGFR and albuminuria were strongly associated with both mortality and ESRD in a wide range of studies across the full age range. Importantly, the results were largely consistent across diverse cohorts in terms of demographic and clinical characteristics.”

The authors add that their findings have several important implications. “First, our study shows that the kidney measures used for defining and staging CKD are strong predictors of clinical risk across the full age range, including age 75 years or older in many cohorts. This contradicts concerns raised by some that current CKD guidelines should be used with caution in older individuals and that low eGFR reflects only natural aging. … Second, our data support the recommendations from several investigators that CKD measures should be added to mortality risk equations. … Third, the strong increase in mortality rate along with kidney measures at older ages suggests that older adults should not be left out from management strategies of CKD.”

“Although some variation in management of CKD should be considered by age based on cost and benefits, with respect to risk of mortality and ESRD, our data support a common definition and staging of CKD based on eGFR and albuminuria for all age groups.”
(doi:10.1001/jama. 2012.16817;. 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.

Chronic Kidney Disease–A Challenge For All Ages

Ian H. de Boer, M.D., M.S., of the University of Washington, Seattle, comments on the findings of this study in an accompanying editorial.

“For physicians to help improve the lives of patients with CKD, identifying the presence of CKD and its associated risks is an important first step. In this respect, [the results of this study] makes it clear that CKD is a challenge for all ages. To move forward, CKD identification must be coupled to new treatment strategies tailored to patients with CKD, including older patients with CKD.”
(doi:10.1001/jama. 2012.30761;. 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. de Boer receives research funding from the National Institutes of Health and Abbott Laboratories.

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EMBARGOED FOR EARLY RELEASE: 6:15 A.M. (CT) THURSDAY, OCTOBER 25, 2012

Media Advisory: To contact Asgeir S. Jakola, M.D., email asgeir.s.jakola@ntnu.no. To contact editorial author James M. Markert, M.D., call Bob Shepard at 205-934-8934 or email bshep@uab.edu.

CHICAGO – In a comparison of strategies for treating low-grade gliomas (brain tumors), patients in Norway treated at a hospital that generally favored early surgical resection (removal) had better overall survival than patients treated at a hospital that favored biopsy and watchful waiting, according to a study appearing in JAMA. The study is being release early online to coincide with its presentation at the European Association of Neurosurgical Societies annual meeting.

“Due to diffuse brain infiltration, low-grade gliomas (LGGs) are usually not considered surgically curable. In fact, the effect of surgery on survival remains unclear because current evidence relies on uncontrolled surgical series alone,” according to background information in the article. “Due to lack of better evidence, management of suspected LGGs has remained one of the major controversies in neuro-oncology and treatment strategies often differ considerably between neurosurgical centers.”

Asgeir S. Jakola, M.D., of St. Olavs University Hospital, Trondheim, Norway, and colleagues conducted a study to examine whether early tumor resection, as the preferred strategy, was associated with improved survival among patients with LGG compared with a strategy favoring biopsy and watchful waiting. The study included patients with LGGs at two Norwegian university hospitals with different surgical treatment strategies. In one hospital, diagnostic biopsies followed by a “wait and scan” approach has been favored (biopsy and watchful waiting), whereas early resections have been advocated in the other hospital (early resection). Histopathology specimens from all adult patients diagnosed with LGG from 1998 through 2009 underwent a blinded histopathological review to ensure uniform classification and inclusion. Follow-up ended April 2011. After the central review of histopathology, 153 patients with diffuse LGG (91 percent of screened cohort) were identified and included in the study; 66 (43 percent) from the center favoring biopsy and watchful waiting and 87 (57 percent) from the center favoring early resection.

There were large regional differences in treatment strategies as biopsy and subsequent watchful waiting was the initial strategy in 47 (71 percent) of LGG patients treated at the center favoring biopsy and watchful waiting compared with only 12 (14 percent) treated at the center favoring early resection. Median (midpoint) follow-up was 7.0 years at the center favoring biopsy and watchful waiting and 7.1 years at the center favoring early resection.

At end of follow-up, 34 patients (52 percent) from the center favoring biopsy and watchful waiting had died compared with 28 patients (32 percent) from the center favoring early resection. The researchers found that overall survival was significantly longer for patients treated at the center favoring early resection over biopsy and watchful waiting. “The survival advantage increased with time: While one year survival was 89 percent vs. 89 percent, the expected 3-year survival was 70 percent vs. 80 percent, expected 5-year survival was 60 percent vs. 74 percent, and expected 7-year survival was 44 percent vs. 68 percent. Median survival at the center favoring biopsy was 5.9 years while median survival is not yet reached where initial resection was preferred.”

“In this comparative population-based study in patients with newly diagnosed LGG, a survival benefit was observed for patients treated at a hospital advocating early resection as opposed to diagnostic biopsy and subsequent watchful waiting,” the authors write. “This significantly strengthens the data in support of early resection in newly diagnosed LGG.”

(doi:10.1001/jama. 2012.12807; 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: The Role of Early Resection vs. Biopsy in the Management of Low-Grade Gliomas

In an accompanying editorial, James M. Markert, M.D., of the University of Alabama at Birmingham, writes that “although class I evidence for surgical resection of LGG remains lacking, National Comprehensive Cancer Center practice guidelines in oncology support maximal safe resection as a feasible first line of treatment for LGG.”

“The majority of these studies, but not all ones published in the past 2 decades, support this approach as well. The study by Jakola et al adds further evidence for this approach. A follow-up study of their cohorts, allowing for more definitive measurement of survival and more rigorous assessment of complications, neurologic deterioration, and malignant degeneration, would be valuable.”

(doi:10.1001/jama. 2012.14523; 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, OCTOBER 23, 2012

Molecular Prognostic Assay May Help Identify Patients at High Risk of Death Despite Small, Node-Negative Lung Tumors

“Low-dose computed tomography screening may increase diagnoses of T1a node-negative non-small-cell lung cancers (NSCLC). One-quarter of these patients die within 5 years. Maximizing the benefit of screening requires a reliable method to identify patients with high mortality risk,” writes Johannes R. Kratz, M.D., of the University of California, San Francisco, and colleagues. “A molecular prognostic assay has been clinically validated for nonsquamous NSCLC, but performance of the assay was not studied in small node-negative tumors.”

As reported in a Research Letter, the study included 269 patients with node-negative tumors of less than 2 cm who had undergone resection of nonsquamous NSCLC. The prognostic test measures the expression of 14 genes using quantitative polymerase chain reaction on RNA extracted from specimens, and assigns patients to low-, intermediate-, and high-risk groups based on clinically validated cutoff values for a calculated risk score. Five-year survival was the primary end point.

The average age of patients was 62 years; median (midpoint) follow-up among survivors was 74 months, and 5-year mortality was 28.6 percent. Ninety-two patients (34.2 percent) were identified as high risk by the prognostic assay; survival was significantly different among the high-risk group (52.3 percent), the intermediate-risk group (69.1 percent), and the low-risk group (83.0 percent). “… these data suggest the potential clinical utility of a new prognostic assay in the postoperative management of node-negative T1a disease. The identification of high-risk patients may further maximize the benefit of early detection of T1a node-negative tumors through low-dose computed tomography screening.”

(JAMA. 2012;308[16]:1629-1631. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Choosing Wisely – Low-Value Services, Utilization, and Patient Cost Sharing

Kevin G. Volpp, M.D., Ph.D., of the Philadelphia Veterans Affairs Medical Center, and colleagues examine the recent Choosing Wisely initiative, which aimed at “encouraging physicians, patients and other health care stakeholders to think and talk about medical tests and procedures that may be unnecessary, and in some instances can cause harm.”

“The Choosing Wisely initiative represents an important first step toward the identification of low-value services, more meaningful because it was a step taken jointly by consumer groups and professional specialties. The next step is to move beyond a list of low-value services toward the testing of approaches to reduce their use, ideally through a combination of benefit design, physician payment policies, and social and professional guidance informed by clinical evidence. Given fiscal realities, reducing low-value services is what will allow continued support for the coverage of high-value services.”

(JAMA. 2012;308[16]:1635-1636. Available pre-embargo to the media at https://media.jamanetwork.com)

What’s Needed Is a Health Care System That Learns – Recommendations From an IOM Report

Mark Smith, M.D., M.B.A., of the California HealthCare Foundation, Oakland, Calif., and co-authors were members of an Institute of Medicine (IOM) committee that produced the recent report, “Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. In this Viewpoint, the authors discuss several recommendations from this report for improving the U.S. health care system.

“The stakes are high. Left unchanged, the U.S. health care system will continue to provide world-class services to some, while others will receive substandard care and experience unnecessary harms. Spiraling costs will continue to strain national, state, and local government; corporate; and family budgets. The actions required to reverse this trend will be notable, substantial, highly disruptive—and absolutely necessary. The choice is not whether or when to begin the overdue transformation, but how.”

(JAMA. 2012;308[16]:1637-1638. 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, OCTOBER 23, 2012

Media Advisory: To contact Ary Serpa Neto, M.D., M.Sc., email aryserpa@terra.com.br. To contact editorial author Niall D. Ferguson, M.D., M.Sc., call Leslie O’Leary at 416-586-4800, ext.8306; or email lo’leary2@mtsinai.on.ca.

CHICAGO –Among patients without acute respiratory distress syndrome, protective mechanical ventilation with use of lower tidal volumes (the volume of air inhaled and exhaled during each breath) was associated with better outcomes including less lung injury, lower mortality, fewer pulmonary infections and a shorter hospital length of stay, according to a meta-analysis of previous studies, reported in the October 24/31 issue of JAMA.

“Mechanical ventilation is a life-saving strategy in patients with acute respiratory failure. However, unequivocal evidence suggests that mechanical ventilation has the potential to aggravate and precipitate lung injury. In acute respiratory distress syndrome (ARDS), and in a milder form of ARDS formerly known as acute lung injury (ALI), mechanical ventilation can cause ventilator-associated lung injury,” according to background information in the article. “Lung-protective mechanical ventilation with the use of lower tidal volumes has been found to improve outcomes of patients with ARDS. It has been suggested that use of lower tidal volumes also benefits patients who do not have ARDS.”

Ary Serpa Neto, M.D., M.Sc., of ABC Medical School, Santo Andre, Sao Paulo, Brazil and colleagues conducted a meta-analysis to determine whether conventional (higher) or protective (lower) tidal volumes would be associated with lung injury, mortality, and pulmonary infection in patients without lung injury at the onset of mechanical ventilation. After a search of the medical literature, the researchers identified 20 articles (2,822 participants) that met criteria for inclusion in the study.

Analysis of the data indicated a 67 percent decreased risk of lung injury development and 36 percent decrease in the risk of death in patients receiving ventilation with lower tidal volumes. The results of lung injury development were similar when stratified by the type of study (randomized vs. nonrandomized) and were significant only in randomized trials for pulmonary infection and only in nonrandomized trials for mortality. Analysis also showed, in protective ventilation groups, a lower incidence of pulmonary infection and lower average hospital length of stay (approximately 7 vs. 9 days, respectively).

“In conclusion, our meta-analysis suggests that among patients without lung injury, protective ventilation with use of lower tidal volumes at onset of mechanical ventilation may be associated with better clinical outcomes. We believe that clinical trials are needed to compare higher vs. lower tidal volumes in a heterogeneous group of patients receiving mechanical ventilation for longer periods,” the authors write.

(JAMA. 2012;308[16]:1651-1659. 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.

Editorial: Low Tidal Volumes for All?

In an accompanying editorial, Niall D. Ferguson, M.D., M.Sc., of Mount Sinai Hospital and the University of Toronto, writes that the “meta-analysis by Serpa Neto and colleagues serves as a convincing summary that the current knowledge base about low trial volume ventilation is inadequate.”

“In addition to confirming or refuting the benefit of setting lower vs. higher tidal volumes in patients without ARDS, additional trials could address the degree of tidal volume limitation required, the patient populations that may benefit most, and whether to actively seek to limit tidal volumes in spontaneously breathing patients or simply avoid setting higher volumes. The role of intraoperative lung-protective ventilation also needs further study. Given the number of ICU patients receiving mechanical ventilation for whom this question applies (i.e., the 95 percent of patients who do not have ARDS at the time of intubation, such trials would have significant clinical importance and would be highly feasible.”

(JAMA. 2012;308[16]:1689-1690. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Ferguson is supported by a New Investigator Award from the Canadian Institutes of Health Research (Ottawa, Ontario, Canada). The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 23, 2012

Media Advisory: To contact corresponding author John P. A. Ioannidis, M.D., D.Sc., call Krista Conger at 650-725-5371 or email kristac@stanford.edu. To contact editorial author Andrew D. Oxman, M.D., email oxman@online.no.

CHICAGO – In an examination of the characteristics of studies that yield large treatment effects from medical interventions, these studies were more likely to be smaller in size, often with limited evidence, and when additional trials were performed, the effect sizes became typically much smaller, according to a study in the October 24/31 issue of JAMA.

“Most effective interventions in health care confer modest, incremental benefits,” according to background information in the article. “Large effects are important to document reliably because in a relative scale they represent potentially the cases in which interventions can have the most impressive effect on health outcomes and because they are more likely to be adopted rapidly and with less evidence. Consequently, it is important to know whether, when observed, very large effects are reliable and in what sort of experimental outcomes they are commonly observed. … Some large treatment effects may represent entirely spurious observations. It is unknown how often studies with seemingly very large effects are repeated.”

Tiago V. Pereira, Ph.D., of the Health Technology Assessment Unit, German Hospital Oswaldo Cruz, Sao Paulo, Brazil, and colleagues conducted a study to evaluate the frequency and features of very large treatment effects of medical interventions that are first recorded in a clinical trial. For the study, the researchers used data from the Cochrane Database of Systematic Reviews (CDSR) and assessed the types of treatments and outcomes in trials with very large effects, examined how often large-effect trials were followed up by other trials on the same topic, and how these effects compared against the effects of the respective meta-analyses.

Among 3,545 available reviews, 3,082 contributed usable information on 85,002 forest plots (a graphical display designed to illustrate the relative strength of treatment effects in multiple studies). Overall, 8,239 forest plots (9.7 percent) had a nominally statistically significant very large effect in the first published trial, group A; 5,158 (6.1 percent) had a nominally statistically significant very large effect found only after the first published trial, group B; and 71,605 (84.2 percent) had no trials with significant very large effects, group C. The researchers found that nominally significant very large effects arose mostly from small trials with few events. For the index trials, the median [midpoint] number of events was only 18 in group A and 15 in the group B. The median number of events in the group C index trials was 14.

The authors also observed that 90 percent and 98 percent of the very large effects observed in first and subsequently published trials, respectively, became smaller in meta-analyses that included other trials; the median odds ratio decreased from approximately 12 to 4 for first trials, and from 10 to 2.5 for subsequent trials.

Topics with very large effects were less likely than other topics to address mortality. Across the whole CDSR, there was only 1 intervention with large beneficial effects on mortality and no major concerns about the quality of the evidence (for a trial on extracorporeal oxygenation for severe respiratory failure in newborns).

“… this empirical evaluation suggests that very large effect estimates are encountered commonly in single trials. Conversely, genuine very large effects with extensive support from substantial evidence appear to be rare in medicine and large benefits for mortality are almost entirely nonexistent. As additional evidence accumulates, caution may still be needed, especially if there is repetitive testing of accumulating trials. Patients, clinicians, investigators, regulators, and the industry should consider this in evaluating very large treatment effects when the evidence is still early and weak,” the researchers write.

(JAMA. 2012;308[16]:1676-1684. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Pereira was supported in part by grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (Sao Paulo Research Foundation). All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Improving the Health of Patients and Populations Requires Humility, Uncertainty, and Collaboration

Andrew D. Oxman, M.D., of the Norwegian Knowledge Centre for the Health Services, Oslo, Norway, comments on the findings of this study in an accompanying editorial.

“Clinicians should be humble about the ability to prevent or treat most health problems, although a large range of effective interventions are available, some with large effects, most have modest (albeit important) effects and the effects of many are uncertain. Acknowledging uncertainty is the first, essential step to reducing important uncertainties through well-designed evaluations. Collaboration is essential to reduce those uncertainties by identifying and agreeing to priorities for evaluation and making sure not to continue to waste scarce resources for research on unimportant questions or poorly designed evaluations. Clinicians need to collaborate on needed evaluations and synthesizing and making the results of evaluations readily available to inform decisions about how best to improve the health of individuals and populations.”

(JAMA. 2012;308[16]:1691-1692. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 23, 2012

Media Advisory: To contact Michel M. Joosten, Ph.D., call Kelly Lawman at 617-667-7305 or email klawman@bidmc.harvard.edu.

CHICAGO – Among nearly 45,000 men who were followed up for more than two decades, those with the risk factors of smoking, hypertension, high cholesterol, and type 2 diabetes had an associated greater risk of developing PAD, according to a study in the October 24/31 issue of JAMA.

“Peripheral artery disease (PAD) is a distinct atherosclerotic syndrome marked by stenosis or occlusion [blockage] of the arteries, particularly of the lower extremities. PAD affects 8 to 10 million individuals in the United States, and is associated with reduced functional capacity and increased risk for cardiovascular morbidity and mortality. Despite its widespread prevalence and negative associations with quality of life, morbidity, and mortality, PAD remains underdiagnosed and undertreated,” according to background information in the article. Preventable or treatable risk factors for PAD are generally thought to be similar to other forms of cardiovascular disease, however their respective associations with risk of PAD and the extent to which they are jointly associated with the incidence of PAD are not well established.

Michel M. Joosten, Ph.D., of Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, and colleagues conducted a study to estimate the individual and cumulative associations of the 4 conventional cardiovascular risk factors of smoking, hypertension, hypercholesterolemia, and type 2 diabetes with the risk of PAD among men. The study included 44,985 men in the United States without a history of cardiovascular disease at the beginning of the study in 1986; participants in the Health Professionals Follow-up Study were followed up for 25 years until January 2011. The presence of risk factors was updated biennially during follow-up.

During a median (midpoint) follow-up of 24.2 years, there were 537 cases of incident PAD. The researchers found that each risk factor was significantly and independently associated with a higher risk of PAD after adjustment for the other 3 risk factors and confounders. Regardless of duration category, all men with a risk factor had higher risks of developing PAD compared with men without risk factors. Each additional risk factor approximately doubled the risk for PAD. Men who did not have any of the 4 risk factors had a 77 percent lower risk for developing PAD compared with all other men in the group. In 96 percent of PAD cases, at least 1 of the 4 risk factors was present at the time of PAD diagnosis.

Risk of PAD tended to increase with duration of both type 2 diabetes and hypercholesterolemia. Among men with a positive history of hypertension, risk of PAD was higher among men who reported use of 1 antihypertensive drug or 2 or more antihypertensive drugs compared with men with hypertension who did not report current use of antihypertensive drugs. Cumulative intensity of smoking demonstrated a graded relationship with risk.

“In conclusion, in this well-characterized cohort of U.S. men followed up for longer than 2 decades, smoking, hypertension, hypercholesterolemia, and type 2 diabetes each demonstrated strong, graded, and independent associations with risk of clinically significant PAD,” the authors write.

(JAMA. 2012;308[16]:1660-1667. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 8:15 A.M. (CT) WEDNESDAY, OCTOBER 17, 2012

Media Advisory: To contact Sangeeta Mehta, M.D., call Nicole Bodnar at 416-978-5811 or email Nicole.bodnar@utoronto.ca.
CHICAGO – For critically ill patients receiving mechanical ventilation, daily sedation interruption did not reduce the duration of mechanical ventilation or appear to offer any benefit to patients, and may have increased both sedation and analgesic use and nurse workload, according to a study appearing in JAMA. The study is being published early online to coincide with its presentation at the European Society of Intensive Care Medicine Annual Congress.

“Critically ill patients wean more quickly from mechanical ventilation, with lower risk of delirium, when clinicians use specific strategies to reduce excessive sedation, according to background information in the article. “Protocolized sedation and daily sedative interruption are 2 strategies to minimize sedation and reduce the duration of mechanical ventilation and intensive care unit (ICU) stay.”

Sangeeta Mehta, M.D., of Mount Sinai Hospital and the University of Toronto, and colleagues conducted a study to examine whether mechanically ventilated adults managed with both protocolized sedation and daily sedation interruption would receive less sedation and have a shorter duration of mechanical ventilation than patients managed with protocolized sedation alone. The randomized controlled trial, which included 430 critically ill, mechanically ventilated adults, was conducted in 16 tertiary care medical and surgical ICUs in Canada and the United States between January 2008 and July 2011. Patients received continuous opioid or benzodiazepine infusions and random allocation to protocolized sedation (n = 209) (control) or to protocolized sedation plus daily sedation interruption (n = 214). Using validated scales, nurses titrated infusions to achieve light sedation. For patients receiving daily interruption, nurses resumed infusions, if indicated, at half of previous doses. Patients were assessed for delirium and for readiness for unassisted breathing.

The median (midpoint) time to successful extubation (removal from mechanical ventilation) was 7 days in both groups. The researchers found that there were no significant between-group differences in ICU or hospital lengths of stay, hospital mortality, rates of unintentional device removal, delirium, ICU neuroimaging, tracheostomy, or organ dysfunction. Daily sedation interruption was associated with higher average daily doses of midazolam and fentanyl, and more daily boluses of benzodiazepines and opiates.

Overall, average Sedation-Agitation Scale scores per patient were similar in the 2 groups. However, nurse workload was significantly higher in the interruption group.

“In this multicenter randomized trial, we found that among mechanically ventilated patients receiving continuous sedation, the combined use of protocolized sedation and daily sedative interruption did not improve on the clinical outcomes observed with protocolized sedation alone. Patients in the daily interruption group received more opioids and benzodiazepines, and self-assessed nursing workload was higher for patients in the daily interruption group than the control group; however, these findings are of uncertain clinical importance,” the authors write.

(doi:10.1001/jama.2012.13872. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Funding was provided by the Canadian Institutes of Health Research. Dr. Cook is a Canada Research Chair of the Canadian Institutes for Health Research. Dr. Burns holds a Clinician Scientist Phase 2 Award of the Canadian Institutes for Health Research. Dr. Fowler is a Clinician Scientist of the Heart and Stroke Foundation (Ontario). All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Please Note: The presentation of this study can be viewed live online at http://www.esicm.org/news-article/lives-2012-hot-topics-session.

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EMBARGOED FOR EARLY RELEASE: 8:15 A.M. (CT) WEDNESDAY, OCTOBER 17, 2012

Media Advisory: To contact corresponding author Greet Van den Berghe, M.D., Ph.D., email greet.vandenberghe@med.kuleuven.be. To contact editorial author Robert C. Tasker, M.B.B.S., M.D., call Keri Stedman at 617-919-3114 or email keri.stedman@childrens.harvard.edu.

CHICAGO – Although there is some concern that hypoglycemia may adversely affect the developing brain, critically ill children who had been treated with tight glucose control during an intensive care unit admission did not have a worse measure of intelligence four years later than children who received usual care, despite frequent, brief episodes of hypoglycemia, according to a study appearing in the October 24/31 issue of JAMA. The study is being published early online to coincide with its presentation at the European Society of Intensive Care Medicine Annual Congress.

In critically ill children, hyperglycemia may deleteriously affect brain integrity and cognition. In 2009, a large randomized controlled trial with 700 patients revealed that tight glucose control (TGC) to normoglycemia reduced intensive care illness and death compared with usual care (UC), but increased hypoglycemia. Symptomatic hypoglycemia in young children has been associated with variable brain damage. “Therefore, the use of TGC in young patients in the intensive care unit (ICU) may have both beneficial and deleterious effects on various parts of the developing brain, with potentially long-term consequences for neurocognitive development,” according to background information in the article.

Dieter Mesotten, M.D., Ph.D., of the Catholic University of Leuven, Belgium, and colleagues conducted a long-term follow-up of a clinical trial that included 700 patients to exclude possible harm evoked by TGC in critically ill children during ICU treatment, and to validate short-term benefits. The randomized controlled trial included patients ages 16 years or younger who were admitted to the pediatric ICU of the University Hospitals in Leuven, Belgium, between October 2004 and December 2007. Follow-up was scheduled after 3 years with infants assessed at 4 years old between August 2008 and January 2012. For comparison, 216 healthy siblings and unrelated children were tested.

The primary outcomes measured for the study were intelligence (full-scale intelligence quotient [IQ]), as assessed with age-adjusted tests. Further neurodevelopmental testing encompassed tests for visual-motor integration; attention, motor coordination, executive functions; memory; and behavior.

Of the 700 patients in the study, 569 patients were alive and eligible for testing at follow-up. Twenty-seven children could not be reached and 86 children declined participation (16 percent of the total population, no difference between TGC and UC groups). At a median (midpoint) of 3.9 years after randomization, TGC in the ICU did not affect full-scale IQ score (median 88.0 vs. 88.5 for UC). The number of patients with a poor outcome (death or disability) at follow-up was similar in the TGC (68/349 [19 percent]) and UC (63/351 [18 percent]) groups. Other scores for intelligence, visual-motor integration, and memory also did not differ between groups. Brief hypoglycemia evoked by TGC was not associated with worse neurocognitive outcome. In the TGC group, motor coordination was actually improved (9 percent to 20 percent better) and also cognitive flexibility (19 percent better).

The authors write that their data “provide evidence that some of the neurocognitive impairment previously reported in children who have been critically ill could be beneficially affected by altering medical care.”

“In conclusion, 4 years after childhood critical illness, TGC to age-adjusted normoglycemia in an experienced ICU, despite having frequently evoked brief episodes of hypoglycemia, did not cause any detectable harm to intelligence and improved other areas of cognition.”

(JAMA. 2012;308[16]:1641-1650. 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.

Please Note: The presentation of this study can be viewed live online at http://www.esicm.org/news-article/lives-2012-hot-topics-session.

Editorial: Pediatric Critical Care, Glycemic Control, and Hypoglycemia – What Is the Real Target?

In an accompanying editorial, Robert C. Tasker, M.B.B.S., M.D., of Boston Children’s Hospital, writes that “future studies should build on these findings to address additional questions, such as is the global neurocognitive deficit a reflection of pre-morbid state and genetic disease?”

“If this is the case, perhaps there is little that can be achieved except for improving the practice of intensive care. Alternatively, is the neurocognitive morbidity a consequence of cumulative and many different noxious agents and insults during anesthesia and postoperative intensive care? If this is the case, physicians and other caregivers now have a new target and an imperative to follow up all critically ill children who receive pediatric ICU care.”

(JAMA. 2012;308[16]:1687-1688. 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. Tasker reported being a co-investigator of the Control of Hyperglycaemia in Paediatric Intensive Care study.

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EMBARGOED FOR EARLY RELEASE: 11:15 A.M. (CT) THURSDAY, OCTOBER 18, 2012

Media Advisory: To contact Tarak K. Trivedi, B.S., call John Easton at 773-795-5225 or email john.easton@uchospitals.edu.

CHICAGO – In a study that included more than 300 Medicare-certified nursing homes, rates of hospitalization and death were substantially increased during outbreaks of norovirus gastroenteritis vs. non-outbreak periods, according to a study appearing in the October 24/31 issue of JAMA. The study is being published early online to coincide with its presentation at the ID (infectious disease) Week meeting.

“In the United States, nursing homes annually provide care to approximately 3.3 million residents’ and 22 percent of all deaths occur in these settings. Gastroenteritis outbreaks are common in nursing homes in high-income countries. Annually, more than 1,000 outbreaks of acute gastroenteritis are reported by nursing homes to U.S. public health agencies, and this likely represents only a fraction of the actual number due to underreporting. Although nearly half of all reported nursing home gastroenteritis outbreaks are never etiologically [the cause] confirmed because of challenges in performing diagnostic testing, norovirus is implicated in 86 percent of etiologically confirmed outbreaks,” according to background information in the article. Because hospitalizations and deaths are common among the vulnerable, elderly population in nursing homes, it is difficult to ascertain if there is actually a greater number of these events during norovirus outbreaks.

Tarak K. Trivedi, B.S., a 4^th year medical student at the University of Chicago Pritzker School of Medicine, and colleagues conducted a study to assess the association between norovirus outbreaks and excess all-cause hospitalization and mortality in nursing homes. The study included 308 Medicare-certified nursing homes in Oregon, Wisconsin, and Pennsylvania that reported at least 1 confirmed or suspected norovirus outbreak to the Centers for Disease Control and Prevention’s National Outbreak Reporting System (NORS), January 2009 to December 2010. Deaths and hospitalizations occurring among residents of these nursing homes were identified through the Medicare Minimum Data Set (MDS). Rates of all-cause hospitalization and mortality during outbreak periods were compared with rates during non-outbreak periods, after adjusting for seasonality.

The nursing homes in the study reported a total of 407 norovirus outbreaks. The median (midpoint) duration of outbreaks was 13 days. Hospitalizations and deaths were reported in 119 (29 percent) and 30 (7 percent) outbreaks, respectively. A total of 67,730 hospitalizations and 26,055 deaths were reported in the nursing home cohort during follow-up. Nursing homes experienced 2,533 hospitalizations (124.0/home-year) and 1,097 deaths (53.7/ home-year) during outbreak periods compared with 65,197 hospitalizations (109.5/home-year) and 24,958 deaths (41.9/home-year) during non-outbreak periods. After adjusting for seasonality by month, the rates of hospitalization and death were significantly elevated during outbreak periods.

The increase in hospitalizations was concentrated in the initial week and the subsequent week, and the increased mortality rate was concentrated in the initial week, relative to outbreak onset. In subsequent weeks, the rates of hospitalizations and deaths returned to the levels observed in non-outbreak periods.

The researchers found that nursing homes with lower daily RN hours per resident had a significantly increased rate of mortality during norovirus outbreaks compared with baseline, while no increased risk was observed in homes with higher daily RN hours per resident. The increase in hospitalization rates did not show a similar pattern.

“In conclusion, we detected a consistently increased risk of hospitalization and death from all causes during norovirus outbreaks among residents in nursing homes from 3 U.S. states. As a next step, research should be directed to determine if this increase is directly attributable to norovirus infection and subsequent disease resulting from gastroenteritis. Additionally, more detailed information is necessary to understand the specific contributory causes and comorbidities of norovirus-associated deaths. Given the lack of diagnostic testing in sporadic illness, outbreaks may provide the best opportunities for identifying such associations between norovirus disease and deaths,” the authors write.

“At present, strategies for averting these severe outcomes include general treatment for dehydration and infection control to prevent and control outbreaks. More targeted interventions would be welcome and in light of recent progress with a norovirus vaccine, these results highlight a setting and population that may benefit if efficacy and safety of immunization can be demonstrated.”

(doi:10.1001/jama.2012.14023. 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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