EMBARGOED FOR EARLY RELEASE: 1 P.M. (CT) SATURDAY, MARCH 29, 2014

Media Advisory: To contact Maryam Kavousi, M.D., Ph.D., email m.kavousi@erasmusmc.nl.

Application of U.S. and European cholesterol guidelines to a European population found that proportions of individuals eligible for statins differed substantially, with one U.S. guideline recommending statins for nearly all men and two-thirds of women, proportions exceeding those of the other guidelines, according to a JAMA study released online to coincide with the 2014 American College of Cardiology Scientific Sessions.

The common approach in cardiovascular disease (CVD) primary prevention is to identify individuals at high enough risk to justify more intensive lifestyle interventions, treatment with medications, or both. The CVD prevention guidelines developed by the National Cholesterol Education Program expert panel, the American College of Cardiology/American Heart Association (ACC/AHA) task force, and the European Society of Cardiology (ESC) are the major guidelines influencing clinical practice. “Varying approaches to CVD risk estimation and application of different criteria for therapeutic recommendations would translate into substantial differences in proportions of individuals qualifying for treatment at a population level,” the authors write.

Maryam Kavousi, M.D., Ph.D., of Erasmus MC-University Medical Center, Rotterdam, the Netherlands, and colleagues conducted a study to determine population-wide implications of the ACC/AHA, the Adult Treatment Panel III (ATP-III), and the ESC guidelines, using 4,854 Dutch participants from the Rotterdam Study (a population-based study of patients 55 years of age or older). The researchers calculated 10-year risks for “hard” (major) atherosclerotic cardiovascular disease (ASCVD) events (including fatal and nonfatal coronary heart disease [CHD] and stroke) (ACC/AHA); hard CHD events (fatal and nonfatal heart attack, CHD mortality) (ATP-III); and atherosclerotic CVD mortality (ESC). The proportions of individuals for whom statins would be recommended were calculated per guideline.

The average age of the participants was 65.5 years; 54.5 percent were women. The researchers found that application of the ACC/AHA guideline recommended treatment for 96.4 percent of men and 65.8 percent of women; for the ATP-III guideline, the portion was 52 percent of men and 35.5 percent of women; and for the ESC guideline, 66.1 percent of men and 39.1 percent of women were included in the category where treatment was recommended.

With the ACC/AHA approach, average predicted risk vs observed major ASCVD events was 21.5 percent vs 12.7 percent for men and 11.6 percent vs 7.9 percent for women.  Similar overestimation occurred with the ATP-III and ESC model.

“Improving risk predictions and setting appropriate population-wide thresholds are necessary to facilitate better clinical decision making,” the authors conclude.

(doi:10.1001/jama.2014.2632; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 # # #

EMBARGOED FOR EARLY RELEASE: 1 P.M. (CT) SATURDAY, MARCH 29, 2014

Media Advisory: To contact Ann Marie Navar-Boggan, M.D., Ph.D., call Sarah Avery at 919-724-5343 or email sarah.avery@duke.edu. To contact editorial author Harlan M. Krumholz, M.D., S.M., call Karen Peart at 203-432-1326 or email karen.peart@yale.edu.
Applying the updated 2014 blood pressure (BP) guideline to the U.S. population suggests that nearly 6 million adults are no longer classified as needing hypertension medication, and that an estimated 13.5 million adults would now be considered as having achieved goal blood pressure, primarily older adults, according to a JAMA study released online to coincide with the 2014 American College of Cardiology Scientific Sessions.

Ann Marie Navar-Boggan, M.D., Ph.D., of Duke University Medical Center, Durham, N.C., and colleagues quantified the proportion of adults potentially affected by the updated 2014 recommendations, compared to the previous guideline, issued nearly 10 years ago (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [JNC 7]). The researchers used data from the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2010 (n = 16,372), and evaluated hypertension control and treatment recommendations for U.S. adults. The new guideline proposed less restrictive BP targets for adults 60 years of age or older and for those with diabetes and chronic kidney disease.

The authors estimate that the proportion of younger adults (18-59 years) in the U.S. considered to have treatment-eligible hypertension would be decreased from 20.3 percent under JNC 7 to 19.2 percent under the 2014 BP guideline and from 68.9 percent to 61.2 percent among older adults (≥ 60 years). Extrapolating these numbers to the population represented by this NHANES sample (U.S. adults in 2007) translates to a reduction in 5.8 million adults no longer classified as needing hypertension medication (70 million under JNC 7 to 64.2 million under the 2014 BP guideline).

The proportion of adults with treatment-eligible hypertension who met BP goals also increased slightly for younger adults, from 41.2 percent under JNC 7 to 47.5 percent under the 2014 BP guideline, and more substantially for older adults, from 40.0 percent to 65.8 percent.

The authors estimate that 13.5 million adults not previously considered to be meeting BP targets would be considered at goal BP under the new guideline, with the majority affected age 60 years and older, and many of whom have diabetes, chronic kidney disease, and cardiovascular disease.

Overall, 1.6 percent of U.S. adults 18-59 years of age and 27.6 percent of adults age 60 years or older were receiving BP-lowering medication and meeting more stringent JNC 7 targets. These patients may be eligible for less stringent or no BP therapy with the 2014 BP guideline.

“Public health messaging should target the large number of adults in the United States with changing recommendations under new guideline to ensure that new recommendations do not result in unintended consequences in adults now with ‘relabeled’ BP status,” the authors write. “Further research is needed to determine how this new guideline affects overall BP levels attained and to determine the related effects on cardiovascular disease outcomes.”

(doi:10.1001/jama.2014.2531 Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This research was supported in part by Duke Clinical Research Institute’s research funds and unrestricted grants from M. Jean de Granpre and Louis and Sylvia Vogel. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

 Editorial: The New Cholesterol and Blood Pressure Guidelines

Harlan M. Krumholz, M.D., S.M., of the Yale University School of Medicine, New Haven, Conn., writes in an accompanying editorial that these new guidelines, with their innovations and controversy, have established a new course.

“Navigating it may be uncomfortable and will perhaps force clinicians to grapple with issues that have been ignored for too long. While it is important to advocate for health and promote healthy environments and behaviors on the broader scale, for medical decision making, it is even more important to ensure informed choice with the full participation of the person who will incur the risks and benefits of the decision. When viewed through this lens, the controversies about the guidelines become less contentious and the focus shifts to refining the evidence and producing better ways to communicate what is known for decision-making purposes. By directing attention to that message, already firmly embedded in these guidelines with their bold recommendations and deference to patient preference, they may have accomplished more than they ever envisioned.”

(doi:10.1001/jama.2014.2634; 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.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 25, 2014

Media Advisory: To contact Edward J. McNulty, M.D., call Janet Byron at 510-891-3115 or email Janet.L.Byron@kp.org.
Chicago –There has been a sharp decline since 2006 in the use of nuclear myocardial perfusion imaging (MPI; an imaging procedure used to determine areas of the heart with decreased blood flow), a decrease that cannot be explained by an increase in other imaging methods, according to a study in the March 26 issue of JAMA.

Nuclear myocardial perfusion imaging accounted for much of the rapid growth in cardiac imaging that occurred from the 1990s through the middle 2000s. Edward J. McNulty, M.D., of Kaiser Permanente Medical Center, San Francisco, and colleagues conducted a study to examine trends in MPI use within a large, community-based population. They obtained patient data for MPI performed from 2000-2011 for members ages 30 years or older from the clinical databases of Kaiser Permanente Northern California, an integrated health care delivery system that provides inpatient and outpatient care for more than 2.3 million adults.

Overall, MPI was used for 302,506 patients at 19 facilities. From 2000 until 2006, MPI use increased by a relative 41 percent. Then between 2006 and 2011, MPI use declined a relative 51 percent. Declines from 2006 to 2011 were greater for outpatients than inpatients (58 percent vs 31 percent) and for persons younger than 65 years. Use of cardiac computed tomography (a newer imaging procedure) increased during this time period, and could have accounted for 5 percent of the observed decline in overall MPI use if performed as a substitute.

“Although the abrupt nature of the decline suggests changing physician behavior played a major role, incident coronary disease, as assessed by [heart attack], also declined [by 27 percent]. We could not determine the relative effects of these factors on MPI use,” the authors write.

“… the substantial reduction in MPI use demonstrates the ability to reduce testing on a large scale with anticipated reductions in health care costs.”

(doi:10.1001/jama.2014.472; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This study was supported by a grant from the Kaiser Permanente Northern California Community Benefits Program.  Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 25, 2014

Media Advisory: To contact corresponding author John Danesh, F.R.C.P., email erfc@phpc.cam.ac.uk.

Chicago – In a study that included nearly 300,000 adults without a known history of diabetes or cardiovascular disease (CVD), adding information about glycated hemoglobin (HbA_1c), a measure of longer-term blood sugar control, to conventional CVD risk factors like smoking and cholesterol was associated with little improvement in the prediction of CVD risk, according to a study in the March 26 issue of JAMA.

Because higher glucose levels have been associated with higher CVD incidence, it has been proposed that information on blood sugar control might improve doctors’ ability to predict who will develop CVD, according to background information in the article.

Emanuele Di Angelantonio, M.D., of the University of Cambridge, United Kingdom, and colleagues with the Emerging Risk Factors Collaboration, conducted an analysis of data available from 73 studies involving 294,998 participants to determine whether adding information on HbA_1c levels to information about conventional cardiovascular risk factors is associated with improvements in the prediction of CVD risk. Predicted 10-year risk categories were classified as low (<5 percent), intermediate (5 percent to <7.5 percent), and high (≥ 7.5 percent).

Among the primary findings of the researchers, adding information on levels of HbA_1c to conventional CVD risk factors was associated with only slight improvement in risk discrimination (how well a statistical model can separate individuals who do and do not go on to develop CVD). In addition, they found that adding information on HbA_1c did not improve the accuracy of probability predictors for patients with and without CVD.

“Contrary to recommendations in some guidelines, the current analysis of individual-participant data in almost 300,000 people without known diabetes and CVD at baseline indicates that measurement of HbA_1c is not associated with clinically meaningful improvement in assessment of CVD risk,” the authors write.

(doi:10.1001/jama.2014.1873; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 25, 2014

Media Advisory: To contact David S. Goldberg, M.D., M.S.C.E., call Lee-Ann Donegan at 215-349-5660 or email leeann.donegan@uphs.upenn.edu.
Chicago – Among veterans meeting eligibility for liver transplantation, greater distance from a Veterans Affairs transplant center or any transplant center was associated with lower likelihood of being put on a waitlist or receiving a transplant, and a greater likelihood of death, according to a study in the March 26 issue of JAMA.

Centralization of specialized health care services is used to control costs, concentrate expertise, and minimize regional differences in quality of care. Although efficient, centralization may offset gains in care delivery by increasing the distance between patients and hospitals. The effect of increased travel on access and outcomes for services such as organ transplantation is not fully understood, according to background information in the article.

David S. Goldberg, M.D., M.S.C.E., of the University of Pennsylvania, Philadelphia, and colleagues linked data from the Veterans Health Administration’s electronic medical record to Organ Procurement and Transplantation Network data to evaluate the association between distance from a Veterans Affairs (VA) transplant center (VATC) and waitlisting for liver transplantation, actually having a transplant, and risk of death.

From 2003-2010, 50,637 veterans were classified as potentially eligible for transplant; 6 percent were waitlisted for transplant, and 49 percent of these veterans were waitlisted at 1 of the 5 VATCs. In various models, increasing distance to closest VATC or any transplant center was associated with lower odds of being waitlisted; with lower transplantation rates; and an increased risk of death.

The authors write that these findings may be explained by (1) long travel times from homes remote from a transplant center reducing the likelihood of getting evaluated for transplantation; or (2) reduced ability to proceed with transplantation because of the need for a patient or his or her family members to relocate.

“This issue of distance and access to care is critical given the focus on accountable care organizations that create large networks of physicians and hospitals. As complex, expensive medical technology evolves, certain services may only be offered at a limited number of sites. Although our findings are consistent with prior studies evaluating the association of distance to care, our study is the first, to our knowledge, to demonstrate the adverse consequences of centralization of specialized care at a limited number of sites,” the researchers write.

“The relationship between these findings and centralizing specialized care deserves further investigation.”

(doi:10.1001/jama.2014.2520; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This work was supported in part by a Health Resources and Services Administration contract. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 25, 2014

Media Advisory: To contact Kypros Kypri, Ph.D., email kypros.kypri@newcastle.edu.au. To contact editorial co-author Timothy S. Naimi, M.D., M.P.H., call Gina DiGravio at 617-638-8480 or email gina.digravio@bmc.org.
Chicago – Among university students in New Zealand, a web-based alcohol screening and brief intervention program produced a modest reduction in the amount of alcohol consumed per drinking episode but not in the frequency of drinking, overall amount consumed, or in related academic problems, according to a study in the March 26 issue of JAMA.

Unhealthy alcohol use is common among young people, including university students. Using an internet site to screening students for unhealthy alcohol use and intervene if appropriate has been suggested as an inexpensive means of reaching large numbers of young people, according to background information in the article.

Kypros Kypri, Ph.D., of the University of Newcastle, Callaghan, NSW, Australia, and colleagues emailed invitations containing hyperlinks to the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) screening test to 14,991 students (ages 17 to 24 years) at 7 New Zealand universities. Participants who screened positive (AUDIT-C score ≥ 4) were randomized to 10 minutes of online assessment and feedback (including comparisons with medical guidelines and peer norms) on alcohol expenditure, peak blood alcohol concentration, alcohol dependence, and access to help and information, or no further intervention. A fully automated 5-month follow-up assessment was conducted that included a questionnaire regarding alcohol consumption.

Of 5,135 screened students, 3,422 scored 4 or greater and were randomized, and 83 percent were followed up at 5 months. Relative to control participants, those who received the intervention consumed less alcohol per typical drinking episode (median [midpoint] 4 drinks vs. 5 drinks), a finding that was no longer statistically significant after accounting for student attrition from the study. The intervention was otherwise not effective; participants who received the intervention did not consume alcohol less often or in lower volume; academic problem scores did not differ between groups, and the intervention did not have an effect on the risk of binge or heavy drinking.

“The findings underline the importance of pragmatic trials to inform preventive medicine. They indicate that web-based alcohol screening and brief intervention should not be relied upon alone to address unhealthy alcohol use in this population,” the authors state, while noting other potential interventions such as restriction in the physical availability and promotion of alcohol.

(doi:10.1001/jama.2014.2138; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, March 25 at this link.

Editorial: Electronic Alcohol Screening and Brief Interventions – Is the Benefit Worth the Effort?

“Although electronic alcohol screening and brief counseling interventions may have effects on participants among subgroups of university students or among other groups, the results of this study and others suggest that the effect of this type of intervention among university students is modest at best,” write Timothy S. Naimi, M.D., M.P.H., of Boston Medical Center, Boston, and Thomas B. Cole, M.D., M.P.H., of JAMA, Chicago, in an accompanying editorial.

“At present, there is little direct evidence demonstrating that electronic alcohol screening and brief counseling intervention has a meaningful population-level effect on excessive alcohol consumption or related harms in any group, and therefore its utility as a stand-alone public health approach is in doubt. As a scientific standard, future studies evaluating possible population-level health effects of this intervention (which, to be clear, was not the purpose of the study by Kypri et al) should assess outcomes at the population level, ideally using instruments external to the study. In addition, corroborating evidence from outcomes other than those based on self-report will be essential to establish effectiveness.”

(doi:10.1001/jama.2014.2139; 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.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 25, 2014

Media Advisory: To contact corresponding author Jacques J. Bergman, M.D., Ph.D., email j.j.bergman@amc.uva.nl. To contact editorial author Klaus Monkemuller, M.D., Ph.D., F.A.S.G.E., call Tyler Greer at 205-934-2041 or email tgreer@uab.edu.

Chicago – Among patients with the condition known as Barrett esophagus, treatment of abnormal cells with radiofrequency ablation (use of heat applied through an endoscope to destroy cells) resulted in a reduced risk of this condition progressing to cancer, according to a study in the March 26 issue of JAMA.

In the last 3 decades, the incidence of esophageal cancer has increased more rapidly that other cancers in the Western world. This type of cancer often originates from Barrett esophagus, a condition that involves abnormal changes in the cells of the lower portion of the esophagus, a complication of severe chronic gastrointestinal reflux disease (GERD), according to background information in the article. Radiofrequency ablation (RFA) is an effective treatment for Barrett esophagus, but its benefits have largely been shown in patients with high-grade dysplasia (precancerous changes more likely to progress quickly to cancer). The question of whether RFA is effective for patients with Barrett esophagus and low-grade dysplasia (precancerous changes that progress more slowly to cancer) “is a clinically important question because 25 percent to 40 percent of patients with Barrett esophagus are diagnosed with low-grade dysplasia at some point during follow-up,” the authors write.

K. Nadine Phoa, M.D., of the University of Amsterdam, the Netherlands, and colleagues randomly assigned 136 patients with a confirmed diagnosis of Barrett esophagus and low-grade dysplasia to radiofrequency ablation (ablation; maximum of 5 sessions allowed) or endoscopic surveillance (control). The researchers assessed the rate of progression to high-grade dysplasia and esophageal cancer. The study was conducted at 9 European sites between June 2007 and June 2011; follow-up ended May 2013.

The researchers found that ablation was associated with reduced absolute risk of progression to high-grade dysplasia or cancer of 25 percent (1.5 percent vs 26.5 percent for control) and a reduced absolute risk of progression to cancer of 7.4 percent (1.5 percent vs 8.8 percent). Complete eradication of dysplasia occurred and persisted in the majority of patients in the ablation group.

The trial was terminated early due to the superiority of ablation for the primary outcome and concerns about patient safety should the trial continue.

“In this multicenter, randomized trial of radiofrequency ablation vs surveillance in patients with Barrett esophagus and a confirmed histological diagnosis of low-grade dysplasia, ablation substantially reduced [tumor] progression to high-grade dysplasia and adenocarcinoma over 3 years of follow-up. Patients with a confirmed diagnosis of low-grade dysplasia should therefore be considered for ablation therapy,” the authors conclude.

(doi:10.1001/jama.2014.2511; 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: Radiofrequency Ablation for Barrett Esophagus With Confirmed Low-Grade Dysplasia

Klaus Monkemuller, M.D., Ph.D., F.A.S.G.E., of the University of Alabama at Birmingham, comments on the findings of this study in an accompanying editorial.

“The clinical trial by Phoa et al provides important evidence to support the use of radiofrequency ablation not only for patients with high-grade dysplasia and early cancer, but also for carefully selected patients [via screening and testing] with Barrett esophagus and confirmed low-grade dysplasia. A proactive endoscopic approach to eliminate dysplasia may result in reduced morbidity and mortality related to the progression of this disease.”

(doi:10.1001/jama.2014.2512; 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.

 # # #

EMBARGOED FOR EARLY RELEASE: 3:30 A.M. (CT) TUESDAY, MARCH 18, 2014

Media Advisory: To contact corresponding author Rinaldo Bellomo, M.D., Ph.D., email Rinaldo.BELLOMO@austin.org.au. To contact editorial co-author Theodore J. Iwashyna, M.D., Ph.D., call Shantell Kirkendoll at 734-764-2220 or email SMKIRK@UMICH.EDU.

Chicago – In critically ill patients in Australia and New Zealand with severe sepsis or septic shock, there was a decrease in the risk of death from 2000 to 2012, findings that were accompanied by changes in the patterns of discharge of intensive care unit (ICU) patients to home, rehabilitation, and other hospitals, according to a study appearing in JAMA. The study is being released early to coincide with its presentation at the International Symposium on Intensive Care and Emergency Medicine.

Severe sepsis and septic shock are the biggest cause of death in critically ill patients. Over the last 20 years, multiple randomized controlled trials have attempted to identify new treatments to improve the survival of these patients, according to background information on the article. It is unknown whether progress has been made in decreasing mortality.

Kirsi-Maija Kaukonen, M.D., Ph.D., E.D.I.C., of Monash University, Melbourne, Australia, and colleagues examined trends in mortality among 101,064 patients with severe sepsis or septic shock from 171 ICUs in Australia and New Zealand from 2000 to 2012.

The researchers found that absolute mortality from severe sepsis decreased from 35.0 percent to 18.4 percent during this time period, an annual rate of absolute decrease of 1.3 percent, and a relative risk reduction of 47.5 percent. The annual decline in mortality did not differ between patients with severe sepsis/septic shock and those with all other diagnoses.

The authors write that their study provides evidence that sepsis-related mortality has steadily decreased over time even after adjustments for illness severity, center effect, regional effects, hospital size and other key variables. “It is unclear whether any improvements in diagnostic procedures, earlier and broader-spectrum antibiotic treatment, or more aggressive supportive therapy according to severity of the disease contributed to this change. The observation that an equivalent improvement occurred in nonseptic patients supports the view that overall changes in ICU practice rather than in the management of sepsis explain most of our findings.”

(doi:10.1001/jama.2014.2637; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Declining Case Fatality Rates for Severe Sepsis

Theodore J. Iwashyna, M.D., Ph.D., of the University of Michigan, Ann Arbor, and Derek C. Angus, M.D., M.P.H., of the University of Pittsburgh, (and Associate Editor, JAMA), comment on the findings of this study in an accompanying editorial.

“Short-term [severe sepsis] mortality has declined to a level at which it no longer reflects the entire story of outcomes for patients with severe sepsis. Although the reduction in sepsis-related mortality is welcome, it makes the need for data on morbidity and longer-term outcomes all the more pressing. Even while awaiting confirmation of this mortality finding in other settings, the general challenge for research is clear. Clinical trials need to adopt longer-term morbidity measures, if only to have the power to be able to detect feasible effect sizes in new trials. Registries and benchmarking programs need to find low-cost ways to assess outcomes other than short-term mortality, if only to remain relevant. Critical care is improving for patients with severe sepsis and throughout the ICU, and clinicians and researchers must raise the standards and broaden measurement to continue such progress.”

(doi:10.1001/jama.2014.2639; 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.

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 18, 2014

Media Advisory: To contact corresponding author Shamez N. Ladhani, M.R.C.P.C.H., Ph.D., email Shamez.Ladhani@phe.gov.uk. To contact editorial author Morven S. Edwards, M.D., call Glenna Picton at 713-798-7973 or email picton@bcm.edu.

Chicago – In a surveillance study of infection with the bacterium Haemophilus influenzae among women of reproductive age in England and Wales from 2009-2012, pregnancy was associated with a greater risk of this infection, which was associated with poor pregnancy outcomes such as premature birth and stillbirth, according to a study in the March 19 issue of JAMA.

Haemophilus influenzae can cause illnesses that include respiratory infections. Some studies have suggested an increased risk of invasive H influenzae disease during pregnancy, although these were based on a small number of cases, according to background information in the article.

Sarah Collins, M.P.H., of Public Health England, London, and colleagues examined the outcomes of invasive H influenzae disease in women of reproductive age during a 4-year period. The study included data from Public Health England, which conducts enhanced national surveillance of invasive H influenzae disease in England and Wales. General practitioners caring for women ages 15 to 44 years with laboratory-confirmed invasive H influenzae disease during 2009-2012 were asked to complete a clinical questionnaire three months after infection.

The incidence of laboratory-confirmed invasive H influenzae disease was low, at 0.50 per 100,000 women (171 women). Pregnant women were at higher risk of infection mainly due to unencapsulated (a category of strain) H influenzae disease. This infection during the first 24 weeks of pregnancy was associated with fetal loss (93.6 percent) and extremely premature birth (6.4 percent). Unencapsulated H influenzae infection during the second half of pregnancy was associated with premature birth in 28.6 percent and stillbirth in 7.1 percent of 28 cases. In addition to the serious infection, these infants were also at risk for the long-term complications of prematurity. Pregnancy loss following invasive H influenzae disease was 2.9 times higher than the U.K. national average.

The authors write that the finding that almost all infections were associated with miscarriage, stillbirth, or premature birth provides evidence of the severity of infection in pregnant women. “Invasive H influenzae disease is a serious infection also among nonpregnant women that requires hospitalization for intravenous antibiotics and close monitoring following appropriate microbiological investigations, particularly given that more than half of the nonpregnant women in this investigation had a concurrent medical condition.”

The researchers note that the overall estimated rates reported in this study should be considered a minimum because only laboratory-confirmed invasive cases were followed up.

(doi:10.1001/jama.2014.1878; 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: Adverse Fetal Outcomes – Expanding the Role of Infection

“What should be the response by the public health community and those providing care to pregnant women and newborns in light of the findings of Collins et al?,” asks Morven S. Edwards, M.D., of the Baylor College of Medicine, Houston, in an accompanying editorial.

“With infectious diseases, the diagnosis is made only when infection is considered a possibility and when appropriate testing is performed. As an immediate goal, laboratories should be aware that H influenzae (especially unencapsulated strains) are potential pathogens in pregnant women and neonates,” Dr. Edwards writes. “Moving forward, it will be important to determine the scope of infection caused by this pathogen in other geographic regions.”

(doi:10.1001/jama.2014.1889; 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.

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 18, 2014

Media Advisory: To contact Asaf Vivante, M.D., email asafvivante@gmail.com.

Chicago – Men who as children had glomerular disease, a disorder of the portion of the kidney that filters blood and one that usually resolves with time, were more likely than men without childhood glomerular disease to have high blood pressure as an adult, according to a study in the March 19 issue of JAMA.

Glomerular disease was defined for this study as glomerulonephritis or nephrotic syndrome (both are kidney disorders). Most children who develop glomerular disease have a favorable prognosis with complete resolution of all signs and symptoms. Yet the long-term complications of resolved childhood glomerular disease are incompletely understood, according to background information in the article.

Asaf Vivante, M.D., of IDF Medical Corps, Tel-Hashomer, Israel, and colleagues conducted a study that included male military personnel in Israel, who had a baseline evaluation conducted prior to recruitment at age 17 years, during which the diagnosis of resolved childhood glomerular disease was determined. Participants were followed up until the diagnosis of hypertension (systolic >140 mm Hg or diastolic >90 mm Hg), retirement from service, or December 31, 2010, whichever came first.

The study included 38,144 career personnel, of whom 264 were diagnosed with a medical history of resolved childhood glomerular disease. During an average follow-up of 18 years, 2,856 participants developed hypertension; 13.6 percent of participants with a medical history of resolved childhood glomerular disease and 7.4 percent of those without such history.

“In this study, resolved childhood glomerular disease was associated with subsequent risk of hypertension in a cohort of young healthy adult men,” the authors write. They add that their results suggest that glomerular disease during childhood may initiate kidney injury that manifests in adulthood, well before sufficient loss of excretory kidney function can be measured with standard laboratory tests, such that the first manifestation may be adult hypertension.

(doi:10.1001/jama.2013.284310; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 18, 2014

Media Advisory: To contact Marc Righini, M.D., email Marc.Righini@hcuge.ch.

Chicago – Using a patient’s age to raise the threshold for an abnormal result of a blood test used to assess patients with a suspected pulmonary embolism (blood clot in lungs) appeared to be safe and led to fewer healthy patients with the diagnosis, according to a study in the March 19 issue of JAMA.

D-dimer is a breakdown product of a blood clot, and measuring D-dimer levels is one way doctors exclude a diagnosis of pulmonary embolism (PE). Several studies have shown that D-dimer levels increase with age. As a result, the proportion of healthy patients with abnormal test results (above 500 µg/L for most available commercial tests) increases with age, limiting the test’s clinical usefulness in older people, according to background information in the article.

Marc Righini, M.D., of Geneva University Hospital, Geneva, Switzerland, and colleagues examined whether an age-adjusted D-dimer threshold, which involved redefining the test value that distinguished abnormal and normal results by multiplying the patient’s age by 10 in patients 50 years or older, safely excluded the diagnosis of PE in elderly patients with suspected PE. The study, conducted at 19 centers in Belgium, France, the Netherlands, and Switzerland between January 2010 and February 2013, included outpatients who underwent a clinical probability assessment (measured by one of two scoring systems based on risk factors and clinical findings), D-dimer measurement, and computed tomography pulmonary angiography (CTPA; image of lungs).

Of the 3,346 patients with suspected PE included in the analysis, the prevalence of PE was 19 percent. The researchers found that combining the probability assessment with adjustment of the D-dimer cutoff for patient age safely excluded the diagnosis of PE and was associated with a low likelihood of subsequent PE or other venous blood clot. In elderly patients, there was an increase in the proportion of patients in whom PE could be excluded without further imaging.

“Future studies should assess the utility of the age-adjusted cutoff in clinical practice. Whether the age-adjusted cutoff can result in improved cost-effectiveness or quality of care remains to be demonstrated,” the authors conclude.

(doi:10.1001/jama.2014.2135; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 18, 2014

Media Advisory: To contact corresponding author Christian F. Christiansen, M.D., Ph.D., email cc@dce.au.dk.

Chicago – Critically ill patients receiving mechanical ventilation had a higher prevalence of prior psychiatric diagnoses and an increased risk of a new psychiatric diagnosis and medication use after hospital discharge, according to a study in the March 19 issue of JAMA.

With recent advances in medical care, more patients are surviving critical illness. Critically ill patients are exposed to stress, including pain, respiratory distress, and delirium, all of which may impact subsequent mental health. The extent of psychiatric illness prior to critical illness, as well as the magnitude of increased risk of psychiatric illness following critical illness, is unclear, according to background information in the article.

Hannah Wunsch, M.D., M.Sc., of Columbia University, New York, and colleagues assessed psychiatric diagnoses and medication prescriptions before and after critical illness. The study included critically ill patients in Denmark from 2006-2008 with follow-up through 2009, and matched comparison groups of hospitalized patients and the general population. Critical illness was defined as intensive care unit (ICU) admission with mechanical ventilation.

Among 24,179 critically ill patients included in the study, 6.2 percent had 1 or more psychiatric diagnoses in the 5 years prior to critical illness vs 5.4 percent for hospitalized patients and 2.4 percent for the general population. The proportion of 5-year preadmission prescriptions for psychoactive drugs (those that affect mental functioning such as mood, behavior, or thinking processes) were similar to those for hospitalized patients (48.7 percent vs 48.8 percent) but higher than those for the general population (33.2 percent).

Among the 9,921 critical illness survivors with no psychiatric history, the absolute risk of new psychiatric diagnoses was low but higher than that for hospitalized patients (0.5 percent vs 0.2 percent over the first 3 months) and the general population group (0.02 percent). The proportion of patients given new psychoactive medication prescriptions was also increased in the first 3 months (12.7 percent vs 5.0 percent for the hospital group) and 0.7 percent for the general population, but the these differences had largely resolved by the end of the first year of follow-up.

“… Our study provides important data on the burden of psychiatric illness among patients who experience critical illness requiring mechanical ventilation, as well as on the risks of psychiatric diagnoses and treatment with psychoactive medications in the year following ICU discharge. Discharge planning for these patients may require more comprehensive discussion of follow-up psychiatric assessment and provision of information to caregivers and other family members regarding potential psychiatric needs,” the authors write.

“Although the absolute risks were low, given the strong association between psychiatric diagnoses, such as depression, and poor outcomes after acute medical events, such as myocardial infarction and surgery, our data suggest that prompt evaluation and management of psychiatric symptoms may be an important focus for future interventions in this high-risk group.”

(doi:10.1001/jama.2014.2137; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the Danish Medical Research Council, the Clinical Institute at Aarhus University, and the Department of Clinical Epidemiology’s Research Foundation at Aarhus University Hospital. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 11, 2014

Media Advisory: To contact corresponding author Ana Marusic, M.D., Ph.D., email ana.marusic@mefst.hr. To contact editorial co-author Annette Flanagin, R.N., M.A., call Jim Michalski at 312-464-5785 or email jim.michalski@jamanetwork.org.

Chicago – An analysis of research on peer review finds that studies aimed at improving methods of peer review and reporting of biomedical research are underrepresented and lack dedicated funding, according to a study in the March 12 issue of JAMA.

Mario Malicki, M.D., M.A., of the University of Split School of Medicine, Split, Croatia, and colleagues analyzed research presented at the International Congress on Peer Review and Biomedical Publication (PRC) since 1989. The first PRC was organized to “subject the editorial review process to some of the rigorous scrutiny that editors and reviewers demand of the scientists whose work they are assessing.” The researchers collected data on authorship, time to publication, declared funding sources, article availability, and citation counts in Web of Science. The analysis included 614 abstracts.

The researchers found that experimental studies aimed at improving methods of peer review and reporting of biomedical research are still underrepresented on the pages of medical journals. “Although the peer review research community is aware of the consequences of nonpublication of research, 39 percent of studies presented at PRCs have not been fully published. In our cohort, we were unable to determine whether the underreporting was selective [e.g., publication favoring positive results] and were not able to determine its causes.”

Peer review and other editorial procedures have the potential to influence the knowledge base of health care, the authors write. “Despite their critical role in biomedical publishing, methods of peer review are still underresearched and lack dedicated funding. Systematic and competitive funding schemes are needed to build and sustain excellence, innovation, and methodological rigor in peer review research.”

(doi:10.1001/jama.2014.143; 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: Research on Peer Review and Biomedical Publication – Furthering the Quest to Improve the Quality of Reporting

In an accompanying editorial, Drummond Rennie, M.D., of the University of California, San Francisco, and Annette Flanagin, R.N., M.A., of JAMA, Chicago, comment on the studies in this issue of JAMA that examine peer review and the publishing of biomedical research.

“… articles on how to improve research, of which publication is an integral part, are important reminders that no matter how much research on peer review and publication has been presented at the Peer Review Congresses and elsewhere, these studies are but part of a widespread movement to improve the scientific literature. As the reports in this issue of JAMA indicate, discovering the extent of the problems and testing methods to correct them will require a massive and prolonged effort on the part of researchers, funders, institutions, and journal editors.”

(doi:10.1001/jama.2014.1362; 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.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 11, 2014

Media Advisory: To contact corresponding author Joseph S. Ross, M.D., M.H.S., call Karen Peart at 203-432-1326 or email karen.peart@yale.edu.
Chicago – During a one year period, among clinical trials published in high-impact journals that reported results on a public clinical trial registry (ClinicalTrials.gov), nearly all had at least 1 discrepancy in the study group, intervention, or results reported between the 2 sources, including discrepancies in the designated primary end points for the studies, according to a study in the March 12 issue of JAMA.

The 2007 Food and Drug Administration (FDA) Amendments Act expanded requirements for ClinicalTrials.gov, mandating results reporting within 12 months of trial completion for all FDA-regulated medical products. “To our knowledge, no studies have examined reporting and accuracy of trial results information. Accordingly, we compared trial information and results reported on ClinicalTrials.gov with corresponding peer-reviewed publications,” write Jessica E. Becker, A.B., of the Yale University School of Medicine, New Haven, Conn., and colleagues.

The researchers identified 96 trials reporting results on ClinicalTrials.gov that were published in high-impact journals from July 1, 2010 and June 30, 2011. For 70 trials (73 percent), industry was the lead funder. Cohort, intervention, and efficacy end point information was reported for 93 percent to 100 percent of trials in both sources. However, 93 of 96 trials had at least one discordance among reported trial information or reported results.

Among trials reporting each cohort characteristic (enrollment and completion, age/sex demographics) and trial intervention information, discordance ranged from 2 percent to 22 percent and was highest for completion rate and trial intervention, for which different descriptions of dosages, frequencies, or duration of intervention were common.

Among 132 primary efficacy end points described in both sources, results for 23 percent could not be compared and 16 percent were discordant. The majority (n = 15) of discordant results did not alter trial interpretation, although for 6 the discordance did. Overall, 52 percent of primary efficacy end points were described in both sources and reported concordant results.

Among 619 secondary efficacy end points described in both sources, results for 37 percent could not be compared, whereas 9 percent were discordant. Overall, 16 percent of secondary efficacy end points were described in both sources and reported concordant results.

“… because articles published in high-impact journals are generally the highest-quality research studies and undergo more rigorous peer review, the trials in our sample likely represent best-case scenarios with respect to the quality of results reporting. Our findings raise questions about accuracy of both ClinicalTrials.gov and publications, as each source’s reported results at times disagreed with the other. Further efforts are needed to ensure accuracy of public clinical trial result reporting efforts.”

(doi:10.1001/jama.2013.285634; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 11, 2014

Media Advisory: To contact corresponding author Matthias Briel, M.D., M.Sc., email matthias.briel@usb.ch.

Chicago – Approximately 25 percent of about 1,000 randomized clinical trials initiated between 2000 and 2003 were discontinued, with the most common reason cited being poor recruitment of volunteers; and less than half of these trials reported the discontinuation to a research ethics committee, or were ever published, according to a study in the March 12 issue of JAMA.

Conducting high-quality randomized clinical trials (RCTs) is challenging and resource-demanding. Trials are often not conducted as planned or are prematurely discontinued, which poses ethical concerns, particularly if results remain unreported, and may represent a considerable waste of scarce research resources. Currently, little is known about the characteristics and publication history of discontinued trials, according to background information in the article.

Benjamin Kasenda, M.D., of University Hospital Basel, Switzerland, and colleagues examined characteristics of 1,017 trials approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. Last follow-up of these RCTs was April 27, 2013.

Among the findings of the researchers:

• Overall, 253 RCTs (24.9 percent) were discontinued;
• Only 38 percent of discontinuations were reported to ethics committees;
• RCTs were most frequently discontinued because of poor recruitment (9.9 percent), followed by administrative reasons (3.8 percent) and futility (3.3 percent);
• Although discontinuation was common for RCTs involving patients (28 percent), it was rare for RCTs involving healthy volunteers (3 percent);
• Discontinued trials were more likely than completed trials to remain unpublished, as were those with industry sponsorship;
• Trials with investigator sponsorship (vs industry sponsorship) were at higher risk of discontinuation due to poor recruitment.

“Greater efforts are needed to make certain that trial discontinuation is reported to research ethics committees and that results of discontinued trials are published,” the authors conclude.

(doi:10.1001/jama.2014.1361; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 11, 2014

Media Advisory: To contact Matthew D. Barber, M.D., M.H.S., call Halle Bishop Weston at 216-445-8592 or email bishoph@ccf.org.
Chicago – For women undergoing surgery for vaginal prolapse and stress urinary incontinence, neither of 2 common repair procedures was superior to the other for functional or adverse event outcomes, and behavioral therapy with pelvic muscle training did not improve urinary symptoms or prolapse outcomes after surgery, according to a study in the March 12 issue of JAMA.

Pelvic organ prolapse (protrusion) occurs when the uterus descends into the lower vagina or vaginal walls protrude beyond the vaginal opening, and can occur as a result of childbirth. Approximately 300,000 surgeries for prolapse are performed annually in the United States; the two most widely used vaginal procedures for correcting apical (upper vaginal) prolapse are sacrospinous ligament fixation (SSLF) and the uterosacral ligament vaginal vault suspension (ULS). To date, no comparative data exist about their relative efficacy and safety, according to background information in the article.

A majority of women seeking vaginal prolapse surgery report urinary incontinence, including the common subtype of stress incontinence or involuntary urine loss with coughing, sneezing, or physical activity. Behavioral therapy with pelvic floor (the area underneath the pelvis composed of muscle fibers and soft tissue) muscle training (BPMT) is an effective stand-alone therapy for incontinence.

Matthew D. Barber, M.D., M.H.S., of the Cleveland Clinic, and colleagues randomized 374 women undergoing surgery to treat both apical vaginal prolapse and stress urinary incontinence at nine U.S. medical centers to SSLF (n = 186) or ULS (n = 188), and to receive BPMT (n = 186) or usual care (n = 188).

The researchers found that in the 84.5 percent of participants followed up at two years, the proportion of patients who had successful surgery (defined as a composite of anatomic results, patient-reported symptoms, and retreatment) was not different between groups: (ULS, 59.2 percent vs SSLF, 60.5 percent). In addition, serious adverse event proportions were comparable (ULS, 16.5 percent vs SSLF, 16.7 percent). BPMT around the time of surgery was not associated with greater improvements in incontinence measures at 6 months; prolapse symptom scores at 24 months; or measures of anatomic success (as defined by certain criteria) at 24 months.

The authors write that their study provides evidence for patients and their surgeons about the benefits, risks, and complications of these two surgical procedures, as well as the role of BPMT. “Although our results do not support routinely offering perioperative BPMT to women undergoing vaginal surgery for prolapse and stress urinary incontinence, previous evidence supports offering individualized treatment, including behavioral or physical therapy, to those who report new or unresolved pelvic floor symptoms.”

They add that although variability in surgical recommendations for vaginal prolapse repair is likely to persist because of individual patient characteristics, their data provide a metric against which other vaginal procedures can be assessed.

(doi:10.1001/jama.2014.1719; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women’s Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, March 11 at this link.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 11, 2014

Media Advisory: To contact corresponding authors Euan A. Ashley, M.R.C.P., D.Phil., or Thomas Quertermous, M.D., call Krista Conger at 650-725-5271 or email kristac@stanford.edu. To contact editorial author William Gregory Feero, M.D., Ph.D., call 207-453-3030 or email w.gregory.feero@mainegeneral.org.
Chicago – In an exploratory study involving 12 adults, the use of whole-genome sequencing (WGS) was associated with incomplete coverage of inherited-disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings, although in certain cases WGS will identify genetic variants warranting early medical intervention, according to a study in the March 12 issue of JAMA.

As technical barriers to human DNA sequencing decrease and costs approach $1,000, whole-genome sequencing (WGS) is increasingly being used in clinical medicine. Sequencing can successfully aid clinical diagnosis and reveal the genetic basis of rare familial diseases. Regardless of context, even in apparently healthy individuals, WGS is expected to uncover genetic findings of potential clinical importance. However, comprehensive clinical interpretation and reporting of clinically significant findings are seldom performed, according to background information in the article. The technical sensitivity and reproducibility of clinical genetic findings using sequencing and the clinical opportunities and costs associated with discovery and reporting of these and other clinical findings remain undefined.

Frederick E. Dewey, M.D., of the Stanford Center for Inherited Cardiovascular Disease, Stanford, Calif., and colleagues recruited 12 volunteer adult participants who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.

The researchers found that the use of WGS was associated with incomplete coverage of inherited-disease genes (important parts of the genome for diseases that run in families are not as easy to read as other regions); there was low reproducibility of detection of genetic variation with the highest potential clinical effects (disagreement around the types of variation particularly important for disease); and there was uncertainty about clinically reportable WGS findings (experts disagree on which findings are most meaningful). Two to 6 personal disease-risk findings were discovered in each participant. Physician review of sequencing findings prompted consideration of a median (midpoint) of 1 to 3 initial diagnostic tests and referrals per participant.

The authors write that their clinical experience with this technology illustrates several challenges to clinical adoption of WGS, including that although analytical validity of WGS is improving, technical challenges to sensitive and accurate assessment of individual genetic variation remain. In addition, the human resource needs for full clinical interpretation of WGS data remains considerable, and much uncertainty remains in classification of potentially disease-causing genetic variants.

“These issues should be considered when determining the role of WGS in clinical medicine.”

(doi:10.1001/jama.2014.1717; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Clinical Application of Whole Genome Sequencing – Proceed With Care

“Medical application of genomic and personalized medicine technologies hold out the real promise of improved decision making and patient outcomes by providing an increased knowledge of the determinants of health and disease at the level of the individual patient,” writes William Gregory Feero, M.D., Ph.D., of the Maine Dartmouth Family Medicine Residency, Fairfield, Maine, (and Associate Editor, JAMA), in an accompanying editorial.

“Like the personal computer, Internet, smartphones, and electronic health records, turning back now from the use of genomic technologies in health care is inconceivable. Studies like that of Dewey et al provide a glimpse of what is possible but demonstrate that much remains to be learned about previously assumed to be ‘known’ information as well as myriad ‘known unknowns’ and ‘unknown unknowns’ before truly successful widespread integration can occur. A question facing potential early adopters of genome sequencing as an adjunct to patient care is whether or not having WGS data, at this time, will decrease uncertainty and improve outcomes or merely exponentially increase the complexity of clinical care.

(doi:10.1001/jama.2014.1718; 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.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 4, 2014

Media Advisory: To contact Deborah A. Zarin, M.D., call Kathleen Cravedi at 301-496-6308 or email Kcravedi@nlm.nih.gov.
Chicago – An analysis of nearly 24,000 active human research clinical trials found that between 5 percent and 16 percent fall into a regulatory gap and are not covered by two major federal regulations, according to a study in the March 5 issue of JAMA. These trials studied interventions other than drugs or devices (e.g., behavioral, surgical).

The primary federal human subjects protections (HSP) policies in the United States, including requirements for institutional review board review and informed consent, are the U.S. Food and Drug Administration (FDA) HSP regulations and the Common Rule. “The first covers FDA-regulated clinical investigations of drugs, biologics, and devices, regardless of funding source, whereas the second applies to human studies funded or conducted by 17 federal entities, regardless of the type of intervention studied. These regulations are largely consistent but contain differences. Concerns have been raised about burdens and inefficiencies for studies covered by both regulations (overlap trials), and about some studies that are covered by neither (gap trials).

Deborah A. Zarin, M.D., of the National Institutes of Health, Bethesda, Md., and colleagues conducted a study to estimate the number of active U.S.-based clinical trials subject to these regulations. From ClinicalTrials.gov records of active trials listing at least 1 U.S.-based facility as of September 2013, the researchers extracted the intervention type, investigational new drug application or investigational device exemption status, sponsor, and collaborators and approximated the number of trials subject to each regulation, using narrow and broad criteria.

Of the 23,936 sampled trials, the authors estimate that 13,165 (55 percent) to 15,576 (65 percent) trials were covered only by FDA-HSP regulations; 1,442 (6 percent) to 2,497 (10 percent) trials were subject only to the Common Rule; 4,578 (19 percent) to 5,633 (24 percent) were overlap trials that studied drugs and devices and have some federal funding; and 5 percent to 16 percent were gap trials that studied interventions other than drugs or devices (e.g., behavioral, surgical) and had no federal funding. The characteristics of gap trials varied widely, but included research in vulnerable populations (e.g., pregnant women, people with major mental illness, children) with primary outcomes that reflected potentially consequential risk (e.g., organ failure, depression relapse, seizure frequency, hospitalization).

The authors write that their analysis provides the first quantitative estimate of the size of the gap in regulatory coverage, and also documents a large number of studies that are subject to both sets of regulations.

“Our data are not precise measures of the current scope of different regulatory categories. Rather, they represent the best current estimates [based on clinical trial registrations], and this analysis is intended to inform ongoing discussions about potential regulatory reforms.”

(doi:10.1001/jama.2013.284306; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 4, 2014

Media Advisory: To contact Juan Jesus Carrero, Ph.D., email Juan.Jesus.Carrero@ki.se. To contact editorial co-author Wolfgang C. Winkelmayer, M.D., M.P.H., Sc.D., call Tracie White at 650-723-7628 or email traciew@stanford.edu.
Chicago – Although some research has suggested that the use of the anticoagulant warfarin for atrial fibrillation among patients with chronic kidney disease would increase the risk of death or stroke, a study that included more than 24,000 patients found a lower l-year risk of the combined outcomes of death, heart attack or stroke without a higher risk of bleeding, according to a study in the March 5 issue of JAMA.

Juan Jesus Carrero, Ph.D., of the Karolinska Institutet, Stockholm, and colleagues examined outcomes associated with warfarin treatment in relation to kidney function among patients with established cardiovascular disease and atrial fibrillation. Using data from a Swedish registry, the study included survivors of a heart attack with atrial fibrillation and known measures of serum creatinine (n = 24,317; a substance used to measure kidney function), including 21.8 percent who were prescribed warfarin at discharge.

About 52 percent of patients had moderate chronic kidney disease (CKD) or worse. The researchers found that warfarin treatment was associated with a lower l-year risk of a composite of the outcomes of death, heart attack, and ischemic stroke without a higher risk of bleeding. This association was observed in patients with moderate, severe, or end-stage CKD. The number of patients who developed the composite outcome, bleeding events, and the total of these 2 outcomes increased with the worsening of CKD categories, as did the rate at which these events occurred.

(doi:10.1001/jama.2014.1334; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be an audio author interview available for this study at 3 p.m. CT Tuesday, March 4, at JAMA.com.

 Editorial: Warfarin Treatment in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease

Wolfgang C. Winkelmayer, M.D., M.P.H., Sc.D., and Mintu P. Turakhia, M.D., M.A.S., of the Stanford University School of Medicine, Palo Alto, Calif., (Dr. Winkelmayer is also an Associate Editor, JAMA), comment on the findings of this study in an accompanying editorial.

“In conclusion, the study by Carrero et al in this issue of JAMA provides the best evidence to date that vitamin K antagonists [anticoagulants] are associated with improved clinical outcomes and no significant increased risk of bleeding in patients with myocardial infarction and atrial fibrillation with advanced CKD.”

(doi:10.1001/jama.2014.1781; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 4, 2014

Media Advisory: To contact Jessica C. Jones-Smith, Ph.D., call Brandon Howard at 410-502-9059 or email bhoward@jhsph.edu. To contact editorial author Neal Halfon, M.D., M.P.H., call Amy Albin at 310-794-8672 or email aalbin@mednet.ucla.edu.
Chicago – The opening or expansion of a casino in a community is associated with increased family income, decreased poverty rates and a decreased risk of childhood overweight or obesity, according to a study in the March 5 issue of JAMA.

Obesity disproportionately affects children with low economic resources at the family and community levels. Few studies have evaluated whether this association is a direct effect of economic resources. “American Indian-owned casinos have resulted in increased economic resources for some tribes and provide an opportunity to test whether these resources are associated with overweight/obesity,” according to background information in the article.

Jessica C. Jones-Smith, Ph.D., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues assessed whether openings or expansions of American Indian-owned casinos were associated with childhood overweight/obesity risk. The authors hypothesized that casinos could alter individual, family, or community resources, reducing barriers to healthful eating and physical activity and decreasing the risk of overweight/obesity. “These resources could include increased income, either via employment or per capita payments, and health-promoting community resources, such as housing, recreation and community centers, and health clinics.”

The researchers used body mass index (BMI) measurements from American Indian children (ages 7-18 years) from 117 school districts that encompassed tribal lands in California between 2001 and 2012 and compared children in districts with tribal lands that either did or did not gain or expand a casino. Besides BMI, other measures included in the analysis were per capita annual income, median (midpoint) annual household income, percentage of population in poverty and total population.

Of the 117 school districts, 57 either opened or expanded a casino, 24 had a preexisting casino but did not undergo expansion, and 36 did not have a casino at any time during the study period. Forty-eight percent of the measurements of the children (n = 11,048) were classified as overweight/obese. The researchers found that every 1 casino slot per capita gained was associated with an increase in average per capita annual income, a decrease in the percentage of the population living in poverty, and a decrease in the percentage of overweight/obesity.

The authors speculate that the association found in this study between casinos and childhood overweight/obesity may be from both increased family/individual and community economic resources, but emphasize that further research is needed to better understand the mechanisms underlying this association.

(doi:10.1001/jama.2014.604; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Funding for this project was provided by a grant from the National Institute of Child Health and Human Development. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Socioeconomic Influences on Child Health – Building New Ladders of Social Opportunity

 Regarding the two studies in this issue of JAMA that examine socioeconomic influences on child health, Neal Halfon, M.D., M.P.H., of the University of California, Los Angeles, writes in an accompanying editorial that “an enormous loss of human potential results from unsafe, uncertain, stressful childhood environments that do not have the basic scaffolding that all children need to thrive.”

“A casino in every neighborhood is not the answer, but increasing family income and removing other pressures that reduce the capacity of families to invest in their children should be part of the solution. While incremental improvements like expanding preschool and extending health insurance may help add new rungs to the existing ladder of social opportunity, the fact is that these ladders are broken, outdated, and designed for a different era and need to be redesigned and transformed from the bottom up.”

(doi:10.1001/jama.2014.608; 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.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 4, 2014

Media Advisory: To contact Ronald C. Kessler, Ph.D., call David Cameron at 617-432-0441 or email david_cameron@hms.harvard.edu.
Chicago – For families who moved out of high-poverty neighborhoods, boys experienced an increase and girls a decrease in rates of depression and conduct disorder, according to a study in the March 5 issue of JAMA.

Observational studies have consistently found that youth in high-poverty neighborhoods have high rates of emotional problems. These findings raise the possibilities that neighborhood characteristics affect emotional functioning and neighborhood-level interventions may reduce emotional problems. Available data from observational studies are unclear, according to background information in the article. “Understanding neighborhood influences on mental health is crucial for designing neighborhood-level interventions.”

Ronald C. Kessler, Ph.D., of Harvard Medical School, Boston, and colleagues analyzed the outcomes of an intervention to encourage moving out of high-poverty neighborhoods and subsequent changes in mental disorders from childhood to adolescence. The intervention (Moving to Opportunity Demonstration) randomized 4,604 volunteer public housing families with 3,689 children in high-poverty neighborhoods from 1994 to 1998 into 1 of 2 housing mobility intervention groups (a low-poverty voucher group vs a traditional voucher group) or a control group. The low-poverty voucher group (n = 1,430) received vouchers to move to low-poverty neighborhoods. The traditional voucher group (n = 1,081) received geographically unrestricted vouchers. Controls (n = 1,178) received no intervention.

The children were ages 0 through 8 years at the beginning of the study, and 13 through 19 years of age at the time of follow-up interviews (10 to 15 years later, June 2008 – April 2010).  A total of 2,872 adolescents were interviewed (1,407 boys and 1,465 girls from 2,134 families). The presence of mental disorders was assessed with the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).

The researcher found that compared with the control group, a higher proportion of boys in the low-poverty voucher group had major depression (7.1 percent vs 3.5 percent), posttraumatic stress disorder (6.2 percent vs 1.9 percent), and conduct disorder (6.4 percent vs 2.1 percent). A higher proportion of boys in the traditional voucher group had PTSD compared with the control group (4.9 percent vs 1.9 percent). However, compared with the control group, a lower proportion of girls in the traditional voucher group had major depression (6.5 percent vs 10.9 percent) and conduct disorder (0.3 percent vs 2.9 percent).

The authors speculate that the sex differences found in this study “were due to girls profiting more than boys from moving to better neighborhoods because of sex differences in both neighborhood experiences and in the social skills needed to capitalize on the new opportunities presented by their improved neighborhoods.”

“It is nonetheless difficult to draw policy implications from these results, because the findings suggest that the interventions might have had harmful effects on boys but protective effects on girls. Future governmental decisions regarding widespread implementation of changes in public housing policy will have to grapple with this complexity based on the realization that no policy decision will have benign effects on both boys and girls.”

“Better understanding of interactions among individual, family, and neighborhood risk factors is needed to guide future public housing policy changes in light of these sex differences,” the authors conclude.

(doi:10.1001/jama.2014.607; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, March 4 at this link.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 25, 2014

Media Advisory: To contact Shelley Ehrlich, M.D., Sc.D., M.P.H., call Jim Feuer at 513-636-4656 or email Jim.Feuer@cchmc.org.

Chicago – Study participants who handled receipts printed on thermal paper continuously for 2 hours without gloves had an increase in urine bisphenol A (BPA) concentrations compared to when they wore gloves, according to a study in the February 26 issue of JAMA.

Human exposure to bisphenol A (BPA) has been associated with adverse health outcomes, including reproductive function in adults and neurodevelopment in children exposed shortly before or after birth. “Exposure to BPA is primarily through dietary ingestion, including consumption of canned foods. A less-studied source of exposure is thermal receipt paper, handled daily by many people at supermarkets, ATM machines, gas stations, and other settings,” according to background information in the article. Thermal paper has a coating that is sensitive to heat, which is used in the process of printing on the paper, and has been shown to be transferred to skin with handling.

Shelley Ehrlich, M.D., Sc.D., M.P.H., of Cincinnati Children’s Hospital Medical Center, and colleagues conducted a study to examine the effect of handling thermal receipts on urine BPA levels. The authors recruited 24 volunteers who provided urine samples before and after handling (with or without gloves) of receipts printed on thermal paper for a continuous two hours. BPA was detected in 83 percent (n = 20) of urine samples at the beginning of the study and in 100 percent of samples after handling receipts without gloves. The researchers observed an increase in urinary BPA concentrations after continuously handling receipts for 2 hours without gloves, but no significant increase when the participants used gloves.

The clinical implications of the height of the peak level and of chronic exposure are unknown, but may be particularly relevant to populations with occupational exposure such as cashiers, who handle receipts 40 or more hours per week, the authors write. “A larger study is needed to confirm our findings and evaluate the clinical implications.”

(doi:10.1001/jama.2013.283735; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This project was supported by a grant from the Harvard-NIOSH Education and Research Center. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 25, 2014

Media Advisory: To contact Mark W. Friedberg, M.D., M.P.P., call Warren Robak at 310-451-6913 or email robak@rand.org. To contact editorial author Thomas L. Schwenk, M.D., call Anne McMillin at 775-682-9254 or email amcmillin@medicine.nevada.edu.
Chicago – One of the first, largest, and longest-running multipayer trials of patient-centered medical home medical practices in the United States was associated with limited improvements in quality and was not associated with reductions in use of hospital, emergency department, or ambulatory care services or total costs of care over 3 years, according to a study in the February 26 issue of JAMA.

The patient-centered medical home is a team-based model of primary care practice intended to improve the quality, efficiency, and patient experience of care. Professional associations, payers, policy makers, and other stakeholders have advocated for the patient-centered medical home model. In general, medical home initiatives have encouraged primary care practices to invest in patient registries, enhanced access options, and other structural changes that might improve patient care in exchange for enhanced payments, according to background information in the article. Dozens of privately and publicly financed trials of the medical home model are under way. “Interventions to transform primary care practices into medical homes are increasingly common, but their effectiveness in improving quality and containing costs is unclear,” the authors write.

Mark W. Friedberg, M.D., M.P.P., of the RAND Corporation, Boston, and colleagues measured associations between participation in the Southeastern Pennsylvania Chronic Care Initiative, a multipayer medical home program, and changes in the quality, utilization, and costs of care. Pilot practices could earn bonus payments for achieving patient-centered medical home recognition by the National Committee for Quality Assurance (NCQA). Thirty-two volunteering primary care practices participated in the pilot (conducted from June 2008 to May 2011). Using claims data from 4 participating health plans, the researchers compared changes in care (in each year, relative to before the intervention) for 64,243 patients who were attributed to pilot practices and 55,959 patients attributed to 29 comparison practices. Measured outcomes included performance on 11 quality measures for diabetes, asthma, and preventive care; utilization of hospital, emergency department, and ambulatory care; standardized costs of care.

Pilot practices successfully achieved NCQA recognition and reported structural transformation on a range of capabilities, such as use of registries to identify patients overdue for chronic disease services (increased from 30 percent to 85 percent of pilot practices) and electronic medication prescribing (increased from 38 percent to 86 percent). Pilot practices accumulated average bonuses of $92,000 per primary care physician during the 3-year intervention.

Of the 11 quality measures evaluated, pilot participation was significantly associated with greater performance improvement, relative to comparison practices, on only l measure: monitoring for kidney disease in diabetes. There were no other statistically significant differences in measures of utilization, costs of care, or rates of multiple same-year hospitalizations or emergency department visits.

The authors conclude that “a multipayer medical home pilot, in which participating practices adopted new structural capabilities and received NCQA certification, was associated with limited improvements in quality and was not associated with reductions in utilization of hospital, emergency department, or ambulatory care services or total costs over 3 years.”

“Despite widespread enthusiasm for the medical home concept, few peer-reviewed publications have found that transforming primary care practices into medical homes produces measurable improvements in the quality and efficiency of care.”

The authors add that their “findings suggest that medical home interventions may need further refinement.”

(doi:10.1001/jama.2014.353; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was sponsored by the Commonwealth Fund and Aetna. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, February 25 at this link.

Editorial: The Patient-Centered Medical Home – One Size Does Not Fit All

“Before confidently promoting the patient-centered medical home (PCMH) as a core component of health care reform, it is necessary to better understand which features and combination of features of the PCMH are most effective for which populations and in what settings,” writes Thomas L. Schwenk, M.D., of the University of Nevada School of Medicine, Reno, in an accompanying editorial.

“The identification of specific PCMH features for various risk strata will likely have significant influence on the work patterns of physicians, who may be responsible for a larger panel of patients than currently but for whom only routine care is needed, often by other members of the health care team. The physician’s time and expertise will be best focused on a relatively small number of the most complex and expensive patients.”

(doi:10.1001/jama.2014.352; 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.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 25, 2014

Media Advisory: To contact Matthew W. Sherwood, M.D, call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

Chicago – In an analysis that included more than two million patients who underwent a percutaneous coronary intervention (PCI; procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries), there was considerable variation in red blood cell transfusion practices among hospitals across the U.S., and receiving a transfusion was associated with an increased risk of in-hospital heart attack, stroke or death, according to a study in the February 26 issue of JAMA.

Red blood cell transfusion among patients with coronary artery disease is controversial. A growing body of evidence suggests that transfusion in the setting of acute coronary syndromes (ACS; such as heart attack or unstable angina) and in hospitalized patients with a history of coronary artery disease may be associated with an increase in risk of heart attack and death. Current guideline statements are cautious about recommending transfusion in hospitalized patients with a history of coronary artery disease and make no recommendation on transfusion in the setting of ACS, citing an absence of definitive evidence, according to background information in the article.

Matthew W. Sherwood, M.D, of Duke Clinical Research Institute, Durham, N.C., and colleagues examined transfusion practice patterns and outcomes in a population representative of patients undergoing PCI across the United States with data from a registry on patient visits (n = 2,258,711) from July 2009 to March 2013 for PCI at 1,431 hospitals.

Overall rate, 2.1 percent of patients undergoing PCI had a transfusion. The researchers found a broad variation in patterns of transfusion across hospitals. Overall, 96.3 percent of sites gave a transfusion to less than 5 percent of patients and 3.7 percent of sites gave a transfusion to 5 percent of patients or more.

Compared to no transfusion, receiving a transfusion was associated with a greater risk of heart attack (4.5 percent vs 1.8 percent), stroke (2.0 percent vs 0.2 percent), and in-hospital death (12.5 percent vs 1.2 percent), irrespective of bleeding complications.

Patients more likely to receive a transfusion were older, were women, and were more likely to have hypertension, diabetes, advanced renal dysfunction, and prior heart attack or heart failure.

The authors speculate that the variation seen in transfusion practice patterns in this study may be related to several factors, including previously held beliefs about the benefit of transfusion and recently published data indicating the lack of benefit and potential hazard associated with transfusion.

“These data highlight the need for randomized trials of transfusion strategies to guide practice in patients undergoing PCI. Until these trials have been completed, operators should use strategies that reduce the risk of bleeding and [need for] transfusion.”

(doi:10.1001/jama.2014.980; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 25, 2014

Media Advisory: To contact Signe Sorup, Ph.D., email sgs@ssi.dk. To contact editorial co-author David Goldblatt, M.B.Ch.B., Ph.D., email d.goldblatt@ucl.ac.uk.

Chicago – In a nationwide group of Danish children, receipt of the live measles, mumps, and rubella (MMR) vaccine on schedule after vaccination for other common infections was associated with a lower rate of hospital admissions for any infections, but particularly for lower respiratory tract infections, according to a study in the February 26 issue of JAMA.

Childhood vaccines are recommended worldwide, based on their protective effect against the targeted diseases.  However, studies from low-income countries show that vaccines may have nonspecific effects that reduce illness and death from non-targeted diseases, according to background information in the study. Such nonspecific effects of vaccines might also be important for the health of children in high-income settings.

Signe Sorup, Ph.D., of the Statens Serum Institut, Copenhagen, Denmark, and colleagues examined whether the live MMR vaccine was associated with lower rates of hospital admissions for infections among children in a higher-income setting (Denmark). The study included children 495,987 born 1997-2006 and followed from ages 11 months to 2 years. The recommended vaccination schedule was inactivated vaccine against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) administered at ages 3, 5, and 12 months; and MMR at age 15 months.

There were 56,889 hospital admissions for any type of infection among the children in the study. The researchers found that receiving the live MMR vaccine after the inactivated DTaP-IPV-Hib vaccine was associated with a lower rate of hospital admissions for any infection. The association was particularly strong for lower respiratory tract infections and for longer hospital admissions. Children who received DTaP-IPV-Hib after MMR had a higher rate of infectious disease admission.

“The coverage with MMR is suboptimal in many high-income countries; in the present study, about 50 percent of children were not vaccinated on time. Physicians should encourage parents to have children vaccinated on time with MMR and avoid giving vaccinations out of sequence, because the present study suggests that timely MMR vaccination averted a considerable number of hospital admissions for any infection between ages 16 and 24 months,” the authors write.

(doi:10.1001/jama.2014.470; 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: Nonspecific Effects of Vaccines

In an accompanying editorial, David Goldblatt, M.B.Ch.B., Ph.D., of the UCL Institute of Child Health and Great Ormond Street Children’s Hospital, London, and Elizabeth Miller, F.R.C.Path., of Public Health England, London, write that the WHO Strategic Advisory Group of Experts recently decided to revisit the issue of nonspecific effects of vaccines as part of its continued appraisal of important issues that could be relevant to inform global immunization policy.

“Systematic reviews of all available epidemiologic and immunologic evidence relevant to the issue of the nonspecific effects of vaccines on childhood mortality will be undertaken to decide whether current evidence is sufficient to lead to adjustments in policy recommendations or to warrant further scientific investigation. The study by Sorup et al is a further contribution to this body of literature. Although reanalysis of the available evidence is important, the ability to properly control for bias and confounding [factors that can influence outcomes] in observational studies is often limited, and without randomized controlled trials specifically designed to test the hypothesis, the issue of nonspecific effects of vaccines may remain subject to continuing debate.”

(doi:10.1001/jama.2014.471; 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. Dr. Goldblatt reported receiving grants from, and serving on advisory boards for, GlaxoSmithKline, Sanofi Pasteur, Merck, and Novartis and serving on an advisory board for Pfizer. No other disclosures were reported.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 25, 2014

Media Advisory: To contact Cynthia L. Ogden, Ph.D., email Jeff Lancashire (jhl1@cdc.gov) or the CDC press office (paoquery@cdc.gov) or call 301-458-4800.
Chicago – The prevalence of obesity remains high in the U.S., with about one-third of adults and 17 percent of children and teens obese in 2011-2012, according to a national survey study in the February 26 issue of JAMA.

Obesity and childhood obesity, in particular, are the focus of many preventive health efforts in the United States, including new regulations implemented by the U.S. Department of Agriculture for food packages; funding by the Centers for Disease Control and Prevention of state- and community-level interventions; and numerous reports and recommendations issued by the Institute of Medicine, the U.S. Surgeon General, and the White House, according to background information in the article.  Two articles published by the authors in JAMA in 2012 demonstrated that the prevalence of obesity leveled off between 2003-2004 and 2009-2010, but “given the focus of public health efforts on obesity, surveillance of trends in obesity remains important.”

Cynthia L. Ogden, Ph.D., and colleagues from the Centers for Disease Control and Prevention, Hyattsville, M.D., examined trends for childhood and adult obesity among 9,120 persons with measured weights and heights (or recumbent length) in the 2011-2012 nationally representative National Health and Nutrition Examination Survey.

The prevalence of high weight for recumbent length, a standard measure of weight among infants and toddlers from birth to age 2 years, was 8.1 percent in 2011-2012, with a difference between boys (5 percent) and girls (11.4 percent). For youth (2- to 19-years of age), 31.8 percent were either overweight or obese, and 16.9 percent were obese. Among adults, more than two-thirds (68.5 percent) were either overweight or obese, 34.9 percent were obese (body mass index [BMI] 30 or greater), and 6.4 percent were extremely obese (BMI 40 or greater).

Overall, there was no change from 2003-2004 through 2011-2012 in high weight for recumbent length among infants and toddlers or in obesity in 2- to 19-year-olds or adults. The prevalence of obesity among children 2 to 5 years of age decreased from 14 percent in 2003-2004 to just over 8 percent in 2011-2012, and increased in women age 60 years and older, from 31.5 percent to more than 38 percent.

The authors conclude that “obesity prevalence remains high and thus it is important to continue surveillance.”

(doi:10.1001/jama.2014.732; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 18, 2014

Media Advisory: To contact corresponding author Claudia A. Steiner, M.D., M.P.H., call Alison Hunt at 301-427-1244 or email Alison.Hunt@ahrq.hhs.gov.
Chicago – In an analysis that included nearly 300,000 patients from eight states who underwent ambulatory surgery (surgery performed on a person who is admitted to and discharged from a hospital on the same day), researchers found that the rates of surgical site infections were relatively low; however, the absolute number of patients with these complications is substantial, according to a study in the February 19 issue of JAMA.

Surgical site infections are among the most common health care-associated infections, accounting for 20 percent to 31 percent of health care-associated infections in hospitalized patients, according to background information in the article. Although ambulatory surgeries represent a substantial portion of surgical health care, there is a lack of information on adverse events, including health care-associated infections.

Pamela L. Owens, Ph.D., of the Agency for Healthcare Research and Quality, Rockville, Md., and colleagues determined the incidence of clinically significant surgical site infections (CS-SSIs) following low- to moderate-risk ambulatory surgery in patients with low risk for surgical complications (defined as not seen in past 30 days in acute care, length of stay less than 2 days, no other surgery on the same day, and discharged home and no infection coded on the same day). The researchers used the 2010 Healthcare Cost and Utilization Project State Ambulatory Surgery and State Inpatient Databases for 8 states (California, Florida, Georgia. Hawaii. Missouri, Nebraska, New York, and Tennessee), representing one-third of the U.S. population. The analysis included 284,098 ambulatory surgical procedures (general surgery, orthopedic, neurosurgical, gynecologic, and urologic) in adult patients; rates were calculated for

14- and 30-day postsurgical acute care visits for CS-SSIs following ambulatory surgery.

The researchers found that the overall rate of postsurgical acute care visits within 14 days for CS-SSIs was relatively low (3.09 per 1,000 ambulatory surgical procedures). When the time frame was extended to 30 days, the rate increased to 4.84. Two-thirds (63.7 percent) of all visits for CS-SSI occurred within 14 days of the surgery; of those visits, 93.2 percent involved treatment in the inpatient setting.

The authors note that although the overall rate of CS-SSIs was low, because of the large number of ambulatory surgical procedures performed annually, in absolute terms, a substantial number of patients develop clinically significant postoperative infections. Most of these infections occurred within 2 weeks after surgery and resulted in hospital admission. “Our findings suggest that earlier access to a clinician or member of the surgical team (e.g., telephone check-in prior to 2 weeks) may help identify and treat these infections early and reduce overall morbidity.”

“Prior studies showing significant lapses in infection control practices at ambulatory surgery centers suggest that quality improvement efforts may facilitate reducing CS-SSIs following ambulatory surgery.”

(doi:10.1001/jama.2014.4; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by the Agency for Healthcare Research and Quality under a contract to Truven Health Analytics to develop and support the Healthcare Cost and Utilization Project. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 18, 2014

Media Advisory: To contact David A. Hanauer, M.D., M.S., call Mary Masson at 734-764-2220 or email mfmasson@med.umich.edu.

Chicago – In a survey of a nationally representative sample of the U.S. population, 65 percent of respondents reported awareness of online physician ratings and about one-fourth reported usage of these sites, according to a study in the February 19 issue of JAMA.

“Patients are increasingly turning to online physician ratings, just as they have sought ratings for other products and services,” according to background information in the article. “Little is known about the public’s awareness and use of online physician ratings, and whether these sites influence decisions about selecting a physician.”

David A. Hanauer, M.D., M.S., of the University of Michigan Medical School, Ann Arbor, Mich., and colleagues surveyed the public in September 2012 about their knowledge and use of online ratings for selecting physicians. Sixty percent (2,137/3,563) of the sample responded. Twenty-one percent of respondents were 18 to 29 years of age; 17 percent, 30 to 39 years; 18 percent, 40 to 49 years; 19 percent, 50 to 59 years; and 26 percent, 60 years or older.

Among the findings of the survey:

Forty percent reported that physician rating sites were “very important” when choosing a physician, although rating sites were endorsed less frequently than other factors, including word of mouth from family and friends;

Awareness of online physician ratings (65 percent) was lower than for consumer goods such as cars (87 percent) and non-health care service providers (71 percent);

Among those who sought online physician ratings in the past year, 35 percent reported selecting a physician based on good ratings and 37 percent had avoided a physician with bad ratings;

For those who had not sought online physician ratings, 43 percent reported a lack of trust in the information on the sites.

The authors conclude that “rating sites that treat reviews of physicians like reviews of movies or mechanics may be useful to the public but the implications should be considered because the stakes are higher.”

(doi:10.1001/jama.2013.283194; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This research was conducted with the support of the C. S. Mott Children’s Hospital National Poll on Children’s Health, sponsored by the Department of Pediatrics and Communicable Diseases at the University of Michigan and the University of Michigan Health System. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 18, 2014

Media Advisory: To contact Anton P. Porsteinsson, M.D., call Julie Philipp at 585-275-1309 or email Julie_Philipp@urmc.rochester.edu. To contact editorial author Gary W. Small, M.D., call Rachel Champeau at 310-794-2270 or email rchampeau@mednet.ucla.edu.

Chicago – The use of the medication citalopram was associated with a reduction in agitation in patients with Alzheimer disease, although at the dosage used in the study, patients experienced mild cognitive and cardiac adverse effects that might limit the practical application of this medication at the dosage of 30 mg per day, according to a study in the February 19 issue of JAMA.

Agitation, which is common in patients with Alzheimer disease, is persistent, difficult to treat, costly, and associated with severe adverse consequences for patients and caregivers. Pharmacologic therapies have proven inadequate and antipsychotic drugs continue to be widely used for this condition despite serious safety concerns, including increased risk of death, and uncertain efficacy, according to background information in the article. Citalopram, an antidepressant drug frequently used in older individuals, has been proposed as an alternative to antipsychotic drugs for agitation and aggression in dementia, yet there is limited evidence for its efficacy and safety.

Anton P. Porsteinsson, M.D., of the University of Rochester School of Medicine and Dentistry, Rochester, N.Y., and colleagues randomized 186 patients with probable Alzheimer disease without major depression and clinically significant agitation from 8 academic centers in the United States and Canada to receive citalopram (n = 94) or placebo (n = 92) for 9 weeks. Both groups received psychological counseling and assistance.

Treatment with citalopram 30 mg per day led to a reduction in agitation, with a clinically relevant effect size: on one measure, 40 percent of citalopram-treated participants were judged to be much or very much improved vs 26 percent of those in the placebo group. The researchers did find a worsening of cognition and higher risk of ECG changes that could predispose to an abnormal heart rhythm in the citalopram group, and conclude that citalopram “cannot be generally recommended as an alternative treatment option at that dose.”

“An assessment of individual patient circumstances, including symptom severity, value of improvement, cognitive function and change, cardiac conduction, vulnerability to adverse effects, and effectiveness of behavioral interventions can help guide appropriate medication use in patients with marked agitation or aggression,” the authors add.

(doi:10.1001/jama.2014.93; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, February 18 at this link.

Editorial: Treating Dementia and Agitation

Until more informative criteria are available for choosing a particular drug treatment for agitation, clinicians should continue to emphasize nonpharmacological strategies and opt for medications with caution, writes Gary W. Small, M.D., of the University of California, Los Angeles, in an accompanying editorial.

“In addition to educating caregivers and family members about the potential risks and benefits of particular medications, physicians should carefully document their treatment plans and aim for short-term treatment to minimize the possible added risks of long-term use. As demonstrated by the results of this study of citalopram, when behavioral interventions fail to improve agitation, multiple factors need consideration for selecting the best medication for an individual patient, including cardiac safety issues and evidence of efficacy from randomized controlled trials. Until more definitive treatments are available, the careful selection and monitoring of pharmacologic agents may help optimize the level of functioning and quality of life for some patients with dementia.”

(doi:10.1001/jama.2014.94; 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.

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 18, 2014

Media Advisory: To contact Carlos A. Morillo, M.D., F.R.C.P.C., call Veronica McGuire at 905-525-9140, ext. 22169, or email vmcguir@mcmaster.ca. To contact editorial co-author Hugh Calkins, M.D., call Stephanie Desmon at 410-955-8665 or email sdesmon1@jhmi.edu.

 
Chicago – Among patients with untreated paroxysmal (intermittent) atrial fibrillation (AF), treatment with electrical energy (radiofrequency ablation) resulted in a lower rate of abnormal atrial rhythms and episodes of AF, according to a study in the February 19 issue of JAMA.

Arial fibrillation affects approximately 5 million people worldwide and is associated with an increased risk of stroke. Drug treatment is recommended by practice guidelines as a first-line therapy in patients with paroxysmal AF. “Radiofrequency ablation is an accepted therapy in patients for whom antiarrhythmic drugs have failed; however, its role as a first-line therapy needs further investigation,” according to background information in the article.

Carlos A. Morillo, M.D., F.R.C.P.C., of McMaster University, Hamilton, Canada, and colleagues compared ablation to drug treatment as first-line therapy in patients with paroxysmal AF who had not previously received treatment. The trial included 127 patients at 16 centers in Europe and North America; 61 patients received antiarrhythmic drug treatment and 66 radiofrequency ablation.

Recurrence of an atrial tachyarrhythmia lasting longer than 30 seconds (the primary measured outcome) occurred more often in the antiarrhythmic drug group than in the ablation group, 44 patients (72 percent) vs. 36 patients (55 percent). Asymptomatic AF was also observed more frequently with drug treatment, 11 patients (18 percent) compared with 6 patients (9 percent). Symptomatic recurrence of abnormal rhythm was more common with drug treatment, 36 patients (59 percent) in the antiarrhythmic drug group compared with 31 patients (47 percent) in the ablation group.

Quality of life was improved overall by both treatments but not significantly different between groups. No deaths or strokes were reported in either group; 4 cases of cardiac tamponade (the accumulation of a large amount of fluid [usually blood] near the heart that interferes with its performance) were reported in the ablation group.

The authors conclude that recurrence of an atrial tachyarrhythmia was frequent in both groups, and that when offering ablation as a therapeutic option to patients with paroxysmal AF who have not previously received antiarrhythmic drugs, the risks and benefits need to be discussed and treatment strategy individually recommended.

(doi:10.1001/jama.2014.467; 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: Has the Time Come to Recommend Catheter Ablation of Atrial Fibrillation as First-Line Therapy?

Hugh Calkins, M.D., of Johns Hopkins Hospital, Baltimore, Md., comments on the findings of this study in an accompanying editorial.

“Morillo and colleagues have made an important contribution in defining the safety, efficacy, and clinical role of catheter ablation of AF in treating symptomatic patients with paroxysmal AF. Their trial not only provides new and important information concerning the efficacy of AF ablation but also serves as another reminder of the potential complications of invasive therapies such as AF ablation.”

(doi:10.1001/jama.2014.468; 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.

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 18, 2014

Media Advisory: To contact Nancy K. Latham, Ph.D., P.T., call Lisa Chedekel at 617-571-6370 or email chedekel@bu.edu.
Chicago – Among patients who had completed standard rehabilitation after hip fracture, the use of a home exercise program that included exercises such as standing from a chair or climbing a step resulted in improved physical function, according to a study in the February 19 issue of JAMA.

More than 250,000 people in the United States fracture their hip each year, with many experiencing severe long-term consequences. “Two years after a hip fracture, more than half of men and 39 percent of women are dead or living in a long-term care facility. Many of these patients are no longer able to independently complete basic functional tasks that they could perform prior to the fracture, such as walking 1 block or climbing 5 steps 2 years after a fracture,” according to background information in the article. The efficacy of a home exercise program with minimal supervision after formal hip fracture rehabilitation ends has not been established.

Nancy K. Latham, Ph.D., P.T., of Boston University, and colleagues randomized 232 functionally limited older adults who had completed traditional rehabilitation after a hip fracture to a home exercise hip rehabilitation program comprising functionally oriented exercises (such as standing from a chair, climbing a step) taught by a physical therapist and performed independently by the participants in their homes for 6 months (n = 120); or in-home and telephone-based cardiovascular nutrition education (n = 112).

Among the 232 randomized patients, 195 were followed up at 6 months and included in the primary analysis. The intervention group (n=100) showed improvement relative to the control group (n=95) in functional mobility on various measures. In addition, balance significantly improved in the intervention group compared with the control group at 6 months.

“The traditional approach to rehabilitation for hip fracture leaves many patients with long-term functional limitations that could be reduced with extended rehabilitation. However, it is unlikely that additional months of highly supervised rehabilitation can be provided to patients with hip fracture,” the authors write.

“Exercise programs are challenging for people to perform on their own without clear feedback about whether they are performing the exercises accurately and safely and without guidance as to how to change the exercises over time. The findings from our study suggest that [the approach used in this study] could be introduced to patients after completion of traditional physical therapy following hip fracture and may provide a more effective way for these patients to continue to exercise in their own homes. However, future research is needed to explore whether the interventions in this trial can be disseminated in a cost-effective manner in real clinical environments.”

(doi:10.1001/jama.2014.469; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by a grant from the National Institute of Nursing Research. All Thera-Band products were donated by Thera-Band. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 11, 2014

Media Advisory: To contact Saad B. Omer, M.B.B.S., M.P.H., Ph.D., call Melva Robertson at 404-727-5692 or email melva.robertson@emory.edu.

Chicago – From 2009-2012, 36 bills introduced in 18 states sought to modify school immunization mandates, with the majority seeking to expand exemptions although none of the bills passed, according to a study in the February 12 issue of JAMA.

“School immunization mandates, implemented through state-level legislation, have played an important role in maintaining high immunization coverage in the United States,” according to background information in the article. Immunization mandates permit exemptions that vary from state to state in terms of type of exemption (e.g., religious, personal belief, medical). Certain types of exemptions (especially personal belief exemptions) and the ease of obtaining them can help predict the increased disease risk among exemptors themselves and in the communities in which they reside

Saad B. Omer, M.B.B.S., M.P.H., Ph.D., of Emory University, Atlanta, and colleagues analyzed legislation proposed from 2009 through 2012 at the state level to modify exemptions to school immunization requirements. The bills were classified into those that did or did not have a personal belief exemption (PBE). In addition, the researchers listed administrative requirements included in each bill, defined as one that would require action from the child’s parent or guardian beyond merely signing an exemption form. Bills were also classified as expanding or restricting exemptions.

Eighteen states introduced 1 or more exemption-related bills. Among 36 bills introduced, 15 contained no administrative requirements, 7 had 1 or 2 administrative requirements, and the remaining 14 contained between 3 and 5 administrative requirements.

Of 20 states with a current PBE, 5 saw a bill introduced to restrict exemptions and 1 saw a bill introduced to expand exemptions. Among the 30 states without a PBE, none saw a bill introduced to restrict exemptions and 13 saw a bill introduced to expand exemptions. Of the 36 bills introduced, 5 were categorized as restricting exemptions and 31 as expanding exemptions. None of the bills categorized as expanding exemptions were passed. Three of the 5 bills categorized as restricting exemptions were passed (Washington, California, and Vermont).

“Exemptions to school immunization requirements continue to be an issue for discussion and debate in many state legislatures,” the authors write.

(doi:10.1001/jama.2013.282869; 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. Hinman reported receiving institutional grant funding from the U.S. Centers for Disease Control and Prevention, the Bill & Melinda Gates Foundation, Novartis Vaccines, and the Merck Company Foundation. No other disclosures were reported.

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 11, 2014

Media Advisory: To contact Kenneth J. Ottenbacher, Ph.D., call Molly Dannenmaier at 409-772-8790 or email mjdannen@utmb.edu; or Mechal Weiss at 212-642-7731, mechal.weiss@edelman.com.

 Chicago – Among rehabilitation facilities providing services to Medicare fee-for-service patients, 30-day hospital readmission rates vary, from about 6 percent for patients with lower extremity joint replacement to nearly 20 percent for patients with debility (weakness or feebleness), according to a study in the February 12 issue of JAMA.

The Centers for Medicare & Medicaid Services (CMS) recently identified 30-day hospital readmission as a national quality indicator for inpatient rehabilitation facilities; reporting will be required in 2014 by the CMS, according to background information in the article.

Kenneth J. Ottenbacher, Ph.D., of the University of Texas Medical Branch, Galveston, Texas, and colleagues conducted a study to determine 30-day readmission rates and factors related to readmission for patients receiving postacute inpatient rehabilitation. The study included records for 736,536 Medicare fee-for-service beneficiaries discharged from 1,365 inpatient rehabilitation facilities to the community between 2006 and 2011. Readmission rates were examined for the 6 most common reasons for receiving inpatient rehabilitation: stroke, lower extremity fracture, lower extremity joint replacement, neurologic disorders, brain dysfunction and debility.

Average rehabilitation length of stay was 12 days. The overall 30-day readmission rate was 11.8 percent, with rates ranging from 5.8 percent for patients with lower extremity joint replacement to 18.8 percent for patients with debility. Rates were highest in men, non-Hispanic blacks, and for persons with longer lengths of stay. Higher motor and cognitive ratings, indicating better patient function, were consistently related to lower readmission rates across all 6 categories. Rates were similar for rural vs urban facilities and freestanding vs hospital-based facilities.

Approximately 50 percent of patients rehospitalized within the 30-day period were readmitted within 11 days of discharge. The most common reasons for readmission (per diagnosis codes) were heart failure, urinary tract infection, pneumonia, septicemia (blood poisoning), nutritional and metabolic disorders, esophagitis (inflammation of the esophagus), gastroenteritis, and digestive disorders.

The authors write that Medicare is currently examining bundled payment models designed to improve quality and contain costs. “The payment options cover different periods and include multiple health care professionals and settings. In the context of bundled payment, what happens to patients during post-acute care becomes important in the management of resources, quality, cost, and readmissions. Recent research has demonstrated that most of the variation in Medicare spending across geographic areas is attributable to postacute care. Readmission will likely add to the cost variation.”

“Questions regarding the validity of readmission as a quality indicator are likely to increase as the accountability for readmission expands to include postacute care settings. Although readmission is an imperfect quality indicator, it has the potential to serve as a platform for efforts to improve patient transitions and care continuity associated with bundling and other initiatives proposed by the Affordable Care Act to reduce cost and improve health outcomes.”

(doi:10.1001/jama.2014.8; 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.

ama_toc_item id=”16419″]

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 11, 2014

Media Advisory: To contact corresponding author Xiaobin Wang, M.D., M.P.H., Sc.D., call Tim Parsons at 410-955-7619 or email tmparson@jhsph.edu. To contact editorial author Mark Hanson, D.Phil., F.R.C.O.G., email M.Hanson@soton.ac.uk.

Chicago – Researchers have found that preterm infants are more likely to have elevated insulin levels at birth and in early childhood compared to full-term infants, findings that provide additional evidence that preterm birth may be a risk factor for type 2 diabetes, according to a study in the February 12 issue of JAMA.

In the United States, 1 in 9 live births are preterm, and l in 5 live births among African Americans are preterm. “There is growing evidence that fetal and early life events may result in permanent metabolic alterations, such as type 2 diabetes and metabolic syndrome [a combination of risk factors that increase the risk for heart disease, diabetes, and stroke]. Although available studies in children and adults support the hypothesis that preterm birth may result in adverse metabolic alterations, it is unclear whether the observed association between preterm birth, later insulin resistance, and type 2 diabetes stems from alterations in insulin metabolism during the in utero [in the uterus] period or in early childhood,” according to background information in the article.

Guoying Wang, M.D., Ph.D., of the Johns Hopkins University Bloomberg School of Public Health, Baltimore, and colleagues tested the hypothesis that preterm birth is associated with elevated plasma insulin levels (indirect evidence of insulin resistance) at birth that persist into early childhood. The study included 1,358 children, born between 1998 and 2010, and followed-up from 2005 to 2012. Random plasma insulin levels were measured at birth and in early childhood.

The researchers found that plasma insulin levels were inversely associated with gestational age at birth and in early childhood. Average insulin levels at birth were 9.2 µIU/mL (micro international units per milliliter) for full term (≥ 39 weeks) and 18.9 µIU/mL for early preterm (<34 weeks) births. In early childhood, random plasma insulin levels were higher for early term, late preterm, and for early preterm both than those born full term.

“These findings provide additional evidence that preterm birth (and perhaps early term birth as well) may be a risk factor for the future development of insulin resistance and type 2 diabetes,” the authors write.

(doi:10.1001/jama.2014.1; 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: Understanding the Origins of Diabetes

In an accompanying editorial, Mark Hanson, D.Phil., F.R.C.O.G., of the University of Southampton and University Hospital Southampton, United Kingdom, writes that “the population studied by Wang et al (i.e., largely urban and minority) has a high risk of preterm birth and also of childhood obesity and later metabolic syndrome.”

“The findings confirm the importance of the developmental origins of health and disease concept to such populations and raise questions about the relative effect size longer-term. However, such populations should not be viewed as special cases; they show a continuum of noncommunicable disease (NCD) risk that is initiated by a range of environmental influences operating across the normal range of early development.”

“Studies such as that by Wang et al reveal just how early the first steps toward prevention of diabetes may be possible and raise the prospect that rigorous studies of early life interventions could form an important aspect of helping to reduce NCD risk.”

(doi:10.1001/jama.2014.2; 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.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 11, 2014

Media Advisory: To contact corresponding author Lisen Arnheim-Dahlström, Ph.D., email lisen.arnheim.dahlstrom@ki.se.

Chicago – Although maximum reduction in the risk of genital warts (condylomata) was seen after 3 doses of human papillomavirus (HPV) vaccine, receipt of 2 vaccine doses was associated with considerable reduction in risk, particularly among women who were younger than 17 years at first vaccination, according to a study in the February 12 issue of JAMA.

HPV infection causes genital warts and cervical cancer, and HPV vaccine prevents both. The typical dose schedule requires 3 doses of vaccine, but small clinical trials have reported measures of vaccine efficacy with fewer than 3 doses. Although the primary goal of HPV vaccination programs is to prevent cervical cancer, genital warts related to HPV types 6 and 11 are prevented with a version of the vaccine and are the earliest measurable preventable disease outcome for the HPV vaccine, according to background information in the study.

Eva Herweijer, M.Sc., of the Karolinska Institutet, Stockholm, Sweden, and colleagues assessed the association between the number of doses of HPV vaccination and genital warts among females 10 to 24 years of age living in Sweden (n = 1,045,165) who were followed up between 2006 and 2010, using the Swedish nationwide population-based health data registers.

Among 20,383 new cases of genital warts, 322 occurred after receipt of at least 1 dose of the vaccine. The researchers found that maximum risk reductions were found after 3 doses, but 2 doses were also protective, although to a lesser extent; there was small difference in the number of cases prevented by 3 doses vs 2 doses.

The authors caution that this study does not account for HPV disease outcomes other than genital warts, and that more studies with longer follow-up are needed to assess if these observed reductions apply for cervical cancer.

(doi:10.1001/jama.2014.95; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, February 11 at this link.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 11, 2014

Media Advisory: To contact corresponding author Dorry L. Segev, M.D., Ph.D., call Stephanie Desmon at 410-955-8665 or email sdesmon1@jhmi.edu. To contact editorial co-author John S. Gill, M.D., call Brian Kladko at 604-827-3301 or email brian.kladko@ubc.ca.

Chicago – An analysis of nearly 100,000 kidney donors finds that there is a small increased lifetime risk of developing end-stage renal disease following donation compared with healthy nondonors, although the risk is still much lower than that in the general population, according to a study in the February 12 issue of JAMA.

Every year in the United States, approximately 6,000 healthy adults accept the risks of kidney donation to help family members, friends, or even strangers. “It is imperative that the transplant community, in due diligence to donors, understands the risk of donation to the fullest extent possible and communicates known risks to those considering donation,” according to background information in the article.

Abimereki D. Muzaale, M.D., M.P.H., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues compared the incidence of end-stage renal disease (ESRD) in donors and healthy nondonors to better understand the risk of ESRD. The study included 96,217 kidney donors (donation between 1994-2011) in the United States and a group of 20,024 participants of the Third National Health and Nutrition Examination Survey (NHANES III), who were linked to Centers for Medicare & Medicaid Services data to ascertain development of ESRD (defined as the initiation of maintenance dialysis, placement on the transplant waiting list, or receipt of a living or deceased donor kidney transplant).

The estimated cumulative incidence of ESRD at 15 years after donation was 30.8 per 10,000 in donors and 3.9 per 10,000 in healthy nondonors. This higher incidence among donors was observed in both black and white donors; absolute risk of ESRD was highest among blacks, regardless of their donor status. By age 80 years, the estimated lifetime risk of ESRD was 90 per 10,000 in donors vs 14 per 10,000 in healthy nondonors. Live donors had much lower estimated lifetime risk of ESRD than did the general population (unscreened nondonors; 326 per 10,000).

The authors write that their findings reaffirm the prevailing belief that lifetime risk of ESRD in live donors is no higher than in the general demographics-matched U.S. population.

“Compared with a matched cohort of healthy nondonors, kidney donors had an increased risk of ESRD; however, the magnitude of the absolute risk increase was small. These findings may help inform discussions with persons considering live kidney donation.”

(doi:10.1001/jama.2013.285141; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the Health Resources and Services Administration. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

ama_toc_item id=”16415″]

Editorial: Understanding Rare Adverse Outcomes Following Living Kidney Donation

In an accompanying editorial, John S. Gill, M.D., of the University of British Columbia, Vancouver, and Marcello Tonelli, M.D., of the University of Alberta, Edmonton, discuss the potential limitations of this study and the very low absolute risk of ESRD following live kidney donation.

“It would be easy to misinterpret the findings of Muzaale et al as suggesting that kidney donation is a risky procedure. In reality, the authors have shown that the absolute risk of ESRD among living donors is extremely low; this is their key finding and does not imply the need to alter existing clinical practice.”

“… it would be prudent for clinicians to emphasize the absolute risk of ESRD in discussions with prospective living donors, ideally using a decision aid that will facilitate the process of obtaining informed consent.”

(doi:10.1001/jama.2013.285142; 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.

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 4, 2014

Media Advisory: To contact Nassir F. Marrouche, M.D., call Phil Sahm at 801-581-2517 or email phil.sahm@hsc.utah.edu.
Chicago – Scarring of tissue in the upper chamber of the heart (atrium) was associated with recurrent rhythm disorder after treatment, according to a study in the February 5 issue of JAMA.

Left atrial fibrosis (formation of scar tissue in the heart) is prominent in patients with atrial fibrillation (AF), according to background information in the article. Extensive atrial tissue fibrosis identified by delayed enhancement magnetic resonance imaging (MRI) has been associated with poor outcomes of AF catheter ablation, a procedure in which electrical energy is used to treat AF.

Nassir F. Marrouche, M.D., of the University of Utah School of Medicine, Salt Lake City, and colleagues conducted a study to characterize the feasibility of measuring atrial scar tissue using delayed enhancement magnetic resonance imaging (MRI), and assessed the association between the amount of scar tissue and response to ablation. The study was conducted between August 2010 and August 2011 at 15 centers in the United States, Europe, and Australia; delayed enhancement MRI images were obtained up to 30 days before ablation.

There were 329 patients enrolled in the study; 57 patients (17.3 percent) were excluded due to poor MRI quality. The researchers found that the incidence of recurrence increased with the amount of scarring, from 15.3 percent recurrence at day 325 with less than 10 percent scarring of the atrial wall to 51.1 percent recurrence for 30 percent or greater scarring.

The authors write that this study demonstrates the feasibility and potential clinical value of using delayed enhancement MRI in the management of patients with AF considered for ablation. “In current practice, criteria for selecting good candidates for AF ablation are limited.”  They add that the amount of left atrial wall fibrosis estimated by delayed enhancement MRI has the potential to offer a noninvasive and effective method for determining which patients with AF are likely to benefit from ablation while avoiding procedures in patients likely to have arrhythmia recurrence.

(doi:10.1001/jama.2014.3; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The Comprehensive Arrhythmia and Research Management Center at the University of Utah provided funding for the study. The George S. and Dolores Dore Eccles Foundation funded part of this study. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 4, 2014

Media Advisory: To contact Barbara Schmidt, M.D., M.Sc., call Alison Fraser at 267-426-6054 or email FraserA1@email.chop.edu.
Chicago – In a group of very low-birth-weight infants, severe retinopathy of prematurity was associated with nonvisual disabilities at age 5 years, according to a study in the February 5 issue of JAMA.

Severe retinopathy (disease of the retina) of prematurity occurs in premature infants treated with excessive concentrations of oxygen and is a serious complication of neonatal intensive care for preterm infants. “Although the incidence of severe retinopathy has increased since the late 1980s, blindness caused by retinopathy has become rare in developed countries. Consequently, clinicians and parents may conclude that severe retinopathy is no longer associated with childhood impairments,” according to background information in the article.

Barbara Schmidt, M.D., M.Sc., of Children’s Hospital of Philadelphia, and colleagues investigated whether infants with severe retinopathy retain an increased risk of nonvisual disabilities compared with those without severe retinopathy. This analysis (using data from a trial, Caffeine for Apnea of Prematurity), included infants with birth weights between 1.1 and 2.8 lbs. who were born between 1999 and 2004 and followed-up at age 5 years (2005-2011).

Of 1,815 eligible infants, 1,582 (87 percent) had complete (n = 1,523) or partial (n = 59) 5-year assessments. Of 95 with severe retinopathy, 40 percent had at least 1 nonvisual disability at 5 years compared with 16 percent of children without it. Fourteen of 94 children (15 percent) with and 36 of 1,487 children (2.4 percent) without severe retinopathy had more than 1 nonvisual disability. Motor impairment, cognitive impairment, and severe hearing loss were 3 to 4 times more common in children with severe retinopathy than those without severe retinopathy.

The authors write that these findings may help improve the ability to counsel parents and to select high-risk infants for long-term follow-up.

“Severe retinopathy of prematurity remains an adverse outcome of neonatal intensive care with poor prognosis for child development, although blindness can mostly be prevented by timely retinal therapy.”

(doi:10.1001/jama.282153; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The Caffeine for Apnea of Prematurity trial was supported by a grant from the Canadian Institutes of Health Research and by the National Health and Medical Research Council of Australia. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 4, 2014

Media Advisory: To contact Norrina B. Allen, Ph.D., M.P.H., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu. To contact editorial co-author George L. Bakris, M.D., call John Easton at 773-795-5225 or email john.easton@uchospitals.edu.
Chicago – In an analysis of blood pressure patterns over a 25-year span from young adulthood to middle age, individuals who exhibited elevated and increasing blood pressure levels throughout this time period had greater odds of having higher measures of coronary artery calcification (a measure of coronary artery atherosclerosis), according to a study in the February 5 issue of JAMA.

“Blood pressure (BP) represents a major modifiable risk factor for cardiovascular disease (CVD). Current risk prediction models take into account BP level only at the time of risk prediction, usually in middle or older age, and do not consider the potential effect of BP levels earlier in life or the changes in BP levels over time,” according to background information in the article.

Norrina B. Allen, Ph.D., M.P.H., of the Feinberg School of Medicine, Northwestern University, Chicago, and colleagues identified common BP trajectories (patterns) throughout early adulthood and sought to determine their association with the presence of coronary artery calcification (CAC) during middle age among 4,681 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. The participants were black and white men and women, 18 to 30 years of age at the beginning of the study in 1985-1986. Data were collected through 25 years of follow-up on systolic BP, diastolic BP, and mid-BP (calculated as [SBP+DBP]/2, an important marker of coronary heart disease risk among younger populations). The primary measured outcome for the study was a higher level of coronary artery calcification detected by computed tomography scan.

The researchers identified 5 distinct trajectories in mid-BP from young adulthood to middle age: 22 percent of participants maintained low BP throughout follow-up (low-stable group); 42 percent had moderate BP levels (moderate-stable group); 12 percent started with moderate BP levels which increased at an average age of 35 years (moderate-increasing group); 19 percent had relatively elevated BP levels throughout (elevated-stable group); and 5 percent started with elevated BP’s which increased during follow-up (elevated-increasing group).

The prevalence of a high CAC score varied from 4 percent in the low-stable BP trajectory group to 25 percent in the elevated-increasing BP trajectory group. Participants who exhibited elevated BP levels throughout the study period and those who had increases in BP levels over this time had larger odds of having a high CAC score.

“Although BP has been a well-known risk factor for CVD for decades, these findings suggest that an individual’s long-term patterns of change in BP starting in early adulthood may provide additional information about his or her risk of development of coronary calcium,” the authors write. “Additional research is needed to examine the utility of specific BP trajectories in risk prediction for clinical CVD events and to explore the effect of lifestyle modification, treatment, and timing of intervention on lifetime trajectories in BP and outcomes.”

(doi:10.1001/jama.2013.285122; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, February 4 at this link.

Editorial: Early Patterns of Blood Pressure Change and Future Coronary Atherosclerosis

Pantelis A. Sarafidis, M.D., M.Sc., Ph.D., of Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece, and George L. Bakris, M.D., of University of Chicago Medicine, comment on the findings of this study in an accompanying editorial.

“The study by Allen and colleagues presents a novel approach for assessing coronary heart disease and CVD risk, and the data offer an important perspective to support a preventive approach to reduce coronary heart disease risk by demonstrating the existence of widely different BP trajectories ranging from young adulthood through middle age … Further research is warranted to explore the associations of BP trajectories with development of advancing chronic kidney disease and heart failure and to provide novel tools for risk prediction to guide interventions for BP lowering in everyday practice.”

(doi:10.1001/jama.2013.285123; 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.

# # #

EMBARGOED FOR EARLY RELEASE: 8 A.M. (CT) TUESDAY, JANUARY 21, 2014

Media Advisory: To contact Richard Smith, M.B.Ch.B., C.B.E., email richardswsmith@yahoo.co.uk.

Chicago – A video of individuals who gave birth to the evidence-based medicine movement features valuable oral histories of the movement, according to an editorial in the January 22/29 issue of JAMA. Evidence-based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.

In the editorial, Richard Smith, M.B.Ch.B., C.B.E., of the UnitedHealth Chronic Disease Initiative in London, and formerly editor, BMJ, and Drummond Rennie, M.D., of the University of California, San Francisco, and formerly contributing deputy editor, JAMA, discuss evidence-based medicine (EBM) and the important contributions of various individuals.

JAMA and the BMJ invited 6 individuals who helped lead the development of EBM to participate in an oral history event and filming. Videos of this event and of interviews with 3 other EBM leaders have been woven together to create the video, “Evidence-Based Medicine: An Oral History,” (available for free at the embargo time at http://ebm.jamanetwork.com).

The video features EBM leaders’ perspectives on the past, present, and future of EBM, some of the barriers and controversies associated with the EBM movement, and personal reflections of clinical and patient encounters and shared decision making in the context of EBM. “The video makes clear that much has been achieved, but that much remains to be done,” the editorial’s authors write.

(doi:10.1001/jama.2013.286182; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: Funding for the Evidence-Based Medicine Oral History event and filming was provided by JAMA and the BMJ. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding for travel to participate in the Evidence-Based Medicine Oral History event and filming was provided by JAMA and the BMJ.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 21, 2014

Media Advisory: To contact corresponding author Julia S. Johansen, M.D., D.M.Sc., email julia.johansen@post3.tele.dk. To contact editorial co-author Donald J. Buchsbaum, Ph.D., email Beena Thannickal at beenat@uab.edu.

Chicago – Researchers have identified diagnostic microRNA panels in whole blood that had the ability to distinguish, to some degree, patients with and without pancreatic cancer, according to a study in the January 22/29 issue of JAMA. The authors caution that the findings are preliminary, and that further research is necessary to understand whether these microRNAs have clinical implications as a screening test for early detection of pancreatic cancer.

MicroRNAs regulate gene expression and play important roles in the development of tumors and tumor metastasis. MicroRNA panels are a combination of several microRNAs.

Pancreatic cancer is the fourth most common cause of cancer death in the Western world and prognosis is poor, according to background information in the article.  Early diagnosis of pancreatic cancer is difficult partly because it is difficult to get useful biopsies of tissue from patients suspected of having pancreatic cancer, so markers of the disease that could help with early diagnosis are needed to improve prognosis. Several specific microRNA profiles (patterns of microRNAs) have been linked to pancreatic cancer tissue. A diagnostic noninvasive blood test for pancreatic cancer would be very valuable, the authors write.

Nicolai A. Schultz, M.D., Ph.D., of Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, and colleagues examined differences in microRNA in whole blood between patients with pancreatic cancer (n  = 409) and healthy participants (n = 312) and patients with chronic pancreatitis (n = 25) to identify diagnostic panels of microRNAs for use in the diagnosis of pancreatic cancer. Serum cancer antigen 19-9 (CA19-9; an antigen that is elevated in approximately 80 percent of patients with pancreatic cancer) was also measured for comparison.

The researchers identified 2 novel panels with the potential for diagnosing pancreatic cancer.

The authors write that the test could result in referral of more individuals with symptoms to imaging. “The test could thereby diagnose more patients with pancreatic cancer, some of them at an early stage, and thus have a potential to increase the number of patients that can be operated on and possibly cured of pancreatic cancer.”

They add that the harms of a high number of false-positives in screening for pancreatic cancer using an inexpensive, noninvasive blood sample from individuals with or without symptoms should be quantified in the future.

“Although we validated the panels, our findings are preliminary. … Further research is necessary to understand whether these have clinical implications for early detection of pancreatic cancer and how much this information adds to serum CA19-9.”

(doi:10.1001/jama.2013.284664; 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: Will Detection of MicroRNA Biomarkers in Blood Improve the Diagnosis and Survival of Patients With Pancreatic Cancer?

In an accompanying editorial, Donald J. Buchsbaum, Ph.D., of the University of Alabama, Birmingham, and Carlo M. Croce, M.D., of Ohio State University, Columbus, write that additional research is needed regarding the use of microRNAs for the early detection of pancreatic cancer.

“Even though the study was relatively large, well-conducted, and addressed the important topic of development of noninvasive methods to detect pancreatic cancer, the authors appropriately acknowledge the exploratory nature of the investigation. … Given the dismal prognosis for patients with pancreatic cancer, it is important that new diagnostic approaches, such as the one used in this study, are sought. However, additional rigorous investigation will be necessary to support and extend these interesting findings.”

(doi:10.1001/jama.2013.284665; 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.

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 21, 2014

Media Advisory: To contact corresponding author Miguel A. Martinez-Gonzalez, M.D., M.P.H., Ph.D., email mamartinez@unav.es.

Chicago – A multicenter study that previously reported a reduction in heart attack and stroke with a Mediterranean diet supplemented with extra-virgin olive oil or with nuts now also reports a lower risk of peripheral artery disease, according to a study in the January 22/29 issue of JAMA.

The hypothesis that a Mediterranean diet may reduce the risk of peripheral artery disease (PAD) has never been tested in a randomized trial, according to background information in the article.

Miguel Ruiz-Canela, Ph.D., of the University of Navarra, Pamplona, Spain, and colleagues assessed the association of Mediterranean diets with the occurrence of symptomatic PAD in a randomized trial conducted from October 2003 and December 2010. Eligible participants were men 55 to 80 years of age and women 60 to 80 years of age without clinical PAD or baseline cardiovascular disease but with type 2 diabetes mellitus or at least 3 cardiovascular risk factors. Participants were randomized to 1 of 3 groups: a Mediterranean diet supplemented with extra-virgin olive oil; a Mediterranean diet supplemented with nuts; or counseling on a low-fat diet (control group). All participants received a comprehensive dietary educational program on a quarterly basis.

The trial included 7,477 participants, with an average age of 67 years, and 58 percent of whom were women. There were 89 confirmed new cases of clinical PAD after a median (midpoint) follow-up of 4.8 years. Both Mediterranean diet interventions were associated with a lower risk of PAD compared with the control group.

“To our knowledge, this is the first randomized primary prevention trial to suggest an association between a dietary intervention and [reduction in] PAD. These results are consistent with previous observational studies and relevant from a public health perspective,” the authors write.

(doi:10.1001/jama.2013.280618; 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. Salas-Salvado reported receiving grant funding from the International Nut Council and serving as a consultant to the International Nut Council. No other disclosures were reported.

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 21, 2014

Media Advisory: To contact corresponding author Aaron S. Kesselheim, M.D., J.D., M.P.H., call Jessica Maki at 617-525-6373 or email jmaki3@partners.org.

Chicago – Many cardiac implantable electronic device models currently in use were approved via a Food and Drug Administration review process in which the models were assumed safe and effective based on approval of prior versions of the device, according to a study in the January 22/29 issue of JAMA.

“In the United States, the Food and Drug Administration (FDA) reviews high-risk medical devices—those that support human life, prevent illness, or present an unreasonable risk—via the premarket approval (PMA) pathway, through which manufacturers collect preclinical and clinical data as necessary to provide ‘reasonable assurance’ of the device’s safety and effectiveness,” according to background information in the article. That process has attracted attention in recent years after recall of device components, like leads from Medtronic Sprint Fidelis and St. Jude Medical Riata implantable cardioverter-defibrillators (ICDs), that were not tested clinically in human trials prior to approval because they were design changes to prior-marketed devices and considered ‘supplements’ to PMA applications submitted almost a decade earlier.

The process of approval by premarket approval supplement “allow[s] patients to benefit from incremental innovation in device technology by providing efficient and inexpensive FDA review pathways for smaller device changes. Supplements may include major or minor design changes as well as routine changes in labeling, materials, or packaging. By statute, the FDA must seek only the ‘least burdensome’ supporting data necessary for review.”

Benjamin N. Rome, B.A., of Harvard Medical School and Brigham and Women’s Hospital, Boston, and colleagues used the FDA’s PMA database to review CIEDs (including pacemakers, ICDs, and cardiac resynchronization therapy [CRT] devices) approved as PMA supplements from 1979 through 2012. They identified the number of supplements to each original PMA and characterized the nature of the changes in each supplement.

Seventy-seven approved PMA applications for CIEDs (46 pacemaker devices, 19 ICDs, and 12 CRT devices) were the basis for 5,829 PMA supplement applications, with a median (midpoint) of 50 supplements per original PMA. In the last decade, the number of approved supplements annually increased to 704. Excluding manufacturing changes that do not alter device design, the number of supplements approved each year averaged 2.6 per PMA per year.

Thirty-seven percent of supplements represented at least minor alterations to the device’s design or materials. Among 180-day supplements (a type of FDA review process) approved between 2010 and 2012, 23 percent included new clinical data to support safety and effectiveness.

“… Our results should not be interpreted to indicate that the FDA is failing to review PMA supplement applications to determine safety and effectiveness,” the authors conclude. However, clinicians and patients should … be aware … that clinical data are rarely collected as part of PMA supplement applications prior to marketing. The recalled Medtronic Sprint Fidelis and St. Jude Riata ICD leads were both PMA supplements — Fidelis a 180-day supplement and Riata a real-time supplement [a type of FDA review process]. Neither lead was studied in human trials prior to FDA approval. The FDA’s approval of many supplements without new human trials, as in the case of these recent ICD changes, highlights the importance of collecting rigorous postapproval performance data,” the authors write.

(doi:10.1001/jama.2013.284986; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 21, 2014

Media Advisory: To contact Leonard V. Sacks, M.B.B.Ch., call Sandy Walsh at 301-796-4669 or email sandy.walsh@fda.hhs.gov.
Chicago – Several potentially preventable deficiencies, including failure to select optimal drug doses and suitable outcome measures for a study, accounted for significant delays in the approval of new drugs by the Food and Drug Administration (FDA), according to a study in the January 22/29 issue of JAMA.

“The road from medical product discovery to marketing is typically long and costly. The interval between initial clinical testing and product approval has been estimated to average 8 years and only 1 in 6 drugs entering clinical trials ultimately obtains U.S. Food and Drug Administration approval,” according to background information in the article. Many drugs do not receive approval not because they are unsafe or ineffective, but because the information supplied is unsatisfactory to make that determination. Delays and failures that occur late in development affect the availability of innovative new drugs and increase the costs of drug development.

Leonard V. Sacks, M.B.B.Ch., of the U.S. Food and Drug Administration, Silver Spring, Md., and colleagues reviewed marketing applications for all new molecular entities (NMEs; active ingredients never before marketed in the United States in any form) first submitted to the FDA between 2000 and 2012. Using FDA correspondence and reviews, the researchers investigated the scientific and regulatory reasons approval of NMEs were delayed or denied.

Of the 302 identified NME applications, 151 (50 percent) were approved when first submitted and 222 (73.5 percent) eventually achieved marketing approval. Of the 151 first-cycle failures, 71 (47.0 percent) eventually obtained approval in a median (midpoint) of 435 days following the first unsuccessful submission.

Among the reasons for failure to initially receive approval:

• Uncertainty about the optimal dose to maximize efficacy and to minimize safety risks;
• Populations that were studied did not reflect the populations likely to use the drug;
• End points used in clinical trials were unsatisfactory;
• Inconsistent results for multiple predefined end points in clinical studies;
• Inconsistencies in efficacy for portions of the study population.

There were 20 drugs (13.2 percent) that despite showing superiority to placebo were considered to have inadequate efficacy compared with the standard of care.

The frequency of safety deficiencies was similar among never-approved drugs compared with those with delayed approval. However, efficacy deficiencies were significantly more frequent among the never-approved drugs than among those with delayed approvals. Among the 48 drugs with initial efficacy concerns alone, only 31.3 percent were eventually approved compared with 61.5 percent of the 39 drugs with safety concerns alone.

“Failures late in drug development are costly, often involving the commitment of many study participants and personnel. It is advantageous to identify products that fail as early as possible in the development process to avoid these issues. For those drugs that require resubmission before approval is obtained, delays are taxing on the industry and regulators, and patients may have to wait for access to promising, and sometimes lifesaving, new treatments,” the authors write.

“Our findings may be helpful to clinicians and policy makers in interpreting the extensive literature reporting the design and outcome of clinical trials, which in turn may have an effect on practice. For drug developers and clinical investigators, our findings suggest areas of deficiencies in new drug applications in which strategies for drug development could be improved. Early and frequent dialogue between the FDA and drug sponsors addressing critical aspects of study design (including the selection of study populations, study end points, and drug doses) has the potential to reduce delays in the approval of new drugs.”

(doi:10.1001/jama.2013.282542; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 21, 2014

Media Advisory: To contact corresponding author Joseph S. Ross, M.D., M.H.S., call Karen Peart at 203-432-1326 or email karen.peart@yale.edu. To contact editorial co-author Steven N. Goodman, M.D., M.H.S., Ph.D., call Ruthann Richter at 650-725-8047 or email richter1@stanford.edu.
Chicago – Clinical trials used by the Food and Drug Administration (FDA) to approve new drugs between 2005 and 2012 vary widely in their characteristics, according to a study in the January 22/29 issue of JAMA.

“FDA review of new drug applications is guided by the Federal Food, Drug, and Cosmetic Act, which requires ‘adequate and well controlled investigations’ to determine efficacy,” according to background information in the article. “Many patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the U.S. FDA has not been evaluated.”

Nicholas S. Downing, A.B., of the Yale University School of Medicine, New Haven, Conn., and colleagues evaluated the strength of clinical trial evidence supporting FDA approval decisions for new therapeutic agents by characterizing key features of pivotal efficacy trials (clinical trials that serve as the basis of FDA approval), such as trial size, design, duration, and end points.

The researchers used publicly available FDA documents to identify 188 novel therapeutic agents approved between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials. The vast majority of pivotal trials were randomized (89 percent) and double-blinded (79.5 percent). More than half of the trials used a placebo for comparison (55 percent), and 32 percent used an active (such as another drug) comparator, and 13 percent had no comparator.

The median (midpoint) number of patients enrolled per indication among all pivotal trials was 760. Among 201 indications, 74 (37 percent) were approved on the basis of a single trial, 77 (38 percent) on 2, and 50 (25 percent) on 3 or more. Trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 91 indications (45 percent).

At least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (34 percent). Trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status (drug used to treat rare medical condition), and accelerated approval.

“The variation in the [amount and type] of clinical trial evidence used by the FDA to assess the efficacy of novel therapeutic agents highlights the agency’s flexible standards for approval,” the authors write. “Such regulatory flexibility allows for a customized approach to approval, including the ability to rapidly approve potentially effective therapies for life-threatening diseases, such as certain cancers, or those diseases for which there is no existing effective treatment, such as orphan diseases. These approvals can be made without requiring costly and time-consuming randomized, double-blinded, controlled trials, although these trials are regarded as the gold standard for evaluation.”

The researchers note that understanding the clinical trial evidence underlying newly approved therapeutic agents has important implications for patients and physicians. “When medications become available on the market, decisions must be made about their use, likely informed by how well safety and effectiveness are understood. Comparative effectiveness information, which is not required as part of FDA approval and involves comparison of an intervention with an active control, was available for less than half of indications, consistent with prior research, but leaving uncertainty about the benefits and safety of these medications when compared with other available therapeutic agents.”

The authors write that the wide variation in clinical trial evidence “has the potential to inform current FDA regulatory approval standards and postmarket surveillance initiatives.”

(doi:10.1001/jama.2013.282034; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, January 21 at this link.

Editorial: Opening the FDA Black Box

In an accompanying editorial, Steven N. Goodman, M.D., M.H.S., Ph.D., of Stanford University, Stanford, Calif., and Rita F. Redberg, M.D., M.Sc., of the University of California, San Francisco, and Editor, JAMA Internal Medicine, comment on the three studies in this issue of JAMA that examine the FDA approval process.

“Although these reports represent important steps in improving understanding of FDA decision making, further commitment to and progress toward ensuring transparency, including reducing report redactions, is needed to help the scientific community and other interested parties answer the questions these studies raise, thereby helping the FDA in its mission to find the right balance between allowing innovation and protecting the public’s health.”

(doi:10.1001/jama.2013.283946; 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. Redberg reported being a member of the U.S. Food and Drug Administration Circulatory System Devices Panel and a member of the California Technology Assessment Forum. No other conflicts of interest were reported.

# # #