EMBARGOED FOR EARLY RELEASE: 3 P.M. (CT) SATURDAY, MAY 3, 2014

Media Advisory: To contact Daniel K. Benjamin Jr., M.D., Ph.D., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

Use of the antifungal medication fluconazole for six weeks for extremely low birth-weight infants did not significantly reduce the risk of death or invasive candidiasis, a serious infection that occurs when candida (a type of fungus) enters the bloodstream and spreads through the body, according to a study in the May 7 issue of JAMA, a theme issue on child health. This issue is being released early to coincide with the Pediatric Academic Societies Annual Meeting.

Invasive candidiasis is an important cause of infection in premature infants; despite treatment with antifungal therapy, invasive candidiasis has serious effects on premature infants, including severe neurodevelopmental impairment and death. Current recommendations include the use of fluconazole for prevention of this infection for infants with a birth weight of less than 1,000 grams (2.2 lbs.) who receive care in neonatal intensive care units (NICUs). However, most NICUs in the United States and the European Union have not uniformly adopted preventive use of fluconazole, based on controversies regarding high-risk patients, resistance, and safety, according to background information in the article.

Daniel K. Benjamin Jr., M.D., Ph.D., of Duke University, Durham, N.C., and colleagues evaluated the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low birth-weight infants (weighing less than 750 grams [1.7 lbs.] at birth). The study included 361 infants from 32 NICUs in the United States who were randomly assigned to receive either fluconazole (6mg/kg of body weight) or placebo twice weekly for 42 days.

The primary composite end point of death or invasive candidiasis by study day 49 was not statistically different between the 2 groups (fluconazole, 16 percent vs placebo, 21 percent). The percentage of infants who died prior to study day 49 was not different between the groups (14 percent vs 14 percent). Fewer infants developed definite or probable invasive candidiasis in the fluconazole (3 percent) vs in the placebo group (9 percent).

“Fluconazole prophylaxis compared with placebo was not associated with a statistically significant difference in the composite primary end point—death or definite or probable invasive candidiasis— although it was associated with a statistically significant reduction in the incidence of definite or probable candidiasis alone.  This study adds new evidence regarding the efficacy of fluconazole prophylaxis, but raises the question of whether prevention of invasive candidiasis translates into substantial improvements in the outcomes of prematurity.”

“Based on both the results of our study in NICUs with a low incidence of invasive candidiasis, and previous prophylaxis trials in high-incidence NICUs, the routine use of fluconazole prophylaxis should be limited to units with moderate-to-high incidence of invasive candidiasis. However, additional research is needed to precisely define the incidence at which the benefits of fluconazole prophylaxis outweigh the risks,” the authors write.

(doi:10.1001/jama.2014.2624; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 3 P.M. (CT) SATURDAY, MAY 3, 2014

Media Advisory: To contact Jorge A. Bezerra, M.D., call Nick Miller at 513-803-6035 or email nicholas.miller@cchmc.org.

Among infants who underwent surgery to repair bile ducts that do not drain properly (biliary atresia), the administration of high-dose steroid therapy following surgery did not significantly improve bile drainage after 6 months, although a small clinical benefit could not be excluded, according to a study in the May 7 issue of JAMA, a theme issue on child health. This issue is being released early to coincide with the Pediatric Academic Societies Annual Meeting.

Biliary atresia progresses to end-stage liver disease (cirrhosis) in more than 70 percent of affected children and is the leading indication for pediatric liver transplantation in the world, accounting for about 50 percent of liver transplants in children. Hepatoportoenterostomy (surgery to improve bile drainage) results in successful bile drainage in only about half of patients with biliary atresia treated in the United States, underscoring the need for additional therapies to improve survival without liver transplantation, according to background information in the article. There have been conflicting reports regarding the effectiveness of the use of corticosteroids to improve bile flow following surgery.

Jorge A. Bezerra, M.D., of Cincinnati Children’s Hospital Medical Center, Cincinnati, and colleagues randomly assigned 140 infants (average age, 2.3 months) to receive high-dose steroid therapy or placebo following surgery to improve bile drainage.

The researchers found that the proportion of infants with improved bile drainage was not significantly improved by steroids at 6 months following surgery (58.6 percent of steroids group vs 48.6 percent of placebo group). The adjusted absolute risk difference was 8.7 percent.

Survival without liver transplantation at 2 years of age for infants treated with steroids was nearly identical to those who received placebo (58.7 percent vs. 59.4 percent). Serious adverse events were com­mon in both treatment groups (81.4 percent for steroids vs 80.0 percent for placebo); however, infants treated with steroids experienced their first serious adverse events earlier than those receiving placebo.

“Based on the strength of the evidence, the addition of high-dose steroids as an adjuvant [supplemental] treatment for infants with biliary atresia after hepatoportoenterostomy cannot be recommended,” the authors write.

(doi:10.1001/jama.2014.2623; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 3 P.M. (CT) SATURDAY, MAY 3, 2014

Media Advisory: To contact Flor M. Munoz, M.D., call Dipali Pathak at 713-798-4710 or email pathak@bcm.edu. To contact editorial co-author Kathryn M. Edwards, M.D., call Craig Boerner at 615-322-4747 or email craig.boerner@vanderbilt.edu.

A preliminary study finds that receipt of the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in the third trimester of pregnancy did not increase the risk of adverse events for the mother or infant, according to a study in the May 7 issue of JAMA, a theme issue on child health. In addition, the authors found high concentrations of pertussis antibodies in infants during the first 2 months of life, a period during which infants are at the highest risk of pertussis-associated illness or death. This issue is being released early to coincide with the Pediatric Academic Societies Annual Meeting.

Pertussis is a highly contagious and potentially fatal vaccine-preventable disease that has re-emerged in the United States despite high childhood immunization rates. Infants younger than 6 months are at greatest risk of disease, hospitalization, and death and account for more than 90 percent of all pertussis-associated deaths in the United States. Infants too young to receive the primary diphtheria and tetanus toxoids and acellular pertussis (DTaP) immunization series (recommended at 2, 4, and 6 months of age) depend on maternal antibodies for protection against pertussis. However, pregnant women have very low concentrations of pertussis antibodies to transfer to their newborn at the time of delivery; maternal immunization with the Tdap vaccine could help prevent infant pertussis, according to background information in the article.

Flor M. Munoz, M.D., of the Baylor College of Medicine, Houston, and colleagues randomly assigned 48 women to receive the Tdap vaccine (n = 33) or placebo (n = 15) at 30 to 32 weeks’ gestation to evaluate the safety and immunogenicity (ability to produce an immune response) of the vaccine administered during pregnancy. Women who received placebo during pregnancy were given Tdap vaccine postpartum prior to hospital discharge, and women who received Tdap during pregnancy were given placebo postpartum.

The researchers found that injection site and systemic reactogenicity (adverse reactions) rates in pregnant women were not significantly different than those observed among postpartum or nonpregnant women. No Tdap-associated serious adverse events occurred in women or infants. Growth and development were similar in both infant groups. No cases of pertussis occurred.

Also, concentrations of vaccine-induced pertussis antibodies in infants born to mothers immunized with Tdap during pregnancy were significantly higher at birth and at age 2 months than in infants whose mothers were immunized postpartum.

In addition, maternal immunization with Tdap did not substantially alter infant responses to scheduled DTaP.

“Further research is needed to provide definitive evidence of the safety and efficacy of Tdap immunization during pregnancy,” the authors write.

(doi:10.1001/jama.2014.3633; 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: Maternal Pertussis Immunization – Can It Help Infants?

Although Tdap has an excellent safety record, future cohort or surveillance studies must continue to assess safety and immunogenicity of Tdap immunization during pregnancy, write Natalia Jimnez-Truque, M.S.C.I., Ph.D., and Kathryn M. Edwards, M.D., of Vanderbilt University Medical Center, Nashville, Tenn., in an accompanying editorial.

“Continued reporting of pertussis cases will also be necessary to assess the effectiveness of administering Tdap during pregnancy. In addition, the assessment of potential interference with DTaP and other vaccine antigens administered during infancy will require large prospective studies. Last, future research must address the safety and immunogenicity of repeated doses of Tdap during each pregnancy, because frequent immunization might lead to a blunted antibody response.”

(doi:10.1001/jama.2014.3555; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 3 P.M. (CT) SATURDAY, MAY 3, 2014

Media Advisory: To contact corresponding author Sarah D. de Ferranti, M.D., M.P.H., call Rob Graham at 617-919-3110 or email Rob.graham@childrens.harvard.edu.

Although some guidelines recommend lipid screening for children and adolescents of certain ages, data indicate that only about 3 percent are having their cholesterol tested during health visits, according to a study in the May 7 issue of JAMA, a theme issue on child health. This issue is being released early to coincide with the Pediatric Academic Societies Annual Meeting.

Abnormal lipid values occur in 1 in 5 U.S. children and adolescents, and are associated with cardiovascular disease in adulthood. Universal pediatric lipid screening is advised by the National Heart, Lung, and Blood Institute (NHLBI) for those ages 9 to 11 years and 17 to 21 years, in addition to the selective screening advised by the American Academy of Pediatrics (AAP) and the American Heart Association. In contrast, the U.S. Preventive Services Task Force (USPSTF) did not find sufficient evidence to recommend any pediatric lipid screening, according to background information in the article.

Samuel R. Vinci, B.A., of Boston Children’s Hospital, and colleagues examined rates and trends in cholesterol testing, including before and after the 2007 USPSTF and 2008 AAP cholesterol statements. For this analysis, the researchers used patient data from the National Ambulatory Medical Care Survey, which provides nationally representative estimates.

During the period from 1995 through 2010, clinicians ordered cholesterol testing at 3.4 percent of 10,159 health maintenance visits. Testing rates increased only slightly from 2.5 percent in 1995 to 3.2 percent in 2010. The authors note that applying the most recent 2011 NHLBI guidelines to 2009 U.S. census data, approximately 35 percent of patients would be eligible for lipid screening in any given year based on age (9-11 years and 17-21 years).

“Testing rates did not appear to increase after 2007-2008, perhaps reflecting the conflicting positions of the AAP and USPSTF,” the authors conclude.

(doi:10.1001/jama.2014.2410; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 3 P.M. (CT) SATURDAY, MAY 3, 2014

Media Advisory: To contact Sven Sandin, M.Sc., email Sven.Sandin@ki.se. To contact editorial co-author Diana E. Schendel, Ph.D., email diana.schendel@folkesundhed.au.dk.
 

The risk of autism may be influenced equally by genetic and environmental factors; in addition, a sibling of a family member with autism has a much higher risk for the disorder, according to a study in the May 7 issue of JAMA, a theme issue on child health. This issue is being released early to coincide with the Pediatric Academic Societies Annual Meeting.

Autism spectrum disorder (ASD) affects almost 1 percent of all children born in the United States and is defined as impairment in social interaction and communication and the presence of restricted interests and repetitive behaviors. Autistic disorder (autism) is the most profound form of ASD, which aggregates in families (increased risk among members of the same family), but the individual risk and to what extent this is caused by genetic or environmental factors is uncertain, according to background information in the article.

Sven Sandin, M.Sc., of the Karolinska Institutet, Stockholm, Sweden, and colleagues estimated the heritability of ASD and risk among family members and assessed the importance of genetic vs. environmental factors by using data of all births in Sweden between 1982 and 2006 (n = 2,049,973). The researchers determined the relative recurrence risk (RRR), which is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis (exposed) compared with the risk in a participant with no diagnosed family member (unexposed).

The study included 14,516 children with ASD, of whom 5,689 (39 percent) had a diagnosis of autistic disorder. The researchers found a 10-fold increased risk of recurrence among siblings of a family member with ASD; cousins had a 2-fold increased risk. This pattern was similar for autistic disorder but of slightly higher magnitude.

Among children born in Sweden, the heritability of ASD was estimated at approximately 50 percent, as was the environmental influence.

“These findings may inform the counseling of families with affected children,” the authors write.

(doi:10.1001/jama.2014.4144; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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

Editorial: The Genetic and Environmental Contributions to Autism

Diana E. Schendel, Ph.D., of Aarhus University, Aarhus, Denmark, and colleagues write in an accompanying editorial that much remains to be understood regarding familial risk for autism.

“Future studies might consider risks from different combinations of diagnoses in the [family member with ASD] and sibling; for example, the risk of any ASD diagnosis in the sibling of a child diagnosed with autistic disorder, or other combinations of ASD-related or comorbid neurodevelopmental diagnoses (e.g., ASD-epilepsy combinations).”

“In conclusion, the work by Sandin et al supports appreciation of the importance of genetic factors in ASD and adds substantial impetus to the growing attention to environmental influences in ASD etiology.”

(doi:10.1001/jama.2014.3554; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 3 P.M. (CT) SATURDAY, MAY 3, 2014

Media Advisory: To contact Maria Makrides, B.Sc., B.N.D., Ph.D., email maria.makrides@health.sa.gov.au.

Although there are recommendations for pregnant women to increase their intake of the omega-3 fatty acid docosahexaenoic acid (DHA) to improve fetal brain development, a randomized trial finds that prenatal DHA supplementation did not result in improved cognitive, problem-solving or language abilities for children at four years of age, according to the study in the May 7 issue of JAMA, a theme issue on child health. This issue is being released early to coincide with the Pediatric Academic Societies Annual Meeting.

Maria Makrides, B.Sc., B.N.D., Ph.D., of the South Australian Health and Medical Research Institute, Adelaide, Australia and colleagues conducted longer-term follow-up from a previously published study in which pregnant women received 800 mg/d of DHA or placebo. In the initial study, the researchers found that average cognitive, language, and motor scores did not differ between children at 18 months of age. For the follow-up study, outcomes were assessed at 4 years, a time point when any subtle effects on development should have emerged and can be more reliably assessed.

The majority (91.9 percent) of eligible families (DHA group, n = 313; control group, n = 333) participated in the follow-up. The authors found that measures of cognition, the ability to perform complex mental processing, language, and executive functioning (such as memory, reasoning, problem solving) did not differ significantly between groups.

“Our data do not support prenatal DHA supplementation to enhance early childhood development.”

(doi:10.1001/jama.2014.2194; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 3 P.M. (CT) SATURDAY, MAY 3, 2014

Media Advisory: To contact Dana Dabelea, M.D., Ph.D., call Tonya Ewers at 303-724-8573 or email tonya.ewers@ucdenver.edu.

In a study that included data from more than three million children and adolescents from diverse geographic regions of the United States, researchers found that the prevalence of both type 1 and type 2 diabetes increased significantly between 2001 and 2009, according to the study in the May 7 issue of JAMA, a theme issue on child health. This issue is being released early to coincide with the Pediatric Academic Societies Annual Meeting.

Dana Dabelea, M.D., Ph.D., of the Colorado School of Public Health, Aurora, Colo., and Elizabeth J. Mayer-Davis, Ph.D., of the University of North Carolina, Chapel Hill, and colleagues with the SEARCH for Diabetes in Youth Study, examined whether the overall prevalence of type 1 and type 2 diabetes among U.S. youth has changed in recent years, and whether it changed by sex, age, and race/ethnicity. Despite concern about an “epidemic,” there have been limited data on trends regarding diabetes. “Understanding changes in prevalence according to population subgroups is important to inform clinicians about care that will be needed for the pediatric population living with diabetes and may provide direction for other studies designed to determine the causes of the observed changes,” the authors write.

The analysis included cases of physician-diagnosed type 1 diabetes in youth ages 0 through 19 years and type 2 diabetes in youth 10 through 19 years of age in 2001 and 2009.  The study population came from five centers located in California, Colorado, Ohio, South Carolina, and Washington state, as well as data from selected American Indian reservations in Arizona and New Mexico.

In 2001, the prevalence of type 1 diabetes among a population of 3.3 million was 1.48 per 1,000, which increased to 1.93 per 1,000 among 3.4 million youth in 2009, which, after adjustment, indicated an increase of 21 percent over the 8-year period. The greatest prevalence increase was observed in youth 15 through 19 years of age. Increases were observed in both sexes and in white, black, Hispanic, and Asian Pacific Islander youth. “Historically, type l diabetes has been considered a disease that affects primarily white youth; however, our findings highlight the increasing burden of type l diabetes experienced by youth of minority racial/ethnic groups as well,” the authors write.

The overall prevalence of type 2 diabetes for youth ages 10 to 19 years increased by an estimated 30.5 percent between 2001 and 2009 (among a population of 1.7 million and 1.8 million youth, respectively).  Increases occurred in white, Hispanic, and black youth, whereas no changes were found in Asian Pacific Islander and American Indian youth. A significant increase was seen in both sexes and all age-groups.

“The increases in prevalence reported herein are important because such youth with diabetes will enter adulthood with several years of disease duration, difficulty in treatment, an increased risk of early complications, and increased frequency of diabetes during reproductive years, which may further increase diabetes in the next generation,” the researchers write. “Further studies are required to determine the causes of these increases.”

(doi:10.1001/jama.2014.3201; 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 Saturday, May 3 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 22, 2014

Media Advisory: To contact James M. Chamberlain, M.D., call Joe Cantlupe at 202-476-4500 or email JCantlupe@childrensnational.org.

Although some studies have suggested that the drug lorazepam may be more effective or safer than the drug diazepam in treating a type of epileptic seizures among children, a randomized trial finds that lorazepam is not better at stopping seizures compared to diazepam, according to a study in the April 23/30 issue of JAMA, a neurology theme issue.

Status epilepticus is a prolonged epileptic seizure or seizures that occurs approximately 10,000 times in children annually in the United States. Rapid control of status epilepticus is essential to avoid permanent injury and life-threatening complications such as respiratory failure. The Food and Drug Administration has approved diazepam, but not lorazepam, for the treatment of status epilepticus in children. Studies involving lorazepam have shown mixed results, according to background information in the article.

James M. Chamberlain, M.D., of the Children’s National Medical Center, Washington, D.C., and colleagues with the Pediatric Emergency Care Applied Research Network, randomly assigned 273 patients (age 3 months to younger than 18 years with convulsive status epilepticus) presenting to one of 11 pediatric emergency departments to receive diazepam or lorazepam intravenously.

The researchers found that the primary measure of effectiveness, cessation of status epilepticus for 10 minutes without recurrence within 30 minutes, occurred in 101 of 140 (72.1 percent) in the diazepam group and 97 of 133 (72.9 percent) in the lorazepam group. Twenty-six patients in each group required assisted ventilation (the primary safety outcome; 16.0 percent given diazepam and 17.6 percent given lorazepam).

There were no significant differences in other outcomes such as rates of seizure recurrence and time to cessation of convulsions, except that patients receiving lorazepam were more likely to experience sedation (67 percent vs 50 percent).

The authors write that the study results have important implications for both outside the hospital and emergency department care. “Diazepam can be stored without refrigeration and thus has been used as the treatment of choice in many prehospital systems. The results of this study do not support the superiority of lorazepam over diazepam as a first-line agent for pediatric status epilepticus.”

The researchers add that future trials should consider newer medications and novel interventions targeting those at highest risk for medication failure or respiratory depression.

(doi:10.1001/jama.2014.2625; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 22, 2014

Media Advisory: To contact Martin Ebinger, M.D., email martin.ebinger@charite.de.

Using an ambulance that included a computed tomography (CT) scanner, point-of-care laboratory, telemedicine connection and a specialized prehospital stroke team resulted in decreased time to treatment for ischemic stroke, according to a study in the April 23/30 issue of JAMA, a neurology theme issue.

Stroke is a leading cause of death and disability. In acute ischemic stroke, thrombolysis (dissolving of blood clots) using intravenous tissue plasminogen activator (tPA) is the treatment of choice after excluding bleeding in the brain by imaging. Past studies have shown time-dependent benefits of tPA, with early treatment associated with better outcomes. Apart from delayed patient presentation, management inside and outside of the hospital contributes to treatment delays. Recent data from the United States indicate that less than 30 percent of patients have a door-to-needle time for receiving tPA within the recommended 60 minutes. A recent study reported time-savings for 12 tPA administrations performed in a special ambulance with a CT scanner and laboratory. Little is known about the overall effects of specialized ambulances for treating patients with stroke, according to background information in the article.

Martin Ebinger, M.D., of Charité–Universitätsmedizin Berlin, Germany, and colleagues conducted a study in which a specialized ambulance (Stroke Emergency Mobile [(STEMO]) was randomly assigned weeks when it was available for response in Berlin, which has an established stroke care system with 14 stroke units. The ambulance was equipped with a CT scanner, point-of-care laboratory, and telemedicine connection; a tool to help identify stroke at the dispatcher level; and a specialized prehospital stroke team, which included a neurologist, paramedic, and a radiology technician. If ischemic stroke was confirmed and contraindications excluded, thrombolysis was started before transport to hospital. The overall study population included 6,182 patients.

The researchers found that compared with control weeks, the average alarm-to-treatment (defined as when the dispatcher activated the alarm to tPA administration) time reduction was 25 minutes among patients receiving tPA after STEMO deployment. Also, the rate of tPA treatment in ischemic stroke was higher after STEMO deployment (33 percent) than during control weeks (21 percent).

STEMO deployment was not associated with increased risk for intracerebral hemorrhage or 7-day mortality.

The authors note that the effects found in this study have to be weighed against costs of the STEMO concept. Depending on the configuration of the vehicle, a single STEMO ambulance costs about $1.4 million. Cost-effectiveness analyses are currently under way.

“Our study showed that the ambulance-based thrombolysis was safe, reduced alarm-to-treatment time, and increased thrombolysis rates,” the researchers write. “Further studies are needed to assess the effects on clinical outcomes.”

(doi:10.1001/jama.2014.2850; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This study was funded by Zukunftsfonds Berlin with co-financing by the European Regional Development Fund. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 22, 2014

Media Advisory: To contact Winston Chiong, M.D., Ph.D., call Laura Kurtzman at 415-476-3163 or email Laura.Kurtzman@ucsf.edu.

The majority of adults surveyed indicated they would want administration of clot-dissolving medications if incapacitated by a stroke, a finding that supports clinicians’ use of this treatment if patient surrogates are not available to provide consent, according to a study in the April 23/30 issue of JAMA, a neurology theme issue.

“In life-threatening emergencies involving incapacitated patients without surrogates, clinicians may intervene without obtaining informed consent, applying the presumption that reasonable people would consent to treatment in such circumstances. Whether this rationale applies to the treatment of acute ischemic stroke with intravenous thrombolysis [administration of clot-busting agent] is controversial because this intervention improves functional outcomes but is not life preserving. Nonetheless, the presumption of consent to thrombolysis for ischemic stroke has recently been endorsed by professional societies,” according to background information in the study.

Winston Chiong, M.D., Ph.D., of the University of California, San Francisco, and colleagues examined presumption of consent by comparing preferences for treatment of acute ischemic stroke with thrombolysis and treatment of sudden cardiac arrest with cardiopulmonary resuscitation (CPR; in which the presumption of consent is generally accepted) in a nationally representative sample of U.S. adults 50 years of age or older. The participants were randomly assigned to read 1 of 2 scenarios: in one they experienced a severe acute ischemic stroke and were brought to a hospital, and in the other they experienced an out-of-hospital cardiac arrest and were attended to by paramedics.

The stroke scenario included a graphical depiction of potential risks and benefits of treatment with thrombolysis. The cardiac arrest scenario included a similar depiction of potential outcomes after paramedic-initiated CPR. All participants were then asked whether they would want the treatment described.

The researchers found that 76.2 percent of older adults (419 of 545 participants) wanted thrombolysis for acute ischemic stroke and 75.9 percent of older adults (422 of 555 participants) wanted CPR for sudden cardiac arrest. Female sex, divorced marital status, and lower educational attainment predicted refusal of thrombolysis; poorer physical health, previous stroke, and possession of a health care advance directive predicted refusal of CPR.

“When an incapacitated older patient’s treatment preferences are unknown and surrogate decision makers are unavailable, there are equally strong empirical grounds for presuming individual consent to thrombolysis for stroke as for presuming individual consent to CPR. Because the presumption of consent is generally accepted for CPR, this finding provides empirical support for policy positions recently taken by professional societies that favor the use of thrombolysis for stroke in emergency circumstances under a presumption of consent,” the authors write.

(doi:10.1001/jama.2014.3302; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 22, 2014

Media Advisory: To contact Michael Wall, M.D., call Jennifer Brown at 319- 356-7124 or email jennifer-l-brown@uiowa.edu. To contact editorial author Jonathan C. Horton, M.D., Ph.D., call Juliana Bunim at 415-476-8810 or email juliana.bunim@ucsf.edu.
In patients with idiopathic intracranial hypertension and mild vision loss, the use of the drug acetazolamide, along with a low-sodium weight-reduction diet, resulted in modest improvement in vision, compared with diet alone, according to a study in the April 23/30 issue of JAMA, a neurology theme issue.

Idiopathic intracranial hypertension (IIH) is a disorder primarily of overweight women of childbearing age, characterized by increased intracranial pressure with its associated signs and symptoms, including debilitating headaches and vision loss. Acetazolamide is commonly used to treat this condition, but strong evidence to support its use is lacking, according to background information in the article.

Michael Wall, M.D., of the University of Iowa, Iowa City, and colleagues with the NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee, randomly assigned 165 participants with IIH and mild visual loss to receive acetazolamide or matching placebo for 6 months to determine its effect on reducing or reversing visual loss. All participants were also asked to follow a low-sodium weight-reduction diet.

The average improvement in perimetric mean deviation (PMD; a measure of global visual field loss) was greater with acetazolamide than with placebo. In addition, there were improvements in papilledema (optic disc swelling) and vision-related quality of life with acetazolamide. Participants who received acetazolamide also experienced a greater reduction in weight.

There were few unexpected adverse events associated with acetazolamide use.

“This is the first multicenter, double-blind, randomized, controlled clinical trial, to our knowledge, to show that acetazolamide improves visual outcome in IIH,” the authors write. “The clinical importance of this improvement remains to be determined.”

(doi:10.1001/jama.2014.3312; 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: Acetazolamide for Pseudotumor Cerebri – Evidence From the NORDIC Trial

“The obesity epidemic has increased the prevalence of pseudotumor cerebri [idiopathic intracranial hypertension]. Consequently, the health care costs associated with the treatment of this disease have escalated sharply,” writes Jonathan C. Horton, M.D., Ph.D., of the University of California, San Francisco, in an accompanying editorial.

“The NORDIC trial has provided solid evidence that patients can be treated effectively by weight loss and acetazolamide. Their visual acuity and visual fields should be tested regularly, at a frequency that depends on the severity of their condition. If vision is failing despite medical treatment, rapid surgical intervention is necessary.”

“Additional studies are needed to refine the management of patients with pseudotumor cerebri to ensure preservation of visual function.”

(doi:10.1001/jama.2014.3325; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 22, 2014

Media Advisory: To contact Rustam Al-Shahi Salman, Ph.D., email Jen Middleton at jen.middleton@ed.ac.uk.

Patients with arteriovenous malformations (abnormal connection between arteries and veins) in the brain that have not ruptured had a lower risk of stroke or death for up to 12 years if they received conservative management of the condition compared to an interventional treatment, according to a study in the April 23/30 issue of JAMA, a neurology theme issue.

Interventional treatment for brain arteriovenous malformations (bAVMs) with procedures such as neurosurgical excision, endovascular embolization, or stereotactic radiosurgery can be used alone or in combination to attempt to obliterate bAVMs. Because interventions may have complications and the untreated clinical course of unruptured bAVMs can be benign, some patients choose conservative management (no intervention). Guidelines have endorsed both intervention and conservative management for unruptured bAVMs. Whether conservative management is superior to interventional treatment for unruptured bAVMs is uncertain because of the lack of long-term experience, according to background information in the article.

Rustam Al-Shahi Salman, Ph.D., of the University of Edinburgh, Scotland, and colleagues with the Scottish Audit of Intracranial Vascular Malformations Collaborators, studied 204 residents of Scotland (16 years of age or older) who were first diagnosed as having an unruptured bAVM during 1999-2003 or 2006-2010 and followed over time. The researchers analyzed the outcomes for patients who received conservative management (no intervention; medications for seizures) or an intervention (any endovascular embolization, neurosurgical excision, or stereotactic radiosurgery alone or in combination).

Of the 204 patients, 103 underwent some type of intervention. Those who underwent intervention were younger, more likely to have presented with seizure, and less likely to have large bAVMs than patients managed conservatively. During a median (midpoint) follow-up of 6.9 years, the rate of progression to sustained disability or death was lower with conservative management during the first 4 years of follow-up, but rates were similar thereafter. The rate of nonfatal stroke or death (due to the bAVM or intervention) was lower with conservative management during 12 years of follow-up (14 vs 38 events).

“The similarity of the results of this observational study and ARUBA [a randomized clinical trial that examined this issue] and the persistent difference between the outcome of conservative management and intervention during 12-year follow-up in our study support the superiority of conservative management to intervention for unruptured bAVMs, which may deter some patients and physicians from intervention,” the authors write.

“Long-term follow-up in both this study and the ARUBA trial is needed to establish whether the superiority of conservative management will persist or change.”

(doi:10.1001/jama.2014.3200; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 22, 2014

Media Advisory: To contact Gregg C. Fonarow, M.D., call Kim Irwin at 310-794-2262 or email kirwin@mednet.ucla.edu. To contact editorial author James C. Grotta, M.D., call Alex Rodriguez Loessin at 713-704-1222 or email alex.loessin@memorialhermann.org.
In a study that included more than 71,000 stroke patients, implementation of a quality initiative was associated with improvement in the time to treatment and a lower risk of in-hospital death, intracranial hemorrhage (bleeding in the brain), and an increase in the portion of patients discharged to their home, according to the study appearing in the April 23/30 issue of JAMA, a neurology theme issue.

Intravenous tissue plasminogen activator (tPA; an enzyme that helps dissolve clots) reduces long-term disability when administered early to eligible patients with acute ischemic stroke. These benefits, however, are highly time dependent. Because of the importance of rapid treatment, national guidelines recommend that hospitals complete the evaluation of patients with acute ischemic stroke and begin intravenous tPA therapy for eligible patients within 60 minutes of hospital arrival. However, prior studies demonstrate that less than one-third of patients are treated within the recommended time frame, and that this measure has improved minimally over time, according to background information in the article.

Gregg C. Fonarow, M.D., of the University of California, Los Angeles, and colleagues examined the results of a national quality improvement initiative (Target: Stroke), that was launched to increase timely stroke care. The initiative included 10 key strategies to achieve faster door-to-needle (DTN) times for tPA administration, provided clinical decision support tools, facilitated hospital participation, and encouraged sharing of best practices. This study included 71,169 patients with acute ischemic stroke treated with tPA from 1,030 participating hospitals.

The researchers found that measures of DTN time for tPA administration improved significantly during the postintervention period compared with the preintervention period as did clinical outcomes. The median (midpoint) door-to-needle time for tPA administration for the preintervention period was 77 minutes, which decreased to 67 minutes for the entire postintervention period. Door-to-needle times for tPA administration of 60 minutes or less increased from 26.5 percent to 41.3 percent (and from 29.6 percent to 53.3 percent at the end of each intervention period). Other improvements included in-hospital deaths (9.9 percent to 8.3 percent); discharge to home (38 percent to 43 percent); independence with walking (42 percent to 45 percent); and symptomatic intracranial hemorrhage within 36 hours (5.7 percent to 4.7 percent).

There was also a more than 4-fold increase in the yearly rate of improvement in the proportion of patients with door-to-needle times of 60 minutes or less after initiation of the intervention.

“These findings further reinforce the importance and clinical benefits of more rapid administration of intravenous tPA,” the authors write.

(doi:10.1001/jama.2014.3203; 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, April 22 at this link.

Editorial: tPA for Stroke – Important Progress in Achieving Faster Treatment

In an accompanying editorial, James C. Grotta, M.D., of the Memorial Hermann Hospital, Clinical Innovation and Research Institute, Houston, comments on the two studies in this issue of JAMA regarding improving the time of tPA administration for stroke.

“Whatever benefits occur from interventions to achieve more rapid tPA treatment for patients with acute stroke need to be balanced against the costs to establish and maintain them, both to the payers who will pay for them and the hospital and emergency medical services organizations that will implement and operate them. This issue requires carefully constructed cost-effectiveness studies carried out in the environments where the interventions will be implemented; these are likely to differ between cities in the United States and in other countries and between rural and urban areas.”

“The studies by Fonarow et al and Ebinger et al in this issue of JAMA indicate exactly where and how to direct efforts in improving treatment outcomes for patients with acute ischemic stroke—namely by reducing time from symptom onset to treatment.”

(doi:10.1001/jama.2014.3322; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Grotta reported having received consulting fees from Specialists on Call, Frazer, and Stryker and grants from Genentech, Lundbeck, Haemonetics, Covidien, and Zolt.

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

Media Advisory: To contact Donald S. A. McLeod, F.R.A.C.P., M.P.H., email donald.mcleod@qimrberghofer.edu.au.

An analysis that included active military personnel finds that the rate of the thyroid disorder Graves disease is more common among blacks and Asian/Pacific Islanders compared with whites, according to a study in the April 16 issue of JAMA.

Donald S. A. McLeod, F.R.A.C.P., M.P.H., of the QIMR Berghofer Medical Research Institute, Queensland, Australia and colleagues studied all U.S. active duty military, ages 20 to 54 years, from January 1997 to December 2011 to determine the rate of Graves disease and Hashimoto thyroiditis (a progressive autoimmune disease of the thyroid gland) by race/ethnicity. Cases were identified from data in the Defense Medical Surveillance System, which maintains comprehensive records of inpatient and outpatient medical diagnoses among all active-duty military personnel. The relationship between Graves disease and race/ethnicity has previously not been known.

During the study period there were 1,378 cases of Graves disease in women and 1,388 cases in men and 758 cases of Hashimoto thyroiditis in women and 548 cases in men. Compared with whites, the incident rates for Graves disease was significantly higher among blacks and Asian/Pacific Islanders. In contrast, Hashimoto thyroiditis incidence was highest in whites and lowest in blacks and Asian/Pacific Islanders.

The authors write that the differences in incidence by race/ethnicity found in this study may be due to different environmental exposures, genetics, or a combination of both.

(doi:10.1001/jama.2013.285606; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: A Cancer Council Queensland PhD scholarship helped support Dr. McLeod. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Cooper reported receiving royalties for serving as an editor to Up-to-Date. No other disclosures were reported.

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

Media Advisory: To contact Dagfinn Aune, M.S., email d.aune@imperial.ac.uk.
Higher maternal body mass index (BMI) before or in early pregnancy is associated with an increased risk of fetal death, stillbirth, and infant death, with women who are severely obese having the greatest risk of these outcomes from their pregnancy, according to a study in the April 16 issue of JAMA.

Worldwide, approximately 2.7 million stillbirths occurred in 2008. In addition, an estimated 3.6 million neonatal deaths (death following live birth of an infant but before age 28 days) occur each year. Several studies have suggested that greater maternal body mass index (BMI) before or during early pregnancy is associated with an increased risk of fetal death, stillbirth, perinatal death (stillbirth and early neonatal death), neonatal death, and infant death, although not all studies have found a significant association. The optimal prepregnancy BMI to prevent fetal and infant death has not been established, according to background information in the article.

Dagfinn Aune, M.S., of Imperial College London, and colleagues conducted a review and meta-analysis to examine the association between maternal BMI (before or in early pregnancy) and risk of fetal death, stillbirth, and infant death. After a search of the medical literature, the researchers identified 38 studies that met criteria for inclusion in the meta-analysis, which included more than 10,147 fetal deaths, more than 16,274 stillbirths, more than 4,311 perinatal deaths, 11,294 neonatal deaths, and 4,983 infant deaths.

The researchers found that even modest increases in maternal BMI were associated with increased risk of fetal death, stillbirth, neonatal death, perinatal death, and infant death. The greatest risk was observed in the category of severely obese women; women with a BMI of 40 had an approximate 2- to 3-fold increase in risk of these outcomes vs. women with a BMI of 20.

The authors suggest that several biological mechanisms could explain the association found in this study, including that being overweight or obese has been associated with increased risk of preeclampsia, gestational diabetes, type 2 diabetes, gestational hypertension, and congenital anomalies, conditions that have been strongly associated with risk of fetal and infant death. “… further studies are needed to investigate the mechanisms involved.”

“Weight management guidelines for women who plan pregnancies should take these findings into consideration to reduce the burden of fetal deaths, stillbirths, and infant deaths.”

(doi:10.1001/jama.2014.2269; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was supported by a grant from the Norwegian SIDS and Stillbirth Society, Oslo, Norway. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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

Media Advisory: To contact Steven D. Pearson, M.D., M.Sc., call Molly Hooven at 301-594-5789 or email Molly.Hooven@nih.gov.
In the creation of lists by specialty societies of medical services deemed least beneficial (the “Choosing Wisely” initiative), inclusion was often justified by evidence suggesting no additional benefit with higher risk, higher cost, or both, compared with other options, according to a study in the April 9 issue of JAMA.

“Aiming to reduce wasteful medical care, the American Board of Internal Medicine Foundation’s Choosing Wisely initiative asks leading physician specialty societies to create a ‘Top 5’ list of medical services that provide no overall benefit to patients in most situations. As of August 2013, 25 participating specialty societies had produced 1 or more Top 5 lists containing a total of 135 services,” according to background information in the article.

Catherine Gliwa, B.A., and Steven D. Pearson, M.D., M.Sc., of the National Institutes of Health, Bethesda, Md., evaluated the role that evidence related to benefits, risks, and costs plays in selecting a service for the Top 5 lists. “As Choosing Wisely continues to grow, clarity on the evidentiary justifications for the lists will be crucial for the overall credibility of the campaign,” they write. Using information provided by the specialty societies, the authors created categories based on the level of certainty of evidence regarding risks and benefits, how the risks and benefits of the service compare with other alternatives, and the comparative cost or cost-effectiveness of the service.

Of the 135 services identified, 36 percent were for diagnosis or monitoring; 34 percent for treatment; and 30 percent for population screening. Most services were included in the Top 5 lists based on evidence that demonstrates equivalent but not superior benefit with higher risk or higher costs, or both, compared with other options.  The second most common rationale was that there was not enough evidence to evaluate benefit for use of the service beyond the established indications, frequency, intensity, or dosage.

The authors assessed the rationales for selecting all 135 services.  Overall, 49 percent mentioned greater risks to patients, 24 percent mentioned higher costs, 16 percent mentioned both greater risk and higher cost, and 42 percent mentioned neither. Of the 25 specialty societies, 60 percent had at least 1 service whose inclusion was justified in part by higher costs.

“Our data show that the issue of cost was almost always raised in the context of a service being judged as good as other options but more expensive. We believe that specialty societies should seek greater opportunities to include within their Top 5 lists services that offer only small incremental benefits at much higher prices,” the authors write.

“Specialty societies can enhance trust in the Choosing Wisely campaign by defining more clearly the types of potentially wasteful medical care they seek to eliminate, and by providing a clear evidentiary justification for the selection of each service.”

(doi:10.1001/jama.2013.285362; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by the Intramural Research Program of the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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

Media Advisory: To contact corresponding author Dong-Wan Kim, M.D., Ph.D., email kimdw@snu.ac.kr.

Among patients with advanced non-small cell lung cancer without a mutation of a certain gene (EGFR), conventional chemotherapy, compared with treatment using epidermal growth factor receptor tyrosine kinase inhibitors, was associated with improvement in survival without progression of the cancer, but not with overall survival, according to a study in the April 9 issue of JAMA.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred treatment option for patients with advanced non-small cell lung cancer (NSCLC) who have mutations in the EGFR gene. These drug-sensitive mutations are found in about 10 percent of Western patients and almost 50 percent of Asian patients with NSCLC. However, a majority of patients with advanced NSCLC worldwide do not have tumors with these mutations (known as wild-type [WT]; no mutation detected within the gene). Studies have shown that TKI treatment is better than conventional chemotherapy in terms of progression-free survival (PFS) among patients with these EGFR mutations; it is not clear that EGFR TKIs are as effective as standard chemotherapy in patients without EGFR mutations, according to background information in the article

June-Koo Lee, M.D., of Seoul National University Hospital, Seoul, Republic of Korea, and colleagues performed a meta-analysis of randomized controlled trials that compared first-generation EGFR TKI (erlotinib and gefitinib) treatment with conventional chemotherapy in patients with advanced NSCLC without mutation of the EGFR gene. The authors identified 11 randomized controlled trials, with 1,605 patients with WT EGFR, which met criteria for inclusion in the meta-analysis.

The results indicated that chemotherapy was associated with longer PFS compared with EGFR TKI in patients with WT tumors. For a median (midpoint) PFS of 6.4 months in patients treated with standard chemotherapy, the corresponding reduction of PFS in patient receiving EGFR TKI would be 1.9 months.

The objective response rate (defined as the proportion of complete response and partial responses among all evaluable patients) was also higher with chemotherapy (92/549, 16.8 percent) compared with TKI (39/540, 7.2 percent). However, the overall survival did not differ between the two groups.

“… this study suggests that, in patients with WT EGFR tumors, conventional chemotherapy could be a preferable treatment option over EGFR TKI, although this recommendation cannot be conclusive because the overall comparisons were not based on randomization. Furthermore, the toxicity outcome was not assessed,” the authors write.

(doi:10.1001/jama.2014.3314; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This work was supported in part by National Research Foundation of Korea grants funded by the Korean government. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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

Media Advisory: To contact corresponding author Walid F. Gellad, M.D., M.P.H., call Allison Hydzik at 412-647-9975 or email hydzikam@upmc.edu.
About 40 percent of pharmaceutical company boards of directors examined had at least one member who held a leadership position at an academic medical center, with annual compensation for these positions averaging approximately $300,000, according to a study in the April 2 issue of JAMA.

“Financial relationships between the pharmaceutical industry and physicians have come under increased scrutiny. Less attention has been paid to relationships between industry and the leadership of academic medical centers (AMCs), who wield considerable influence over research, clinical, and educational missions. When AMC leaders serve on pharmaceutical company boards, they hold a fiduciary responsibility to shareholders to promote the financial success of the company, which may conflict or compete with institutional oversight responsibilities and individual clinical and research practices,” according to background information in the article.

Timothy S. Anderson, M.D., of the University of Pittsburgh Medical Center, and colleagues examined how often AMC leaders served on the boards of directors for pharmaceutical companies. Data on board composition and academic positions were collected in January 2013 from the websites of the 50 largest pharmaceutical companies based on 2012 global prescription drug sales. Financial compensation information was collected from company proxy statements and from shareholder reports. AMCs were defined as U.S. medical schools, health professional schools, teaching hospitals, and health care systems; leadership positions included CEOs, clinical department chairs, division directors, medical school deans, and hospital boards of directors, in addition to university presidents and boards of directors.

Of the 50 companies examined, 3 private companies lacked public data on governance. Nineteen of 47 (40 percent) companies had at least 1 board member who also held a leadership position at an AMC, including 16 of 17 (94 percent) U.S. companies. Forty-one board members held AMC leadership positions in 2012, receiving an average financial compensation for board membership of $312,564 (excluding the 6 industry executives). Eighteen industry board members (3 percent of all board members) held 21 clinical or administrative leadership positions, including 2 university presidents, 6 deans, 6 hospital or health system executive officers, and 7 clinical department chairs or center directors.

The authors note that they “do not make any conclusions about whether specifically identified relationships led to actual, rather than potential, conflicts of interest.”

“However, given the magnitude of competing priorities between academic institutions and pharmaceutical companies, dual leadership roles cannot simply be managed by internal disclosure. These relationships present potentially far-reaching consequences beyond those created when individual physicians consult with industry or receive gifts.”

(doi:10.1001/jama.2013.284925; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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

Media Advisory: To contact corresponding author Mary A.M. Rogers, Ph.D., call Beata Mostafavi at 734- 764-2220 or email bmostafa@umich.edu. To contact editorial author Jeffrey L. Carson, M.D., call Jennifer Forbes at 732-235-6356 or email jenn.forbes@rwjms.rutgers.edu.

Restricting red blood cell (RBC) transfusions among hospitalized patients to those with hemoglobin (the iron-containing protein in RBCs) measures below a certain level is associated with a lower risk of health care-associated infections, according to a study in the April 2 issue of JAMA.

Efforts to prevent health care-associated infection are among the priorities for the U.S. Department of Health and Human Services. The estimated annual direct medical costs of health care-associated infections to U.S. hospitals ranges from $28 billion to $45 billion, with about 1 in every 20 inpatients developing an infection related to their hospital care. Transfusion of RBCs is a common inpatient therapy, with approximately 14 million units transfused in 2011 in the United States, according to background information in the article. One potential approach to reducing the risk of infection associated with transfusions is lowering the hemoglobin thresholds (levels) at which RBC transfusions are indicated, so-called restrictive threshold strategies. The association between RBC transfusion strategies and health care-associated infection is not fully understood.

Jeffrey M. Rohde, M.D., of the University of Michigan, Ann Arbor, and colleagues compared restrictive vs liberal RBC transfusion strategies to evaluate their association with the risk of health care-associated infection. The study consisted of a review and meta-analysis of the data from 21 randomized trials with 8,735 patients who underwent transfusion; 18 trials (n = 7,593 patients) contained sufficient information for inclusion in the meta-analyses. The main outcomes measured for the analysis were the incidence of health care-associated infection such as pneumonia, mediastinitis (inflammation of tissue in the chest cavity), wound infection, and sepsis.

The researchers found that for those patients receiving the restrictive transfusion strategies, the risk of infection (for all serious infections) was 11.8 percent, and for patients receiving the liberal transfusion strategies, was 16.9 percent. Even with a reduction in the level of white blood cells (via the processing of blood), the risk of infection remained reduced with a restrictive strategy. The meta-analysis of randomized trials suggested that for every 1,000 patients in which RBC transfusion is under consideration, 26 could potentially be spared an infection if restrictive strategies were used.

The authors found no significant differences in the incidence of infection by RBC threshold for patients with cardiac disease, the critically ill, those with acute upper gastrointestinal bleeding, or for infants with low birth weight. The risk of infection was lower in patients undergoing orthopedic surgery or with sepsis and who received a restrictive transfusion strategy.

The authors write that the results of this review provide further support to a recent systematic review and clinical practice guideline put forth by the AABB (formerly the American Association of Blood Banks), that recommends adherence to a restrictive transfusion strategy for the majority of hospitalized patients and lists specific hemoglobin-based recommendations for different patient populations.

(doi:10.1001/jama.2014.2726; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Blood Transfusion and Risk of Infection – New Convincing Evidence

Jeffrey L. Carson, M.D., of the Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., comments on this study in accompanying editorial.

“The only outcome evaluated in the report by Rohde et al was infection risk. However, other important outcomes such as mortality, myocardial infarction, and function should be considered in the overall risk-benefit analysis of transfusion.”

“The study by Rohde et al confirms another potential adverse outcome associated with transfusion: serious infectious disease. Clinical trials are needed to establish the optimal transfusion thresholds, to provide additional information about the risks and benefits of RBC transfusion, and to determine how best to use RBC transfusion.”

(doi:10.1001/jama.2014.2727; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Carson reports serving as a consultant to Cerus for a trial unrelated to this article and reports grant funding to his institution from the National Institutes of Health.

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

Media Advisory: To contact Thomas M. Pisansky, M.D., call Joe Dangor at 507-266-0696 or email dangor.yusuf@mayo.edu.
Among men undergoing radiation therapy for prostate cancer, daily use of the erectile dysfunction drug tadalafil, compared with placebo, did not prevent loss of erectile function, according to a study in the April 2 issue of JAMA.

Erectile dysfunction (ED) is a common condition resulting from many causes, including prostate cancer treatment. An estimated 40 percent of men report ED after radiation therapy, and half of all men use erectile aids following this therapy. Tadalafil is used to treat erectile dysfunction after prostate cancer treatment, but its role as a preventive agent has not been determined, according to background information in the article.

Thomas M. Pisansky, M.D., of the Mayo Clinic, Rochester, Minn., and colleagues with the Radiation Therapy Oncology Group, randomly assigned 242 men with prostate cancer to receive tadalafil (5 mg) or placebo daily for 24 weeks starting with radiation therapy (either with external radiotherapy [63 percent] or brachytherapy [37 percent]). The study was conducted at 76 sites in the United States and Canada; participants were recruited between November 2009 and February 2012, with follow-up through March 2013.

Between weeks 28 and 30 after the start of radiation therapy, among evaluable participants, 79 percent who received tadalafil retained erectile function compared with 74 percent who received placebo, an absolute difference of 5 percent. A significant difference between groups was also not observed at 1 year (72 percent vs 71 percent). Tadalafil was not associated with improved overall sexual function or satisfaction, and partners of men assigned tadalafil noted no significant effect on sexual satisfaction.

“These findings do not support the scheduled once-daily use of tadalafil to prevent ED in men undergoing radiotherapy for localized prostate cancer,” the authors write.

They add that alternative strategies to prevent ED in this context appear warranted, including different dosing or further refinements of radiation therapy delivery methods.

(doi:10.1001/jama.2014.2626; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This trial was conducted by the Radiation Therapy Oncology Group, which was supported by grants from the National Cancer Institute and by Eli Lilly & Co. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR EARLY RELEASE: 7 A.M. (CT) SUNDAY, MARCH 30, 2014

Media Advisory: To contact A. Michael Lincoff, M.D., call Wyatt DuBois at 216-904-3344 or email DUBOISW@ccf.org.

Use of the drug aleglitazar, which has shown the ability to lower glucose levels and have favorable effects on cholesterol, did not reduce the risk of cardiovascular death, heart attack or stroke among patients with type 2 diabetes and recent heart attack or unstable angina, according to a JAMA study released online to coincide with presentation at the 2014 American College of Cardiology Scientific Sessions.

Cardiovascular disease remains the dominant cause of death among patients with type 2 diabetes. No drug therapy specifically directed against diabetes nor strategy for tight glucose control has been shown to unequivocally reduce the rate of cardiovascular complications in this population, according to background information in the article. In phase 2 trials, aleglitazar significantly reduced glycated hemoglobin levels (measure of blood glucose over an extended period of time), triglycerides, and low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol (HDL-C).

A. Michael Lincoff, M.D., of the Cleveland Clinic, and colleagues conducted a phase 3 trial in which 7,226 patients hospitalized for heart attack or unstable angina with type 2 diabetes were randomly assigned to receive aleglitazar or placebo daily. The AleCardio trial was conducted in 720 hospitals in 26 countries throughout North America, Latin America, Europe, and Asia-Pacific regions.

The trial was terminated early (July 2013) after an average follow-up of 104 weeks, due to lack of efficacy and a higher rate of adverse events in the aleglitazar group.

The researchers found that although aleglitazar reduced glycated hemoglobin and improved serum HDL-C and triglyceride levels, the drug did not decrease the time to cardiovascular death, nonfatal heart attack, or nonfatal stroke (primary end points). These events occurred in 344 patients (9.5 percent) in the aleglitazar group and 360 patients (10.0 percent) in the placebo group.

Aleglitazar use was associated with increased risk of kidney abnormalities, bone fractures, gastrointestinal bleeding, and hypoglycemia (low blood sugars).

“These findings do not support the use of aleglitazar in this setting with a goal of reducing cardiovascular risk,” the authors conclude.

(doi:10.1001/jama.2014.3321 Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 9:45 A.M. (CT) MONDAY, MARCH 31, 2014

Media Advisory: To contact corresponding author Takeshi Kimura, M.D., email taketaka@kuhp.kyoto-u.ac.jp.

A comparison of the safety of biodegradable polymer biolimus-eluting stents vs durable polymer everolimus-eluting stents finds similar outcomes for measures including death and heart attack after two years, according to a JAMA study released online to coincide with presentation at the 2014 American College of Cardiology Scientific Sessions.

Recent studies have raised concerns about the safety of biodegradable polymer drug-eluting stents (BP-DES) compared with durable polymer everolimus-eluting stents (DP-EES). The NOBORI Biolimus-Eluting vs XIENCE/PROMUS Everolimus-Eluting Stent Trial (NEXT) is a study evaluating the efficacy and safety of biodegradable polymer biolimus-eluting stents (BP-BES) vs. DP-EES. The primary efficacy outcome of target-lesion revascularization (restoration of blood flow in coronary arteries) at 1 year demonstrated noninferiority (not worse than) of BP-BES compared with DP-EES. However, the advantages of BP-BES could emerge beyond 1 year when polymer has fully degraded, according to background information in the article. Masahiro Natsuaki, M.D., of Saiseikai Fukuoka General Hospital, Fukuoka, Japan, and colleagues examined outcomes of this trial after two years.

Of 3,235 patients, 1,617 were randomly assigned to receive BP-BES and 1,618 to DP-EES. The researchers found that treatment outcomes with BP-BES were noninferior to DP-EES for death or heart attack (7.8 percent vs 7.7 percent, respectively) and target-lesion revascularization (TLR) (6.2 percent vs 6.0 percent). The rates of death or heart attack and TLR were not significantly different between the groups at 2 years.

“In NEXT, the safety and efficacy outcomes of BP-BES were noninferior to those of DP-EES at 2 years. However, 2 years is not long enough to confirm the long-term safety of BP-BES, and the study was underpowered for the interim analysis. Follow-up at 3 years will be important,” the authors write.

(doi:10.1001/jama.2014.3584 Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 7 A.M. (CT) MONDAY, MARCH 31, 2014

Media Advisory: To contact corresponding author Iwan C.C. van der Horst, M.D., Ph.D., email i.c.c.van.der.horst@umcg.nl.
Although some research has suggested that metformin, a medication often used in the treatment of diabetes, may have favorable effects on ventricular (heart) function, among patients without diabetes who underwent percutaneous coronary intervention (PCI; a procedure such as stent placement used to open narrowed coronary arteries) for ST-segment elevation myocardial infarction (STEMI; a certain pattern on an electrocardiogram following a heart attack), treatment with metformin did not result in improved ventricular function, according to a JAMA study released online to coincide with its presentation at the 2014 American College of Cardiology Scientific Sessions.

Treatment for STEMI includes immediate treatment with anticlotting medications and PCI to restore coronary blood flow. STEMI results in left ventricular dysfunction (decreased pump function) in up to 50 percent of patients, and approximately 20 percent to 40 percent of patients develop heart failure sometime after STEMI; heart failure after STEMI is associated with a 3 to 4 times higher risk of death. Left ventricular dysfunction is regarded as the strongest predictor for adverse outcome after STEMI, according to background information in the article.

Chris P. H. Lexis, M.D., of the University of Groningen, Groningen, the Netherlands, and colleagues randomly assigned 380 patients who underwent PCI for STEMI to receive metformin hydrochloride or placebo twice daily for 4 months to determine whether metformin helps preserve left ventricular function after STEMI in patients without diabetes. Left ventricular ejection fraction (a measure of how well the left ventricle of the heart pumps blood with each contraction) was assessed by magnetic resonance imaging.

Left ventricular ejection fraction 4 months after beginning the study did not differ between the metformin group (53.1 percent) and the placebo group (54.8 percent). In addition, N-terminal pro-brain natriuretic peptide level (a cardiac biomarker) was not different between the 2 groups.

Major adverse cardiac events were observed in 6 patients (3.1 percent) in the metformin group and in 2 patients (1.1 percent) in the placebo group.

“Because left ventricular function is currently regarded as the most important predictor of morbidity and mortality after STEMI, it is unlikely that metformin will have a significant effect on long-term outcome after STEMI in patients without diabetes,” the authors write.

“The present findings do not support the use of metformin in this setting.”

(doi:10.1001/jama.2014.3315 Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This study was supported by a grant from ZonMw, the Netherlands Organization for Health Research and Development, The Hague, the Netherlands. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR EARLY RELEASE: 7 A.M. (CT) SUNDAY, MARCH 30, 2014

Media Advisory: To contact Mohamed Abdel-Wahab, M.D., email mohamed.abdel-wahab@segebergerkliniken.de. To contact editorial co-author E. Murat Tuzcu, M.D., call Wyatt DuBois at 216-904-3344 or email DUBOISW@ccf.org.
Among patients undergoing aortic valve replacement using a catheter tube, a comparison of two types of heart valve technologies, balloon-expandable or self-expandable valve systems, found a greater rate of device success with the balloon-expandable valve, according to a JAMA study released online to coincide with presentation at the 2014 American College of Cardiology Scientific Sessions.

Transcatheter aortic valve replacement (TAVR) has emerged as a new option for patients with severe narrowing of the aortic valve and as an effective alternative treatment method to surgical aortic valve replacement in selected high-risk patients. Different from surgery, transcatheter placement (via the patient’s groin) of aortic valve prostheses requires either a self-expandable or balloon-expandable system. A direct comparison of these 2 systems has not been previously performed, according to background information in the article.

Mohamed Abdel-Wahab, M.D., of the Segeberger Kliniken, Bad Segeberg, Germany, and colleagues with the CHOICE trial, randomly assigned patients with aortic stenosis (narrowing) who met other criteria to receive either a balloon-expandable valve (n = 121) or self-expandable valve (n = 120). Device success was defined by several measures, including successful vascular access and deployment of the device and retrieval of the delivery system, correct position of the device, and performance of the heart valve without moderate or severe regurgitation (backflow of blood through the valve).

The researchers found that device success occurred in 116 of 121 patients (95.9 percent) in the balloon-expandable group and 93 of 120 patients (77.5 percent) of patients in the self-expandable group. This difference was attributed to a lower frequency of more-than-mild aortic regurgitation (4.1 percent vs 18.3 percent) and the less frequent need for implanting more than 1 valve (0.8 percent vs 5.8 percent) in the balloon-expandable valve group.

Bleeding and vascular complications were not significantly different between groups. Cardiovascular mortality at 30 days was 4.1 percent in the balloon-expandable valve group and 4.3 percent in the self-expandable valve group.  Need for placement of a new permanent pacemaker was less frequent in the balloon-expandable valve group.

“With an accumulating body of evidence linking more-than-mild aortic regurgitation and consequently device failure with a worse clinical outcome after transcatheter aortic valve replacement, the findings of the CHOICE trial may have important clinical implications. Notably, at short-term follow-up, improvement of heart failure symptoms was more frequently observed with the balloon-expandable valve, whereas minor stroke rates were numerically higher. Nevertheless, long-term follow-up of the CHOICE population should be awaited to determine whether the observed differences in device success will translate into a clinically relevant overall benefit for the balloon-expandable valve,” the authors write.

(doi:10.1001/jama.2014.3316; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This trial was sponsored by the Heart Center, Segeberger Kliniken GmbH, Bad Segeberg, Germany. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

 Editorial: Selection of Valves for TAVR – Is the CHOICE Clear?

Further investigation is needed to determine which valve examined in this study will provide better long-term survival rate and better quality of life, write E. Murat Tuzcu, M.D., and Samir R. Kapadia, M.D., of the Cleveland Clinic, in an accompanying editorial.

“Continued efforts at understanding the risks and benefits of TAVR particularly in relation to patient characteristics, and long term outcomes are imperative for continued progress and refinement of these revolutionary devices. Additional rigorous randomized trials, like the CHOICE trial, will provide the quality of evidence necessary to ensure optimal use and optimal patient outcomes from TAVR.”

(doi:10.1001/jama.2014.3317; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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

Media Advisory: To contact Paul Muntner, Ph.D., call Nicole Wyatt at 205-934-8938 or email nwyatt@uab.edu.
In an analysis of almost 11,000 patients, an assessment of equations that help guide whether a patient should begin taking a statin (cholesterol lowering medication) found that observed and predicted 5-year atherosclerotic cardiovascular disease risks were similar, suggesting that these equations are helpful for clinical decision making, according to a JAMA study released online to coincide with presentation at the 2014 American College of Cardiology Scientific Sessions.

The American College of Cardiology (ACC) and the American Heart Association (AHA) recently published the 2013 Guideline on the Assessment of Cardiovascular Risk. As part of this guideline, a group of experts developed the Pooled Cohort risk equations, which were designed to estimate 10-year risk for nonfatal myocardial infarction (MI; heart attack), coronary heart disease (CHD) death, and nonfatal or fatal stroke, according to background information in the article.

Paul Muntner, Ph.D., of the University of Alabama at Birmingham, and colleagues examined the Pooled Cohort risk equations in adults (age 45 to 79 years) enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study between January 2003 and October 2007, and followed up through December 2010. The researchers studied participants for whom atherosclerotic CVD risk may trigger a discussion of statin initiation (patients without clinical atherosclerotic CVD or diabetes, low-density lipoprotein cholesterol level between 70 and 189 mg/dL, and not taking statins; n = 10,997). Additional analyses, limited to Medicare beneficiaries (n = 3,333), added atherosclerotic CVD events identified in Medicare claims data.

Among the study population (n=10,997) for whom statin treatment should be considered based on atherosclerotic CVD risk there were 338 events (192 CHD events, 146 strokes). The researchers found that the observed and predicted 5-year atherosclerotic CVD incidence rates were similar.

There were 234 atherosclerotic CVD events (120 CHD events, 114 strokes) among the subset of Medicare beneficiaries and the observed and predicted 5-year atherosclerotic CVD incidence rates were also similar for the various risk categories in this population.

“These findings support the validity of the Pooled Cohort risk equations to inform clinical management decisions,” the authors write.  “Because the Pooled Cohort risk equations were designed to estimate 10-year atherosclerotic cardiovascular disease risk, studies are needed to ensure its accurate calibration over a longer duration.”

(doi:10.1001/jama.2014.2630 Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This research project is supported by a cooperative agreement from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services. Additional support was provided by grants from the National Heart, Lung, and Blood Institute. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR EARLY RELEASE: 1 P.M. (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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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