EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 6, 2015

Media Advisory: To contact Trevor J. Orchard, M.D., email Allison Hydzik at hydzikam@upmc.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.16107

Intensive Treatment for Type 1 Diabetes Associated With Decreased Risk of Death

After an average of 27 years’ follow-up of patients with type 1 diabetes, 6.5 years of initial intensive diabetes therapy was associated with a modestly lower all-cause rate of death, compared with conventional therapy, according to a study in the January 6 issue of JAMA.

Based on the demonstrated reductions in illness, intensive diabetes therapy is now the recommended standard of care; however, it has not been established whether mortality in type 1 diabetes mellitus is affected following a period of intensive diabetes therapy. In type 2 diabetes treatment, reducing glycemia (blood sugar) closer to the nondiabetic range has not consistently reduced mortality, according to background information in the article.

Trevor J. Orchard, M.D., of the University of Pittsburgh, and colleagues examined whether mortality differed between the original intensive and conventional treatment groups in the long-term follow-up of the Diabetes Control and Complications Trial (DCCT) cohort. The DCCT (1983-1993) randomly assigned 1,441 healthy volunteers with type 1 diabetes mellitus between the ages of 13 and 39 years to intensive or conventional therapy, with the goal of studying the effects of near-normal blood sugars on long-term diabetes complications. After the DCCT ended, participants were followed up in a multisite (27 U.S. and Canadian academic clinical centers) observational study (Epidemiology of Diabetes Interventions and Complications; EDIC) until December 31, 2012.

During the initial clinical trial, participants were randomly assigned to receive intensive therapy (n = 711) aimed at achieving blood sugar control  as close to the nondiabetic range as safely possible, or conventional therapy (n = 730) with the goal of avoiding symptomatic hypoglycemia (abnormally low blood sugar) and hyperglycemia (abnormally high blood sugar).  At the end of the DCCT, after an average of 6.5 years, intensive therapy was taught and recommended to all participants and diabetes care was returned to personal physicians.

Vital status was ascertained for 1,429 (99.2 percent) participants. Of the 107 (7.4 percent) deaths, 43 (6.0 percent) were in the intensive treatment group and 64 (8.8 percent) were in the conventional treatment group. Overall mortality risk in the intensive group was lower than that in the conventional group, although the absolute risk reduction was small.

Primary causes of death were cardiovascular disease, cancer, acute diabetes complications, and accidents or suicide. Higher levels of glycated hemoglobin (a common lab test that gauges overall blood sugar control) were associated with all-cause mortality, as well as the development of albuminuria (the presence of excessive protein in the urine).

The authors write that intensive therapy is associated with increased hypoglycemic risk, which in turn has been associated with increased mortality. “The current data suggest net mortality benefit from intensive therapy … These results provide reassurance that adoption of 6.5 years of intensive therapy in type 1 diabetes does not incur increased risk of overall mortality.”

(doi:10.1001/jama.2014.16107; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 23, 2014

Media Advisory: To contact Keith P. West Jr., Dr.P.H., call Stephanie Desmon at 410-955-7619 or email Sdesmon1@jhu.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.16819.

Maternal Supplementation with Multiple Micronutrients, Compared With Iron-Folic Acid, Does Not Reduce Infant Mortality

In Bangladesh, daily maternal supplementation of multiple micronutrients compared to iron-folic acid before and after childbirth did not reduce all-cause infant mortality to age 6 months, but did result in significant reductions in preterm birth and low birth weight, according to a study in the December 24/31 issue of JAMA.

Multiple micronutrient deficiencies are common among pregnant women in resource-poor regions of the world, especially in southern Asia. Coexisting with poor maternal nutrition across the region are excessive burdens of low birth weight (LBW), preterm birth, small size for gestational age, stillbirth, infant mortality, and maternal mortality. Gestational micronutrient deficiencies may contribute to avertable adverse birth outcomes. Data for effects of antenatal (before birth) multiple micronutrient (MM) supplementation on longer-term infant mortality are sparse for guiding policies in southern Asia, according to background information in the article.

Keith P. West Jr., Dr.P.H., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues conducted a study in which pregnant women in Bangladesh (n = 44,567) were randomly assigned to receive supplements containing 15 micronutrients or iron-folic acid alone, taken daily from early pregnancy to 12 weeks postpartum.

Among the 22,405 pregnancies in the multiple micronutrient group and the 22,162 pregnancies in the iron-folic acid group, there were 14,374 and 14,142 live-born infants, respectively, included in the analysis. At 6 months, multiple micronutrients did not significantly reduce infant mortality; there were 764 deaths (54.0 per 1,000 live births) in the iron-folic acid group and 741 deaths (51.6 per 1,000 live births) in the multiple micronutrient group.

Multiple micronutrient supplementation resulted in a non-statistically significant reduction in stillbirths (43.1 vs 48.2 per 1,000 births) and significant reductions in preterm births (18.6 vs 21.8 per 100 live births) and low birth weight (40.2 vs 45.7 per 100 live births).

“Our study’s null finding is in agreement with a small number of trials that have provided an antenatal multiple micronutrient vs iron supplement, with or without folic acid, and found no effect on neonatal mortality,” the authors write.

“Reasons for a null effect on postnatal survival after improvement in some birth outcomes with antenatal multiple micronutrient supplement use remain unknown but may reflect a complex interplay between maternal and newborn sizes and differential responses to supplementation by causes of death.”

(doi:10.1001/jama.2014.16819; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 23, 2014

Media Advisory: To contact Chang-Fu Kuo, M.D., email zandis@gmail.com.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14484.

Many Patients with Gout Do Not Receive Recommended Treatment

Among patients in England with gout, only a minority of those with indications to receive urate-lowering therapy were treated according to guideline recommendations, according to a study in the December 24/31 issue of JAMA.

Current guidelines recommend urate (a metabolite derived from uric acid)-lowering treatment for patients with more severe gout or accompanying conditions. However, after the first diagnosis, it remains unclear when such treatment is appropriate, according to background information in the article.

Chang-Fu Kuo, M.D., of Chang Gung Memorial Hospital, Taoyuan, Taiwan, and colleagues investigated the timing of eligibility for and prescription of urate-lowering treatment following first gout diagnosis. Patients diagnosed with incident gout in 1997-2010 were identified using the Clinical Practice Research Datalink, containing anonymized information including patient demographics, diagnoses, examination findings, laboratory results, and prescribed medications from approximately 8 percent of the U.K. population.

Of 52,164 patients with incident gout, the median time to first treatment indication (such as multiple attacks, chronic kidney disease, diuretic use) was 5 months and the cumulative probability of fulfilling any indication was 44 percent at 0 years from diagnosis, 61 percent at 1 year, 87 percent at 5 years, and 94 percent at 10 years. The cumulative probabilities for prescription at the same time points were 0 percent, 17 percent, 30 percent, and 41 percent.

The median prescription rate for urate-lowering treatment among practices was 32.5 percent. Examined patient- and practice-level factors accounted for only one-fifth of the variance in prescriptions. “The unexplained variance may be accounted for by factors not available in the database. Recognized barriers to care include suboptimal patient and physician knowledge of gout, its treatment, and clinical recommendations, and patient and physician preferences for treatment.”

“In conclusion, our study supports including urate-lowering treatment in the information about gout provided to patients around the time of first diagnosis.”

(doi:10.1001/jama.2014.14484; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 23, 2014

Media Advisory: To contact corresponding author Francesca Dominici, Ph.D., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15715.

Extreme Heat in U.S. Associated With Increased Risk of Hospitalization Among Older Adults

Between 1999 and 2010, periods of extreme heat in the U.S. were associated with an increased risk of hospitalization for older adults for fluid and electrolyte disorders, kidney failure, urinary tract infections, septicemia and heat stroke, according to a study in the December 24/31 issue of JAMA. The authors note that the absolute risk increase was small and of uncertain clinical importance.

Extreme heat is the most common cause of severe weather fatalities in the United States, and these weather-related outcomes are expected to escalate as heat waves become more frequent, more intense, and longer lasting with climate change. Although extreme heat is known to adversely affect multiple physiological processes, previous studies of the health effects have examined only a few major categories of health outcomes, such as cardiovascular and respiratory diseases or well-known heat-related diseases, such as heat stroke or dehydration, according to background information in the article.

Jennifer F. Bobb, Ph.D., of the Harvard School of Public Health, Boston, and colleagues used Medicare inpatient claims data to systematically examine possible ways in which exposure to heat waves might be associated with serious illness requiring hospitalization in older adults. The study included hospital admissions of Medicare enrollees (23.7 million fee-for-service beneficiaries [65 years of age or older] per year; 85 percent of all Medicare enrollees) for the period 1999 to 2010 in 1,943 counties in the United States, along with at least five summers of near-complete (>95 percent) daily temperature data. Heat wave periods, defined as two or more consecutive days with temperatures exceeding the 99th percentile of county-specific daily temperatures, were matched to non-heat wave periods by county and week.

Of 214 disease groups that accounted for 99.9% of hospitalizations, 5 diseases (fluid and electrolyte disorders, renal [kidney] failure, urinary tract infections, heat stroke, and septicemia [body-wide illness with toxicity due to invasion of the bloodstream by bacteria usually coming from a localized site of infection]) had statistically significantly elevated risk of hospitalization during heat wave days. These risks were larger when the heat wave periods were longer and more extreme and were largest on the heat wave day but remained elevated and statistically significant for 1 to 5 subsequent days.

Absolute risk differences were 0.34 excess daily admissions per 100,000 individuals at risk for fluid and electrolyte disorders, 0.25 for renal failure, 0.24 for urinary tract infections, 0.21 for septicemia, and 0.16 for heat stroke.

The researchers write that their analysis of hospitalization rates on days after a heat wave provides 2 additional insights. “For some diseases, risk of hospitalization remained elevated for up to 5 days following a heat wave day. This suggests that prevention and treatment of heat-related illnesses is critical not only during the heat wave itself but also on subsequent days. Additionally, quantifying the extra number of hospital admissions attributable to heat waves without consideration of a delayed effect may underestimate the health care burden of heat.”

(doi:10.1001/jama.2014.15715; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 23, 2014

Media Advisory: To contact Seetha Shankaran, M.D., email Philip Van Hulle at pvanhulle@med.wayne.edu. To contact editorial co-author Neil Marlow, D.M., F.Med.Sci., email N.Marlow@ucl.ac.uk.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.16058.  This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15959.

Longer Duration, Deeper Body Cooling for Newborns with Neurological Condition Does Not Reduce Risk of Death

Among full-term newborns with moderate or severe hypoxic ischemic encephalopathy (damage to cells in the central nervous system from inadequate oxygen), receiving deeper or longer duration cooling did not reduce risk of neonatal intensive care unit death, compared to usual care, according to a study in the December 24/31 issue of JAMA.

Hypoxic ischemic encephalopathy is an important cause of childhood neurodevelopmental deficits among infants born at full-term. Hypothermia (reduced body temperature) at 33.5°C for 72 hours reduces death or disability, according to background information in the article. Longer cooling and deeper cooling has been found to be neuroprotective in animal models.

Seetha Shankaran, M.D., of Wayne State University, Detroit, and colleagues conducted a study in which full-term infants were randomly assigned to four hypothermia groups: 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours, to examine if longer duration and deeper cooling would improve outcomes at 18 to 22 months. Infants admitted to the neonatal intensive care until within 6 hours of birth were candidates for the study when seizures or moderate or severe encephalopathy was present. The trial was closed for safety and futility issues and included 364 infants (of 726 planned).

Mortality in the neonatal intensive care unit (NICU) was 7 percent for the 33.5°C for 72 hours group, 14 percent for the 32.0°C for 72 hours group, 16 percent for the 33.5°C for 120 hours group, and 17 percent for the 32.0°C for 120 hours group.

Among neonates with moderate hypoxic ischemic encephalopathy, death in the NICU occurred in 4 percent in the 72 hours group; 8 percent in the 120 hours group; 7 percent in the 33.5°C group; and in 5 percent in the 32.0°C group. Among neonates with severe hypoxic ischemic encephalopathy, deaths in the NICU occurred in 34 percent in the 72 hours group; 42 percent in the 120 hours group; 31 percent in the 33.5°C group; and in 44 percent in the 32.0°C group.

Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1 percent in the 120 hours group vs 3 percent in the 72 hours group. Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2 percent.

“Among neonates of at least 36 weeks’ gestational age with moderate or severe hypoxic ischemic encephalopathy, deeper cooling or longer duration of cooling compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and the design of future trials,” the authors conclude.

(doi:10.1001/jama.2014.16058; 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: Depth and Duration of Cooling for Perinatal Asphyxial Encephalopathy

In an accompanying editorial, Nicola J. Robertson, M.B.Ch.B., Ph.D., and Neil Marlow, D.M., F.Med.Sci., of University College London, United Kingdom, comment on the findings of this study.

“Therapeutic hypothermia would not be a safe and effective therapy in neonatal care if not for the willingness and enthusiasm of neonatologists to take on the extra work needed to enter neonates into clinical trials. In the trial by Shankaran et al, clinical practice did not bear out preceding preclinical studies. However, the persistent high mortality and morbidity found with perinatal asphyxial encephalopathy encourages continuing efforts to improve the efficacy of treatment and minimize intercurrent and subsequent complications from this unpredictable and often devastating condition. The current focus is on adjunct therapies that can augment 72 hours of hypothermic neuroprotection at 33°C to 34°C.”

(doi:10.1001/jama.2014.15959; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 23, 2014

Media Advisory: To contact Ricardo A. Mosquera, M.D., email Deborah Mann Lake at deborah.m.lake@uth.tmc.edu. To contact editorial author James M. Perrin, M.D., call Cassandra Aviles at 617-724-6433 or email cmaviles@partners.org.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.16419.  This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.16514.

Comprehensive Care for High-Risk, Chronically Ill Children Reduces Serious Illnesses, Costs

High-risk children with chronic illness who received care at a clinic that provided both primary and specialty care and features to promote prompt effective care had an increase in access to care and parent satisfaction and a reduction in serious illnesses and costs, according to a study in the December 24/31 issue of JAMA.

Although the patient-centered or family-centered medical home is widely recommended, its value in improving clinical outcomes or reducing health care costs remains to be demonstrated. Medical homes are potentially the most cost-effective for high-risk patients, particularly high-risk children with chronic illness whose care is often fragmented, costly, and ineffective. “With the inadequate current payments for outpatient pediatric care and the necessity to restrain health care spending, the payments required to develop and sustain such medical homes may not be forthcoming unless they are shown to improve outcomes with minimal or no increase in costs,” the authors write.

Ricardo A. Mosquera, M.D., of the University of Texas Medical School, Houston, and colleagues randomly assigned 201 high-risk children with chronic illness to receive comprehensive care (n = 105; included treatment from primary care clinicians and specialists in the same clinic with multiple features to promote prompt effective care) or usual care (n = 96; provided locally in private offices or faculty-supervised clinics without modification). Patients were defined as high-risk with chronic illness if they had three or more emergency department visits, two or more hospitalizations, or one or more pediatric intensive care unit admissions during the previous year, and a greater than 50 percent estimated risk for hospitalization. The children were treated at a high-risk clinic at the University of Texas in Houston.

Comprehensive care (or enhanced medical home), compared to usual care, reduced the number of children with a serious illness (by 55 percent) and total hospital and clinic costs ($16,523 vs. $26,781 per child-year respectively). Rates were also reduced for emergency department visits, hospitalizations, number of days in the hospital, intensive care unit (ICU) admissions and days in the ICU.

“In this randomized clinical trial, the triple aim of improved care, improved health, and lower costs was achieved in an enhanced medical home providing comprehensive care to high- risk children with chronic illness compared with usual care,” the authors write.

“These findings from a single site of selected patients with a limited number of clinicians require study in larger, broader populations before conclusions about generalizability to other settings can be reached.”

(doi:10.1001/jama.2014.16419; 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.

TV Note – There will be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, December 23 at this link.

Editorial: Patient-Centered Medical Home for High-Risk Children With Chronic Illness

James M. Perrin, M.D., of Harvard Medical School and MassGeneral Hospital for Children, Boston, writes in an accompanying editorial that lessons from this study and the dual-eligible accountable care organizations can inform the development of medical home programs for patients with complex conditions.

“First, regular, almost daily, contact with the patient is critical. It is more difficult to reduce hospitalization rates once a patient enters the emergency department. Second, care must be comprehensive and responsive to the needs of the patient. What may seem a trivial problem to physicians may be important to patients. Third, care teams should have intimate knowledge of the patient (and their families).”

Dr. Perrin adds that although not a part of the current study, new technologies also can enhance management of complex chronic conditions. “Equipping families with mobile technologies that would allow them to enter data about their child’s health and wellness status could provide clinic staff real-time information and encourage scheduling of follow-up visits based mainly on the child’s clinical status and less on arbitrary prearranged follow-up times.”

(doi:10.1001/jama.2014.16514; 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, DECEMBER 16, 2014

Media Advisory: To contact corresponding author Tongyu Lin, M.D., Ph.D., email tongyulin@hotmail.com. To contact editorial co-author Jeremy S. Abramson, M.D., call Terri Ogan at 617-726-0954 or email togan@partners.org.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15704. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.16095.

Study Compares Effectiveness of Antiviral Drugs to Prevent Hepatitis B Virus-Related Hepatitis among Patients Receiving Chemotherapy for Lymphoma

Among patients with lymphoma undergoing a certain type of chemotherapy, receiving the antiviral drug entecavir resulted in a lower incidence of hepatitis B virus (HBV)-related hepatitis and HBV reactivation, compared with the antiviral drug lamivudine, according to a study in the December 17 issue of JAMA.

Hepatitis B virus reactivation is a well­documented chemotherapy complication, with diverse manifestations including life-threatening liver failure, as well as delays in chemotherapy or premature termination, all of which can jeopardize clinical outcomes. The reported incidence of HBV reactivation in patients seropositive for the hepatitis B surface antigen undergoing chemotherapy is 26 percent to 53 percent. This HBV reactivation risk exists for patients with lymphoma treated with chemotherapies containing the drug rituximab. An optimal approach to prevention of HBV reactivation has not been determined, according to background information in the article.

He Huang, M.D., of the Sun Yat-sen University Cancer Center, Guangzhou, China, and colleagues randomly assigned 121 patients seropositive for the hepatitis B surface antigen with untreated diffuse large B-cell lymphoma receiving chemotherapy treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) to either entecavir (n = 61) or lamivudine (n = 60). Patients received these drugs beginning 1 week before the initiation of R-CHOP treatment to 6 months after completion of chemotherapy. The study was conducted from February 2008 through December 2012 at 10 medical centers in China. This trial was a substudy of a parent study designed to compare a 3-week with a 2-week R-CHOP chemotherapy regimen for untreated diffuse large B-cell lymphoma.

The date of last patient follow-up was May 25, 2013. The researchers found that the rates were significantly lower for the entecavir group vs the lamivudine group for hepatitis (8.2 percent vs 23.3 percent), HBV-related hepatitis (0 percent vs 13.3 percent), HBV reactivation (6.6 percent vs 30 percent), delayed hepatitis B (0 percent vs 8.3 percent), and chemotherapy disruption (1.6 percent vs 18.3 percent).

Of the patients in the entecavir group, 24.6 percent experienced treatment-related adverse events, compared to 30.0 percent of patients in the lamivudine group.

The authors note that because entecavir is more expensive than lamivudine, further studies are needed to determine whether all patients seropositive for the hepatitis B surface antigen who receive rituximab-based immunosuppressive therapy should be given entecavir to prevent HBV flares and to determine which patients will benefit most from entecavir prophylaxis.

“If replicated, these findings support the use of entecavir in these patients.”

(doi:10.1001/jama.2014.15704; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the Foundation of 5010 Clinical Trials of Sun Yat-sen University. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Reactivation in Patients Receiving Rituximab-Based Chemotherapy for Lymphoma

Jeremy S. Abramson, M.D., and Raymond T. Chung, M.D., of Massachusetts General Hospital, Boston, comment on the findings of this study in an accompanying editorial.

“For HBV carriers as well as patients with cleared HBV infection, entecavir prophylaxis can be recommended to reduce the rate of HBV reactivation and hepatitis. For patients unable to receive antiviral prophylaxis, HBV DNA viral loads must be closely monitored during and after completion of chemotherapy. A more nuanced approach may be possible, in which patients at low risk for HBV reactivation can be identified and preferentially followed up with surveillance alone, such as those who are seropositive for both the core antibody and surface antibody. The answer to this question warrants ongoing investigation, as does the definition of the optimal duration of prophylactic antiviral therapy. The screening for and management of patients infected with HBV who receive chemotherapy should be viewed as nothing less than optimal care of patients with lymphoma.”

(doi:10.1001/jama.2014.16095; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 16, 2014

Media Advisory: To contact Frank M. Sacks, M.D., call Jessica Caragher at 617-525-6373 or email jcaragher@partners.org. To contact editorial author Robert H. Eckel, M.D., call Mark Couch at 303-724-5377 or email mark.couch@ucdenver.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.16658. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15338.

Low-Glycemic Index Carbohydrate Diet Does Not Improve Cardiovascular Risk Factors, Insulin Resistance

In a study that included overweight and obese participants, those with diets with low glycemic index of dietary carbohydrate did not have improvements in insulin sensitivity, lipid levels, or systolic blood pressure, according to a study in the December 17 issue of JAMA.

Foods that have similar carbohydrate content can differ in the amount they raise blood glucose, a property called the glycemic index. Even though some nutrition policies advocate consumption of low-glycemic index foods and even promote food labeling with glycemic index values, the independent benefits of glycemic index, and its effect on risk factors for cardiovascular disease and diabetes, are not well understood, according to background information in the article.

Frank M. Sacks, M.D., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues conducted a trial in which 163 overweight adults with prehypertension or stage 1 hypertension were given 4 different complete diets that contained all of their meals, snacks, and calorie-containing beverages, each for 5 weeks; and completed at least 2 study diets. The four diets were (1) a high-glycemic index (65 percent on the glucose scale), high-carbohydrate diet (58 percent energy); (2) a low-glycemic index (40 percent), high-carbohydrate diet; (3) a high-glycemic index, low-carbohydrate diet (40 percent energy); and (4) a low-glycemic index, low-carbohydrate diet. Each diet was based on a healthful Dietary Approaches to Stop Hypertension (DASH)-type diet, which is rich in fruits, vegetables, and low-fat dairy foods, and low in saturated and total fat.

The researchers found that at high dietary carbohydrate content, the low- compared with high-glycemic index level decreased insulin sensitivity; increased low-density lipoprotein (LDL) cholesterol; and did not affect levels of high-density lipoprotein (HDL) cholesterol, triglycerides, or blood pressure. At low carbohydrate content, the low- compared with high-glycemic index level did not affect the outcomes except for decreasing triglycerides. In the primary diet contrast, the low-glycemic index, low-carbohydrate diet, compared with the high-glycemic index, high-carbohydrate diet, did not affect insulin sensitivity, systolic blood pressure, LDL cholesterol, or HDL cholesterol but did lower triglycerides.

“In the context of an overall DASH-type diet, using glycemic index to select specific foods may not improve cardiovascular risk factors or insulin resistance,” the authors conclude.

(doi:10.1001/jama.2014.16658; 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.

TV Note – This week’s JAMA Report video is on the effect of a high- vs low-glycemic index carbohydrate diet on cardiovascular risk and insulin resistance. The video, along with embedded and downloadable video, audio files, text, documents and related links will be available at 3 p.m. CT Tuesday, December 16 at this link.

Editorial: Role of Glycemic Index in the Context of an Overall Heart-Healthy Diet

Robert H. Eckel, M.D., of the University of Colorado Anschutz Medical Campus, Aurora, writes in an accompanying editorial that many of the results of this study were contrary to what had been expected.

“When glycemic index was lower in the high­carbohydrate diet, insulin sensitivity not only did not increase but decreased. With the same diet pattern, levels of LDL cholesterol and apolipoprotein B (a secondary end point) increased, with no changes in HDL cholesterol or triglyceride level or blood pressure.”

“The unexpected findings of the study by Sacks et al suggest that the concept of glycemic index is less important than previously thought, especially in the context of an overall healthy diet, as tested in this study. These findings should therefore direct attention back to the importance of maintaining an overall heart-healthy lifestyle, including diet pattern.”

(doi:10.1001/jama.2014.15338; 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: 10:00 A.M. (CT) WEDNESDAY, DECEMBER 10, 2014

Media Advisory: To contact Justin E. Bekelman, M.D., call Steve Graff at 215-349-5653 or email stephen.graff@uphs.upenn.edu.

Many Breast Cancer Surgery Patients Do Not Receive Shorter, Less Costly Radiation Treatment

Although the use of a type of radiation treatment that is shorter in duration and less costly has increased among women with early-stage breast cancer who had breast conserving surgery, most patients who meet guidelines to receive this treatment do not, according to a study appearing in JAMA. The study is being released to coincide with the San Antonio Breast Cancer Symposium.

Breast cancer accounts for the largest portion of national expenditures on cancer care, estimated to reach $158 billion in 2020. Breast conservation therapy is the most common treatment for early-stage breast cancer. Whole breast irradiation (WBI), recommended for most women after breast conserving surgery, reduces local recurrence and improves overall survival. Conventional WBI, comprising 5 to 7 weeks of daily radiation fractions (i.e., treatments), has been the mainstay of treatment in the United States. Hypofractionated WBI is a shorter duration treatment alternative to conventional WBI, comprising fewer but higher-dose fractions generally delivered over 3 weeks. Based on high quality evidence from clinical trials, expert guidelines in 2011 endorsed hypofractionated WBI for selected patients with early-stage breast cancer and permitted hypofractionated WBI for other patients, according to background information in the article.

“Hypofractionated WBI increases convenience, reduces treatment burden, and lowers health care costs while offering similar cancer control and cosmesis [cosmetic outcomes] to conventional WBI. Furthermore, patients prefer shorter radiation treatment regimens,” the authors write.

Justin E. Bekelman, M.D., of the University of Pennsylvania Perelman School of Medicine, Philadelphia, and colleagues examined the usage and costs of hypofractionated WBI between 2008 and 2013—before and after the publication of key clinical trials and updated practice guidelines. The researchers used administrative claims data from 14 commercial health care plans covering 7.4 percent of U.S. adult women in 2013, and classified patients with incident early-stage breast cancer treated with lumpectomy and WBI from 2008 and 2013 into 2 groups: (1) the hypofractionation- endorsed cohort (n = 8,924) included patients 50 years of age or older without prior chemotherapy or axillary lymph node involvement and (2) the hypofractionation-permitted cohort (n = 6,719) included patients younger than 50 years or those with prior chemotherapy or axillary lymph node involvement. For this analysis, hypofractionated WBI was 3-5 weeks of treatment; conventional WBI was 5-7 weeks.

The researchers found that hypofractionated WBI increased from 10.6 percent in 2008 to 34.5 percent in 2013 in the hypofractionation-endorsed group and from 8.1 percent in 2008 to 21.2 percent in 2013 in the hypofractionation-permitted group. Adjusted average total health care expenditures in the 1 year after diagnosis were $28,747 for hypofractionated and $31,641 for conventional WBI in the hypofractionation-endorsed group (difference, $2,894) and $64,273 for hypofractionated and $72,860 for conventional WBI in the hypofractionation-permitted group (difference, $8,587). Adjusted average total 1-year patient out-of-pocket expenses were not significantly different between hypofractionated vs conventional WBI in either group.

“In the United States, although the 2011 practice guidelines concluded that hypofractionated and conventional WBI were ‘equally effective for in-breast tumor control and comparable in long-term side effects’ for selected women, the guidelines stopped short of recommending hypofractionated WBI as a care standard to be used in place of conventional WBI. The absence of a clear recommendation may have contributed to slower uptake of hypofractionation in the United States than in other countries. In 2013, we observed more pronounced uptake of hypofractionation; evaluation of future treatment patterns will be important to document whether or not this trend reflects the beginning of more widespread adoption,” the authors write.

(doi:10.1001/jama.2014.16616; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Bekelman received support from a grant from the National Cancer Institute. WellPoint provided funds to support research at HealthCore, a wholly-owned WellPoint subsidiary. 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, DECEMBER 9, 2014

Media Advisory: To contact Stephen R. Pitts, M.D., M.P.H., email Janet Christenbury at JMCHRIS@emory.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.16172.

Study Finds Greater Emergency Department Resource Use by Supervised Residents vs. Attending Physicians Alone

In a sample of U.S. emergency departments, compared to attending physicians alone, supervised visits (involving both resident and attending physicians) were associated with a greater likelihood of hospital admission and use of advanced imaging and with longer emergency department stays, according to a study in the December 10 issue of JAMA, a theme issue on medical education.

A common assumption is that care at academic medical centers costs more than care at nonteaching hospitals in part because of a higher frequency of testing and other resource use in teaching settings. Cost-effective care is among the “mile­stones” now used to evaluate emergency medicine residents and accredit emergency medicine residency programs.  Although there is evidence that resident supervision may improve some patient outcomes, few studies of supervised learning have explicitly evaluated resource use as an outcome, according to background information in the article.

Stephen R. Pitts, M.D., M.P.H., of the Emory University School of Medicine, Atlanta, and colleagues compared resources used in supervised vs attending-only visits with data from the National Hospital Ambulatory Medical Care Survey (2010), a sample of U.S. emergency departments (EDs) and ED visits.

Of 29,182 ED visits to the 336 nonpediatric EDs in the sample, 3,374 visits were supervised visits. Compared with the 25,808 attending-only visits, supervised visits were significantly associated with more frequent hospital admission (21 percent vs 14 percent), advanced imaging (computed tomography, ultrasound, or magnetic resonance imaging; 28 percent vs 21 percent), and a longer median ED stay (226 vs 153 minutes), but not with blood testing (53 percent vs 45 percent).

“In our study of a nationally representative sample of ED visits, we hypothesized that supervised visits would consume more resources than nonsupervised visits, reasoning that supervised learning favors a more deliberate, reflective decision-making style than nonteaching clinical visits. We confirmed consistently higher use of several ED resources among supervised visits even after adjustment for several other possible determinants of resource use that were available in the survey,” the authors write.

(doi:10.1001/jama.2014.16172; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 9, 2014

Media Advisory: To contact Sunny Smith, M.D., call Jacqueline Carr at 619-543-6427 or email jcarr@ucsd.edu.

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Number of Medical Schools with Student-Run Free Clinics Has More Than Doubled

There has been a doubling during the last decade in the number of U.S. medical schools that have student-run free clinics, with more than half of medical students involved with these clinics, according to a study in the December 10 issue of JAMA, a theme issue on medical education.

Sunny Smith, M.D., of the University of California, San Diego, and colleagues conducted a study to assess whether there has been growth of student-run free clinics (SRFCs) in medical schools and describe the characteristics of these clinics. The first national study of SRFCs conducted in 2005 described 111 SRFCs at 49 Association of American Medical Colleges (AAMC) member institutions. The researchers developed a 39 item survey with yes/no, multiple-choice, and open-ended responses. SRFCs and their medical student leaders were identified through the Society of Student-Run Free Clinics.

The authors identified SRFCs at 106 of 141 (75.2 percent) U.S. AAMC member institutions. The survey response rate was 81.1 percent (86/106). The 86 responding institutions reported 208 SRFC sites. More than half of medical students were reported to be involved in SRFCs, including first- through fourth­ year students. Fifty-three percent of institutions reportedly offered no academic credit for participation.

The most common core services provided by the SRFCs were outpatient adult medicine, health care maintenance, chronic disease management, language interpreters and social work. The most common diseases treated were diabetes and hypertension.

In open-ended responses, students identified the greatest strengths of SRFCs as serving the underserved and student education. The biggest challenges were obtaining sufficient faculty staffing and funding.

“Despite the lack of academic credit at many institutions, most medical students are volunteering in this setting. Given the ubiquity of SRFCs in the education of future physicians, further research is needed to assess their educational and clinical outcomes,” the authors write.

“The lack of funding and sufficient faculty supervisors identified as the biggest challenges in SRFCs are actionable items because institutional support could help stabilize and improve these educational opportunities for years to come.”

(doi:10.1001/jama.2014.16066; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 9, 2014

Media Advisory: To contact Bradley M. Gray, Ph.D., call Lorie Slass at 215-399-4005 or email lslass@abim.org. To contact John Hayes, M.D., email Gary Kunich at gary.kunich@va.gov. To contact editorial author Thomas H. Lee, M.D., M.Sc., email Kristen Berry at kberry@ariamarketing.com.

To place an electronic embedded link to this study and editorial in your story  This link to the 1^st study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.12716. This link to the 2nd study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13992. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13566.

Studies Examine Effect on Patient Care and Costs of Requirements for Maintaining Board Certification

Two studies in the December 10 issue of JAMA, a theme issue on medical education, evaluate the effect of the requirement of maintaining board certification on hospitalizations, health care costs and quality of patient care.

One of the largest changes in physician accreditation policy was the initiation of a 10-year Maintenance of Certification (MOC) requirement in 1990 by the American Board of Internal Medicine (ABIM). This change was also adopted by 24 certifying boards of the American Board of Medical Specialties, affecting 85 percent of all U.S. physicians. Despite the importance of this change, there has been limited research examining associations between the MOC requirement and patient outcomes.

In one study, Bradley M. Gray, Ph.D., of the American Board of Internal Medicine, Philadelphia, and colleagues examined outcomes of care for Medicare beneficiaries treated in 2001 by two groups of ABIM-certified internal medicine physicians (general internists). One group (n = 956), initially certified in 1991, was required to fulfill the MOC program in 2001 (MOC-required) and treated 84,215 beneficiaries in the sample; the other group (n = 974), initially certified in 1989, was grandfathered out of the MOC requirement (MOC-grandfathered) and treated 69,830 similar beneficiaries in the sample. The primary outcome measured was ambulatory care-sensitive hospitalizations (ACSHs), which are hospitalizations triggered by conditions (such as diabetes and asthma) thought to be potentially preventable through better access to and quality of outpatient care.  Other outcomes included health care cost measures (adjusted to 2013 dollars).

Annual incidence of ACSHs (per 1,000 beneficiaries) increased from the pre-MOC period (37.9 for MOC-required beneficiaries vs 37.0 for MOC-grandfathered beneficiaries) to the post-MOC period (61.8 for MOC-required beneficiaries vs 61.4 for MOC-grandfathered beneficiaries) for both groups, as did annual per-beneficiary health care costs (pre-MOC period, $5,157 for MOC-required beneficiaries vs $5,133 for MOC-grandfathered beneficiaries; post-MOC period, $7,633 for MOC-required beneficiaries vs $7,793 for MOC-grandfathered beneficiaries). The MOC requirement was not statistically associated with group differences in the growth of the annual ACSH rate.

The researchers found that the MOC requirement was associated with a decreased growth in costs related to laboratory tests, imaging, and specialty visits.

“Imposition of the MOC requirement was not associated with a difference in the increase in ACSHs but was associated with a small reduction in the growth differences of costs for a cohort of Medicare beneficiaries,” the authors write.

The authors note that this research should be replicated for the current MOC program using more robust measures of care quality, across other patient populations as well as across internal medicine subspecialties, and for other certification boards’ MOC requirements.

(doi:10.1001/jama.2014.12716; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Financial and material support was provided by the American Board of Internal Medicine. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

In an another study in the December 10 issue of JAMA, John Hayes, M.D., of the Clement J. Zablocki VA Medical Center, Milwaukee, Wisc., and colleagues examined whether there are differences in the quality of primary care provided between internists with time-limited board certification and those with time-unlimited certification. Before 1990, board certification was time-unlimited. Since 1990, to maintain certification internists must pass an examination every 10 years.

American Board of Internal Medicine initiatives encourage internists with time-unlimited certificates to recertify. However, there are limited data evaluating differences in performance between internists with time-limited or time-unlimited board certification, according to background information in the article.

The study consisted of an analysis of data for 10 primary care performance measures (such as blood pressure control, colorectal cancer screening) from 1 year (2012-2013) at four Veterans Affairs (VA) medical centers. Participants were internists with time-limited (n = 71) or time-unlimited (n = 34) ABIM certification providing primary care to 68,213 patients.

After adjustment for various factors, the researchers found no significant differences in outcomes for patients cared for by internists with time-limited or time-unlimited certification for any of the performance measures. “To whatever extent a goal of MOC is to improve the quality of patient care, these findings raise a question of whether that goal is being achieved, at least among internists at these VA hospitals.”

“Additional research to examine the difference in patient outcomes among holders of time-unlimited and time-limited certificates in VA and nonacademic settings and the association with other ABIM goals may help clarify the potential benefit of MOC participation,” the authors conclude.

(doi:10.1001/jama.2014.13992; 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: Certifying the Good Physician – A Work in Progress

Physicians should work constructively to help MOC improve, much as physicians should work continuously to improve how they collaborate with colleagues and with patients, writes Thomas H. Lee, M.D., M.Sc., of Press Ganey, Brigham and Women’s Hospital, Harvard Medical School, Boston, in an editorial in this issue of JAMA.

“In addition, physicians must make the commitment to lifelong, meaningful learning to ensure that their knowledge and skills remain current and relevant. Patients would be disappointed by anything less. The medical profession may never fully understand the effect of MOC, but that does not mean that physicians should give up or stop trying to make it better. The MOC program is a work in progress, as are all good physicians.”

(doi:10.1001/jama.2014.13566; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 9, 2014

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

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15444.

Gap Exists Between Languages Spoken by Medical Residency Applicants and U.S. Patients with Limited English Proficiency

An analysis of the non-English-language skills of U.S. medical residency applicants finds that although they are linguistically diverse, most of their languages do not match the languages spoken by the U.S. population with limited English proficiency, according to a study in the December 10 issue of JAMA, a theme issue on medical education.

More than 25 million U.S. residents have limited English proficiency, an 80 percent increase from 1990 to 2010. Limited English proficiency (LEP) may impede participation in the English­language-dominant health care system. Little is known about the non-English-language skills of physicians in training, according to background information in the article.

Lisa Diamond, M.D., M.P.H., of Memorial Sloan Kettering Cancer Center, New York, and colleagues conducted a study to characterize the language diversity of all U.S. residency applicants through the Electronic Residency Application Service and contrast applicant language skills with the predominant languages of the U.S. population with LEP. Applicants were asked to self-report proficiency in all languages spoken. The five response options were: native/functionally native; advanced; good; fair; and basic. The applicants’ linguistic diversity was contrasted with the U.S. LEP population. The top 25 LEP languages spoken were obtained from the U.S. Census Bureau for individuals 5 years and older between 2007 and 2011.

Most (84.4 percent) of the 52,982 applicants for 2013 reported some proficiency in at least 1 non-English language. The most common languages were Spanish (53.2 percent), Hindi (20.5 percent), French (15.6 percent), Urdu (10.1 percent), and Arabic (9.8 percent). Only 21 percent of applicants reported advanced Spanish proficiency.

Among the 25.1million U.S. LEP speakers, 16.4 million speak Spanish. For every 100,000 U.S. LEP speakers, there were 105 applicants who reported at least advanced proficiency in a non­English language. Relative to this rate, there was an over-representation of Hindi-speaking applicants, and an under-representation of Spanish, Vietnamese, Korean, and Tagalog, which are 4 of the top 5 U.S. LEP languages.

“Further research is needed on whether increasing the number of bilingual residents, educating trainees on language services, or implementing medical Spanish courses as a supplement to (not a substitute for) interpreter use would improve care for LEP patients,” the authors write.

(doi:10.1001/jama.2014.15444; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Diamond was supported by Memorial Sloan Kettering Cancer Center, Department of Psychiatry and Behavioral Sciences, Immigrant Health and Cancer Disparities Service. 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, DECEMBER 9, 2014

Media Advisory: To contact co-author Fitzhugh Mullan, M.D., call Kathy Fackelmann at 202-994-8354 or email kfackelmann@gwu.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15973.

Region of Medical Residency Training May Affect Future Spending Patterns of Physician

Among primary care physicians, the spending patterns in the regions in which their residency program was located were associated with expenditures for subsequent care they provided as practicing physicians, with those trained in lower-spending regions continuing to practice in a less costly manner, even when they moved to higher-spending regions, and vice versa, according to a study in the December 10 issue of JAMA, a theme issue on medical education.

Regional and system-level variations in Medicare spending and overall intensity of medical services delivered to patients represent the collective practice decisions of clinicians in these different systems. Some research suggests that the nature of residency training influences the nature of physician practice, which raises the question of whether exposure to different practice and spending patterns during residency influences physicians’ practice patterns and cost of care after training, according to background information in the article.

Candice Chen, M.D., M.P.H., of George Washington University, Washington, D.C., and colleagues examined the relationship between spending patterns in the region of a physician’s graduate medical education training and individual physician practice spending patterns after training. The study consisted of an analysis of 2011 Medicare claims data (Part A hospital and Part B physician) for a random, nationally representative sample of family medicine and internal medicine physicians completing residency between 1992 and 2010 with Medicare patient panels of 40 or more patients (2,851 physicians providing care to 491,948 Medicare beneficiaries). Locations of practice and residency training were matched with Dartmouth Atlas Hospital Referral Region (HRR) files. Training and practice HRRs were categorized into low-, average-, and high-spending groups, with approximately equal distribution of beneficiary numbers.

For physicians practicing in high-spending regions, those trained in high-spending regions had an average spending per Medicare beneficiary per year $1,926 higher than those trained in low-spending regions. For practice in average-spending HRRs, average spending per beneficiary was $897 higher for physicians trained in high- vs low-spending regions. For practice in low-spending HRRs, the difference across training HRR levels was not significant ($533).

Overall, there was approximately a 7 percent difference in spending between physicians trained in the highest and lowest training HRR spending groups, corresponding to an estimated $522 difference between low- and high-spending training regions.

For physicians 1 to 7 years in practice, there was a 29 percent difference in spending between those trained in low- and high-spending regions; however, after 16 to 19 years, there was no significant difference.

“These observations suggest an imprinting of care-related spending behaviors that may take place during residency. Decay of the effect over time would be consistent with a training imprint that wanes because of practice environment. These findings are notable for the initial size and continuation of the association of training with physician spending patterns for up to 15 years after training. This potential imprinting has implications for physician training and potentially for hiring, particularly because major efforts are under way to reduce health care spending,” the authors write.

(doi:10.1001/jama.2014.15973; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 9, 2014

Media Advisory: To contact Mitesh S. Patel, M.D., M.B.A., M.S., call Anna Duerr at 215-349-8369 or email anna.duerr@uphs.upenn.edu. To contact the corresponding author for the 2^nd study, Karl Y. Bilimoria, M.D., M.S., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu. To contact editorial co-author James A. Arrighi, M.D., call David Orenstein at 401-863-1862 or email david_orenstein@brown.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the 1^st study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15273. This link to the 2nd study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15277. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15580.

Resident Duty Hour Reforms Do Not Appear to Have Had Significant Effect on Patient Outcomes or on Resident Board Examination Scores

An examination of the effect of resident duty hour reforms in 2011 finds no significant change in mortality or readmission rates for hospitalized patients or outcomes for general surgery patients, according to two studies in the December 10 issue of JAMA, a theme issue on medical education.

In 2011, the Accreditation Council for Graduate Medical Education (ACGME) implemented new duty hour reforms for all ACGME-accredited residency programs. The revisions maintain the weekly limit of 80 hours set forth by the 2003 duty hour reforms but reduced the work hour limit from 30 consecutive hours to 16 hours for first­year residents (interns) and 24 hours for upper-year residents (with an additional 4 hours to perform transitions of care and participate in educational activities). Initial duty hour reforms in 2003 were prompted by wide­spread concern about the effects of resident fatigue. There has been concern that the 2011 duty hour reforms may adversely affect the quality of resident education, increase handoffs in care, and put both patient safety and outcomes at risk.

In one study, Mitesh S. Patel, M.D., M.B.A., M.S., of the Veterans Administration Hospital and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues evaluated the association of the 2011 ACGME duty hour reforms with mortality and readmissions among hospitalized Medicare patients during the first year after the reforms. The study analyzed Medicare patient admissions (6,384,273 admissions from 2,790,356 patients) to short-term, acute care hospitals (n = 3,104) with principal medical diagnoses of heart attack, stroke, gastrointestinal bleeding, or congestive heart failure or a classification of general, orthopedic, or vascular surgery.

After an analysis of the number of hospital admissions, deaths and readmissions in the two years before duty hour reforms compared with these figures in the first year after the reforms, the researchers found no significant positive or negative associations of duty hour reforms with 30-day mortality for any of the medical conditions or surgical categories in this study, and no significant positive or negative associations of these reforms with 30-day all-cause readmissions for combined medical conditions or combined surgical categories.

The authors write that their findings suggest that in the first year after the 2011 duty hour reforms, the goals of improving the quality and safety of patient care, as measured by decreased 30-day mortality and all-cause readmissions rates “were not being achieved. Conversely, concerns that outcomes might actually worsen because of decreased continuity of care have not been borne out.”

(doi:10.1001/jama.2014.15273; 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.

In an another study in the December 10 issue of JAMA, Ravi Rajaram, M.D., of the American College of Surgeons, Chicago, and colleagues conducted a study to determine if the 2011 ACGME duty hour reform was associated with a change in general surgery patient outcomes or in resident examination performance.

The study examined general surgery patient outcomes two years before (academic years 2009-2010) and after (academic years 2012-2013) the 2011 duty hour reform. Patients were those undergoing surgery at hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program. General surgery resident performance on the annual in-training, written board, and oral board examinations was assessed for this same period.

In the main analysis, 204,641 patients were identified from 23 teaching (n = 102,525) and 31 nonteaching (n = 102,116) hospitals. In adjusted analyses, the researchers found that the duty hour reform was not associated with a significant change in death or serious illness in either post-reform year 1 or post-reform year 2 or when both post-reform years were combined. There was also no association between duty hour reform and any other postoperative adverse outcome.

Average in-training examination scores did not significantly change from 2010 to 2013 for first-year residents, for residents from other postgraduate years, or for first-time examinees taking the written or oral board examinations during this period.

The authors write that the study findings could be interpreted in at least two ways. “First, there is no evidence of worsened patient care or resident education, and given assumed improvements to resident well-being, this could indicate that current policies should continue forward as they are. Conversely, the potential harm from poor continuity of care, increased handoffs, trainees feeling unprepared to practice, and concern regarding residents developing a shift-work mentality engendered by these policies could suggest that the duty hour reform may require significant revision  or reconsideration. Although many of these concerns have not been substantiated by consistent evidence, they reflect the intense interest duty hour reform has generated from the clinical and educational community.”

“The implications of these findings should be considered when evaluating the merit of the 2011 ACGME duty hour reform and revising related policies in the future.”

(doi:10.1001/jama.2014.15277; 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: Duty Hour Requirements – Time for a New Approach?

“How should the studies in this issue of JAMA and other literature on duty hour restrictions be interpreted,” asks James A. Arrighi, M.D., of the Warren Alpert Medical School of Brown University and the Lifespan Cardiovascular Institute, Providence, R.I., and James C. Hebert, M.D., of the University of Vermont College of Medicine and Fletcher Allen Healthcare, Burlington, Vt., in an accompanying editorial.

“First, with regard to potential short-term policy decisions on duty hour requirements, is it important to decide whether a null association with safety and education metrics is a positive or negative finding? In our roles as residency review committee chairs, we think this is the wrong question to ask because there was no justification for making the rules more complex or restrictive, as occurred in 2011.”

“Second, in the absence of improvement in patient outcomes in these 2 studies, how should the 2011 duty hour revisions be judged? … Many program directors have expressed great concern about the potential negative effects of this second set of changes, including effects on resident education, preparedness for senior roles, patient safety, and continuity of care. Thus, in the absence of clear data demonstrating benefit, the concerns of the educational community should be given credence and not be dismissed as mere perceptions.”

“Third, although high-quality observational studies such as these are very helpful, randomized data are lacking. Recognizing this gap in research, the educational community has proposed 2 randomized trials on duty hour requirements in medical and surgical residents that may provide more definitive information.”

(doi:10.1001/jama.2014.15580; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 2, 2014

Media Advisory: To contact corresponding author Shabbir M. H. Alibhai, M.D., M.Sc., call Jane Finlayson at 416-946-2846 or email jane.finlayson@uhn.ca.

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Prescriptions for Drugs to Strengthen Bones Remains Low Despite Recommended Use for Men Receiving Androgen Deprivation Therapy

Although some guidelines recommend use of bisphosphonates (a class of drugs used to strengthen bone) for men on androgen deprivation therapy, an analysis finds that prescriptions for these drugs remains low, even for those men at high risk of subsequent fractures, according to a study in the December 3 issue of JAMA.

Androgen deprivation therapy (ADT) is an effective, widely used therapy for men with prostate cancer. Adverse effects include bone loss and increased fracture risk. Canadian guidelines recommended bisphosphonate use in men with osteoporosis or fragility fracture as early as 2002 and in men on ADT in 2006. Bisphosphonate prescribing patterns are relatively unknown and may have changed over time because of increasing awareness of bone effects of ADT and evidence of bisphosphonate efficacy, according to background information in the article.

Using administrative databases at the Institute for Clinical Evaluative Sciences and the Ontario Cancer Registry, Husayn Gulamhusein, B.H.Sc., of the University Health Network, Toronto, and colleagues examined rates of bisphosphonate prescriptions in men initiating ADT in Ontario between 1995 and 2012. The study group included men 66 years of age or older starting ADT for prostate cancer, who had undergone surgical removal of one or both testicles or received at least 6 months of continuous medical ADT and survived at least 1 year after ADT initiation. Any bisphosphonate claim within 12 months of ADT initiation was captured through drug database claims. Bisphosphonate prescription over time was examined for three groups: all nonusers of bisphosphonates, those with prior osteoporosis, and those with prior fragility fracture.

A total of 35,487 men with prostate cancer who began ADT during the study period were identified. Bisphosphonate claims among all nonusers increased from 0.35 per 100 persons in 1995-1997 to 3.40 per 100 persons in 2010-2012. Even among those with prior osteoporosis or fragility fracture, rates remained low. Among all 3 groups, peak bisphosphonate claims occurred in 2007-2009, with a high of 11.89 per 100 persons in those with prior osteoporosis.

As the most widely used class of prescription drugs for osteoporosis, the authors write that these findings suggest “limited awareness among clinicians regarding optimal bone health management.”

The researchers speculate that the decrease in bisphosphonate prescriptions after 2009 may be partly due to recent negative media regarding the association of bisphosphonates with rare osteonecrosis (bone death) of the jaw and atypical femoral fractures. “This is appropriate for groups at low risk for fractures, but the decrease in use for high-risk patients is concerning.”

“Although the optimal rate of bisphosphonate use in men on ADT is unknown, it is reasonable that most men with prior osteoporosis or fracture should be taking a bisphosphonate or other effective bone medication.”

(doi:10.1001/jama.2014.14038; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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

Media Advisory: To contact corresponding author Lisa M. Schwartz, M.D., M.S., call Annmarie Christensen at 603-653-0897 or email Annmarie.Christensen@dartmouth.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13329.

Study Examines FDA Influence on Design of Pivotal Drug Studies

An examination of the potential interaction between pharmaceutical companies and the U.S. Food and Drug Administration (FDA) to discuss future studies finds that one-quarter of recent new drug approvals occurred without any meeting, and when such meetings occurred, pharmaceutical companies did not comply with one-quarter of the recommendations made by the FDA regarding study design or primary outcome, according to a study in the November 26 issue of JAMA.

To enhance protocol quality, federal regulations encourage but do not require meetings between pharmaceutical companies and the FDA during the design phase of pivotal studies assessing drug efficacy and safety for the proposed indication. These meetings often generate FDA recommendations for improving research, although companies are not bound to follow them, according to background information in the article.

Steven Woloshin, M.D., M.S., of the Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, N.H., and colleagues reviewed and analyzed approximated 200 FDA documents (memos; meeting minutes; filing checklists; and medical, statistical, and summary reviews) for 35 new drugs approved between February 1, 2011, and February 29, 2012. The researchers identified all FDA comments and analyzed recommendations about pivotal study design or primary outcomes and characterized the effect of recommendations on study quality.

Of 35 new drug approvals, companies met with the FDA to discuss pivotal studies for 28. The FDA made 53 recommendations about design (e.g., controls, doses, study length) or primary outcome for 21 approvals. Fifty-one recommendations were judged as increasing study quality (e.g., adding controls, blinding, or specific measures and frequency for toxicity assessments, lengthening studies to assess outcome durability) and two as having an uncertain effect. Companies complied with 40 of the 53 recommendations. Examples of non-compliance include a request for randomized trials of brentuximab and crizotinib, but the companies conducted uncontrolled studies. Other cases included primary outcome choice (e.g., progression­free instead of overall survival) and drug (active comparator) doses tested.

Companies can also request FDA review of pivotal trial protocols.  If FDA endorses the protocol it agrees not to object to any study design issues when reviewing the drug for approval.  Companies requested protocol review for only 21 of the 35 new drug approvals – and FDA endorsed the protocol for 12.

The authors write that instituting mandatory FDA review of pivotal trial protocols with the power to issue binding recommendations could be an effective way to optimize study quality.  They believe that such review may be even more important with increasingly flexible approval pathways. “An independent FDA-commissioned report suggested that stronger early FDA involvement could avoid deficiencies that delay approval of effective drugs and more clearly identify ineffective or harmful ones.”

(doi:10.1001/jama.2014.13329; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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

Media Advisory: To contact Arthur J. Reynolds, Ph.D., call Andrea Cournoyer at 612-625-9436 or email acournoy@umn.edu. To contact editorial author Lawrence J. Schweinhart, Ph.D., email schweinhart@att.net.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15376. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15124.

Full-Day Preschool Associated With Increased School Readiness, Reduced Absences, Compared with Part-Day

Children who attended a full-day preschool program had higher scores on measures of school readiness skills (language, math, socio-emotional development, and physical health), increased attendance, and reduced chronic absences compared to children who attended part-day preschool, according to a study in the November 26 issue of JAMA.

Participation in high-quality early childhood programs at ages 3 and 4 years is associated with greater school readiness and achievement, higher rates of educational attainment and socioeconomic status, and lower rates of crime. Although publicly funded preschool such as Head Start and state prekindergarten serve an estimated 42 percent of U.S. 4-year­ olds, most provide only part-day services, and only 15 percent of 3-year-olds enroll. These rates plus differences in quality may account for only about half of entering kindergartners having mastered skills needed for school success. One approach for enhancing effectiveness is increasing from a part-day to a full-day schedule; whether this improves outcomes is unknown, according to background information in the article.

Arthur J. Reynolds, Ph.D., of the University of Minnesota, Minneapolis, and colleagues investigated whether full-day preschool was associated with higher levels of school readiness, attendance, and parent involvement compared with part-day participation. The study consisted of an end-of-preschool follow-up of a group of predominantly low-income, ethnic minority children enrolled in the Child-Parent Centers (CPC) for the full day (7 hours; n = 409) or part day (3 hours on average; n = 573) in the 2012-2013 school year in 11 schools in Chicago.

Implemented in the Chicago Public Schools since 1967, the Midwest CPC Education Program provides comprehensive education and family services beginning in preschool. A scale-up of the CPC program began in 2012 in more diverse communities. The model was revised to incorporate advances in teaching practices and family services and included the opening of full-day preschool classrooms in some sites.

At the end of preschool, the researchers evaluated school readiness skills (in several domains) of the children, attendance and chronic absences, and parental involvement. They found that full-day preschool participants had higher scores than part-day peers on measures of socio-emotional development (58.6 vs 54.5), language (39.9 vs 37.3), math (40.0 vs 36.4), and physical health (35.5 vs 33.6). Scores for literacy (64.5 vs 58.6) and cognitive development (59.7 vs 57.7) were not significantly different.

Full-day preschool graduates also had higher rates of attendance (85.9 percent vs 80.4 percent) and lower rates of chronic absences (10 percent or greater days missed; 53.0 percent vs 71.6 percent; 20 percent or greater days missed; 21.2 percent vs 38.8 percent), but no differences in parental involvement.

“Full-day preschool appears to be a promising strategy for school readiness. The size and breadth of associations go beyond previous studies. The positive association of full-day preschool also suggests that increasing access to early childhood programs should consider the optimal dosage of services. In addition to increased educational enrichment, full-day preschool benefits parents by providing children with a continually enriched environment throughout the day, thereby freeing parental time to pursue career and educational opportunities. By offering another service option, full-day preschool also can increase access for families who may not otherwise enroll,” the authors write.

They add that these findings need to be replicated in other programs and contexts.

(doi:10.1001/jama.2014.15376; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: The Value of High-Quality Full-Day Preschool

In an accompanying editorial, Lawrence J. Schweinhart, Ph.D., of the HighScope Educational Research Foundation, Ann Arbor, Mich., writes that although the associations found in this study were statistically significant, “they may not be substantial enough to justify the larger expense of full-day preschool, essentially twice that of part-day preschool.”

“This must be debated and discussed by parents, educators, and policy makers and the longer-term effects and economic returns studied. But the findings are large enough to assure parents and the rest of the public that the positive benefits found for high-quality part-day preschool were found in high-quality full-day preschool to an even greater extent.”

“In part, the importance of the study by Reynolds and colleagues is that it represents a contemporary sample of children and their families. As the demand for preschool programs shifts from part-day to full-day, it is important to know whether this shift is educationally valuable as well. The study by Reynolds and colleagues provides evidence that high­quality, full-day programs are educationally more valuable than part-day programs.”

(doi:10.1001/jama.2014.15124; 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: 10:45 A.M. (CT) MONDAY, NOVEMBER 17, 2014
Media Advisory: To contact Joseph B. Muhlestein, M.D., email Jess Gomez at Jess.Gomez@imail.org. To contact editorial author Raymond J. Gibbons, M.D., call Traci Klein at 507-990-1182 or email Klein.Traci@mayo.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15825. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15958.

Findings Do Not Support Routine Screening of Patients with Diabetes for Coronary Artery Disease with CT Angiography

Joseph B. Muhlestein, M.D., of the Intermountain Medical Center Heart Institute, Murray, Utah, and colleagues examined whether screening patients with diabetes deemed to be at high cardiac risk with coronary computed tomographic angiography (CCTA) would result in a significant long­term reduction in death, heart attack, or hospitalization for unstable angina. The study appears in JAMA and is being released to coincide with its presentation at the American Heart Association’s Scientific Sessions 2014.

Diabetes mellitus is the most important coronary artery disease (CAD) risk factor; patients with diabetes often develop severe but asymptomatic CAD. The combination of aggressive, asymptomatic CAD has made it the most common cause of death in patients with diabetes. The development of cardiac imaging with high-resolution CCTA now provides the opportunity to evaluate the actual coronary anatomy noninvasively and ascertain the overall extent and severity of coronary atherosclerosis. However, whether routine CCTA screening in high-risk populations can effect changes in treatment (such as preemptive coronary revascularization or more aggressive medical therapy), leading to a reduction in cardiac events, remains unproven, according to background information in the article.

The trial randomly assigned 900 patients with types 1 or 2 diabetes of at least 3 to 5 years’ duration and without symptoms of CAD to CAD screening with CCTA (n = 452) or to standard national guidelines-based optimal diabetic care (n = 448). Patients were recruited from 45 clinics and practices of a single health system (Intermountain Healthcare, Utah). Standard or aggressive therapy (for treating abnormal lipid, blood pressure and glucose levels) was recommended based on CCTA findings.

At an average follow-up time of 4 years, the primary outcome event rates (composite of all-cause death, nonfatal heart attack, or unstable angina requiring hospitalization) were not significantly different between the CCTA and the control groups (6.2 percent [28 events] vs 7.6 percent [34 events]). The incidence of the composite secondary end point of ischemic major adverse cardiac events (CAD death, nonfatal heart attack, or unstable angina) also did not differ between groups (4.4 percent [20 events] vs 3.8 percent [17 events]).

“Coronary computed tomographic angiography involves significant expense and radiation exposure, so that justification of routine screening requires demonstration of net benefit in an appropriately high-risk population,” the authors write. “These findings do not support CCTA screening in this population.”
(doi:10.1001/jama.2014.15825; 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: Optimal Medical Therapy vs CT Angiography Screening for Patients with Diabetes

“What are the take-home messages from this randomized trial,” asks Raymond J. Gibbons, M.D., of the Mayo Clinic, Rochester, Minn., in an accompanying editorial.

“Although studies like this are often characterized as ‘negative,’ there are several important messages. As suggested by the authors, future randomized trials of cardiac imaging in asymptomatic patients with diabetes should be larger and focused on an enriched study population at higher risk. Such a strategy would certainly enhance the chances of success. A more important and more currently applicable message is that guideline-directed medical therapy for hypertension and hyperlipidemia is effective in asymptomatic patients with diabetes and should be implemented more consistently. The data in this study suggest that Intermountain Healthcare has set a new published standard for what is achievable in patients with diabetes with respect to blood pressure control and lipid-lowering therapy and that, when therapy is applied this effectively, patients with diabetes are no longer at high risk for major cardiovascular events.”
(doi:10.1001/jama.2014.15958; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported serving as a consultant for Lantheus Medical Imaging.

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EMBARGOED FOR RELEASE: 10:45 A.M. (CT) MONDAY, NOVEMBER 17, 2014
Media Advisory: To contact Yasuo Ikeda, M.D., email yikeda@aoni.waseda.jp. To contact editorial co-author J. Michael Gaziano, M.D., M.P.H., call Jessica Caragher at 617-525-6373 or email jcaragher@partners.org.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15690. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.16047.

Once-Daily, Low-Dose Aspirin Does Not Reduce Risk of CV Death and Other Adverse Outcomes in Older Patients with Certain Risk Factors

Yasuo Ikeda, M.D., of Waseda University, Tokyo, Japan, and colleagues examined whether once-daily, low-dose aspirin would reduce the total number of cardiovascular (CV) events (death from CV causes, nonfatal heart attack or stroke) compared with no aspirin in Japanese patients 60 years or older with hypertension, diabetes, or poor cholesterol or triglyceride levels. The study appears in JAMA and is being released to coincide with its presentation at the American Heart Association’s Scientific Sessions 2014.

The World Health Organization estimates that annual global mortality due to cardiovascular diseases (including heart attack and stroke) will approach 25 million by 2030. A recent study of trends in cardiovascular disease in Japan indicated that there has been, from 1960 to 2000, a steep increase in the prevalence of glucose intolerance, hypercholesterolemia, and obesity, probably due to the adoption of Western diets and lifestyles. By 2030, it is estimated that 32 percent of the Japanese population will be 65 years or older. Prevention of atherosclerotic cardiovascular diseases is an important public health priority in Japan due to an aging population, according to background information in the article.

This study included 14,464 patients (60 to 85 years of age) with hypertension, dyslipidemia (poor cholesterol or triglyceride levels), or diabetes mellitus who were randomized to aspirin (100 mg/d) or no aspirin in addition to ongoing medications. The patients were recruited by primary care physicians at 1,007 clinics in Japan. The study was terminated early by the data monitoring committee after a median follow-up of 5.02 years based on likely futility.

The researchers found that there was no statistically significant difference between the two groups in time to the primary end point (a composite of death from cardiovascular causes, nonfatal stroke, and nonfatal heart attack). At 5 years after randomization, the cumulative primary event rate was similar in participants in the aspirin group (2.77 percent) and those in the no aspirin group (2.96 percent).

Aspirin significantly reduced incidence of nonfatal heart attack and transient ischemic attack, and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization.

The authors write that despite inconsistent evidence for the benefit of aspirin in primary prevention of cardiovascular events, the benefits in secondary prevention are well documented, including in Japanese patients. “There is also a growing body of evidence to suggest benefits for aspirin in the prevention of colorectal and other cancers, and the prevention of cancer recurrence, including in the Japanese population. Reduction in the incidence of colorectal cancer may influence the overall benefit­risk profile of aspirin. Further analyses of [this] study data are planned, including analysis of deaths associated with cancers, to allow more precise identification of the patients for whom aspirin treatment may be most beneficial.”
(doi:10.1001/jama.2014.15690; 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: When Should Aspirin Be Used for Prevention of Cardiovascular Events?

J. Michael Gaziano, M.D., M.P.H., of the Veterans Affairs Boston Healthcare System, Brigham and Women’s Hospital, Harvard Medical School, Boston, and Associate Editor, JAMA, and Philip Greenland, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, and Senior Editor, JAMA, write in an accompanying editorial that the findings from this study adds to the body of evidence that helps refine the answer to the question of when aspirin should be used to prevent vascular events.

“Decision making involves an assessment of individual risk-to-benefit that should be discussed between clinician and patient. However, at present the choice of aspirin remains clear in several situations. Aspirin is indicated for patients at high short-term risk due to an acute vascular event and those undergoing certain vascular procedures; patients with any evidence of vascular disease should be given daily aspirin. On the other hand, patients at very low risk of vascular events should not take aspirin for prevention of vascular events, even at low dose.”

“However, some individuals who do not have overt vascular disease will have risk levels that approach those of patients with CVD (such as patients with multiple risk factors). It remains likely that there is some level of risk of CVD events that would result in a positive trade-off of benefit and risk for the use of aspirin, but the precise level of risk is uncertain.”
(doi:10.1001/jama.2014.16047; 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: 7 A.M. (CT) MONDAY, NOVEMBER 17, 2014
Media Advisory: To contact Mikhail Kosiborod, M.D., call Laurel Gifford at 816-502-8532 or email lgifford@saint-lukes.org. To contact editorial author Bradley S. Dixon, M.D., call Tom Moore at 319-356-3945 or email thomas-moore@uiowa.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15688. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15736

Drug Helps Lower High Potassium Levels Associated With Potentially Lethal Cardiac Arrhythmias

Mikhail Kosiborod, M.D., of Saint Luke’s Mid America Heart Institute, Kansas City, and colleagues evaluated the efficacy and safety of the drug zirconium cyclosilicate in patients with hyperkalemia (higher than normal potassium levels). The study appears in JAMA and is being released to coincide with its presentation at the American Heart Association’s Scientific Sessions 2014.

Hyperkalemia is a common electrolyte disorder which can cause potentially life-threatening cardiac arrhythmias and is associated with chronic kidney disease, heart failure, and diabetes mellitus. There is a lack of effective and safe therapies for the management of this disorder in the outpatient setting. Sodium zirconium cyclosilicate (zirconium cyclosilicate) is an agent designed to entrap potassium in the intestine, according to background information in the article. In previous studies, this drug was well tolerated and effective in lowering potassium within 48 hours of administration; for this study, outcomes for 28 days were evaluated.

In this phase 3 trial, ambulatory patients with hyperkalemia (n = 258) received zirconium cyclosilicate three times daily in the initial 48-hour open-label phase. Patients (n = 237) achieving normal potassium levels were then randomized to receive zirconium cyclosilicate, 5 g (n = 45 patients), 10 g (n = 51), or 15 g (n = 56), or placebo (n = 85) daily for 28 days. Patients were recruited from 44 sites in the United States, Australia, and South Africa.

The researchers found that zirconium cyclosilicate was effective both in rapidly lowering potassium to normal range and maintaining normal potassium levels for up to 4 weeks in patients with various degrees of hyperkalemia. The potassium-lowering effect of zirconium cyclosilicate was consistent across all patient subgroups and observed immediately (after 1 hour of the first dose), and normal levels of potassium was achieved in 84 percent of the patients within 24 hours and 98 percent within 48 hours of treatment initiation. Compared with placebo, all three doses of zirconium cyclosilicate resulted in significantly higher proportions of patients with normal potassium levels for up to 28 days. These outcomes occurred with a tolerability profile that was comparable with that of placebo.

“Further studies are needed to evaluate the efficacy and safety of zirconium cyclosilicate beyond 4 weeks and to assess long-term clinical outcomes,” the authors write.
(doi:10.1001/jama.2014.15688; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was sponsored and funded by ZS Pharma. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Zirconium Cyclosilicate for Treatment of Hyperkalemia

Bradley S. Dixon, M.D., of the Veterans Administration Medical Center and the University of Iowa, Iowa City, comments on the findings of this study in an accompanying editorial.

“The findings reported by Kosiborod et al suggest that zirconium cyclosilicate may represent a promising new therapy for the acute and short-term (i.e., 28-day) treatment of outpatients with mild hyperkalemia. However, longer-term studies are needed to assess the clinical benefits and risks that may be related to more extended use of this product, especially among hospitalized patients, as well as those with more severe hyperkalemia, other medical conditions, and other medications that affect potassium [levels].”
(doi:10.1001/jama.2014.15736; 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: 8:30 A.M. (CT) SATURDAY, NOVEMBER 15, 2014
Media Advisory: To contact corresponding author John S. Gill, M.D., M.S., email Dave Lefebvre at dlefebvre@providencehealth.bc.ca.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14721.

Administration of Antibiotic Following Kidney Transplantation Does Not Prevent Virus Infection

Among kidney transplant recipients, a 3-month course of the antibiotic levofloxacin following transplantation did not prevent the major complication known as BK virus from appearing in the urine. The intervention was associated with an increased risk of adverse events such as bacterial resistance, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the American Society of Nephrology’s annual Kidney Week meeting.

Kidney transplantation is the preferred treatment for end­stage renal disease. The development of potent immunosuppressant medications has reduced the incidence of acute rejection to less than 10 percent; however, immunosuppression can lead to reactivation of the BK virus, a polyomavirus which has a prevalence of 60 percent to 80 percent in the general population. BK virus infection progresses through discrete stages, appearing first in the urine (BK viruria), which is associated with a high risk of transplant failure. There are currently no therapies to prevent or treat BK virus infection. Quinolone antibiotics have antiviral properties against BK virus but efficacy at preventing this infection has not been shown in prospective controlled studies, according to background information in the article.

Greg A. Knoll, M.D., of the Ottawa Hospital Research Institute and University of Ottawa, Ontario, Canada, and colleagues randomly assigned 154 patients who received a living or deceased donor kidney-only transplant in 7 Canadian transplant centers to receive a 3-month course of levofloxacin (n = 76) or placebo (n = 78) starting within 5 days after transplantation. Patients were tested for occurrence of BK viruria within the first year after transplantation.

The overall average follow-up time was 46.5 weeks in the levofloxacin group and 46.3 weeks in the placebo group; 27 patients had follow-up terminated before end of the planned follow-up period or development of viruria because the trial was stopped early because of lack of funding. BK viruria occurred in 22 patients (29 percent) in the levofloxacin group and in 26 patients (33.3 percent) in the placebo group.

Analysis of other virologic measures including occurrence of BK viremia (virus in the blood), peak urine and blood viral loads, and time to sustained viruria showed that such measures were not significantly different between groups. There was an increased risk of resistant infection associated with isolates usually sensitive to quinolones in the levofloxacin group (58 percent vs 33 percent) and also a nonsignificant increase in suspected tendinitis (8 percent vs. 1 percent).

“These findings do not support the use of levofloxacin to prevent posttransplantation BK virus infection,” the authors conclude.
(doi:10.1001/jama.2014.14721; 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: 8:30 A.M. (CT) SATURDAY, NOVEMBER 15, 2014
Media Advisory: To contact Amit X. Garg, M.D., Ph.D., email Crystal Mackay at crystal.mackay@schulich.uwo.ca. To contact editorial co-author Wolfgang C. Winkelmayer, M.D., M.P.H., Sc.D., email Julia Parsons at Julia.Parsons@bcm.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15284. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14548.

Use of Aspirin or Blood Pressure Medication Before and After Surgery Does Not Reduce Risk of Kidney Injury

In patients undergoing noncardiac surgery, neither aspirin nor clonidine (a medication primarily used to treat high blood pressure) taken before and after surgery reduced the risk of acute kidney injury, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the American Society of Nephrology’s annual Kidney Week meeting.

About 10 percent of the 200 million adults estimated to undergo major noncardiac surgery each year develop acute kidney injury (a sudden loss of kidney function). Perioperative (around the time of surgery) acute kidney injury is associated with poor outcomes, a long hospital stay, and high health care costs. Some studies suggest aspirin or clonidine administered during the perioperative period reduces the risk of acute kidney injury; however these effects are uncertain and each intervention has the potential for harm (bleeding with aspirin and abnormally low blood pressure with clonidine), which could increase the risk of acute kidney injury, according to background information in the article.

Amit X. Garg, M.D., Ph.D., of the London Health Sciences Centre and Western University, London, Ontario, Canada, and colleagues randomly assigned 6,905 patients undergoing noncardiac surgery from 88 centers in 22 countries to take aspirin (200 mg) or placebo 2 to 4 hours before surgery and then aspirin (100 mg) or placebo daily up to 30 days after surgery; oral clonidine (0.2 mg) or placebo 2 to 4 hours before surgery, and then a transdermal clonidine patch (applied to the skin) or placebo patch that remained until 72 hours after surgery. Acute kidney injury was primarily defined as a certain increase in serum creatinine concentration (a substance commonly found in blood, urine, and muscle tissue and used as an indicator of kidney function).

The researchers found that neither aspirin nor clonidine reduced the risk of acute kidney injury. The percentage of patients in each study group who experienced acute kidney injury: aspirin 13.4 percent vs 12.3 percent (placebo); clonidine 13.0 percent vs 12.7 percent (placebo).

Aspirin increased the risk of major bleeding. In turn, major bleeding was associated with a greater risk of subsequent acute kidney injury (23.3 percent when bleeding was present vs 12.3 percent when bleeding was absent). Similarly, clonidine increased the risk of clinically important hypotension (abnormally low blood pressure). Such hypotension was associated with a greater risk of subsequent acute kidney injury (14.3 percent when hypotension was present vs 11.8 percent when hypotension was absent).

The authors write that future large trials to prevent acute kidney injury in the surgical setting should focus on interventions that target pathways other than inhibiting platelet aggregation and alpha 2-adrenergic agonism. “Interventions that prevent perioperative bleeding and perioperative hypotension may prove useful.”
(doi:10.1001/jama.2014.15284; 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: Prevention of Acute Kidney Injury Using Vasoactive or Antiplatelet Treatment

Wolfgang C. Winkelmayer, M.D., M.P.H., Sc.D., of the Baylor College of Medicine, Houston, and Associate Editor, JAMA, and Kevin W. Finkel, M.D., of the University of Texas Medical School, Houston, comment on this study in an accompanying editorial.

“In their contribution, Garg and colleagues once again have embarked on a promising mechanism to generate evidence for kidney outcomes, which involved partnering with investigators of large cardiovascular trials and proposing (and then executing) ancillary studies of kidney-relevant end points. Given the disproportionate paucity of randomized trials in nephrology, this is a useful and economical approach, especially in light of the many risk factors that cardiovascular disease and both acute and chronic kidney disease share. It is almost unfathomable that funding agencies would have funded a stand-alone trial of interventions for the primary prevention of acute kidney injury of the size and scope of [this study].”
(doi:10.1001/jama.2014.14548; 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: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact Stefanie Schulz-Schupke, M.D., email schulzs@dhm.mhn.de.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15305

Comparison of Outcomes, Complications For Methods to Achieve Artery Closure Following Coronary Angiography

Stefanie Schulz-Schupke, M.D., of the Deutsches Herzzentrum Munchen, Technische Universitat, Munich, Germany and colleagues assessed whether vascular closure devices are noninferior (not worse than) to manual compression in terms of access site-related vascular complications in patients undergoing diagnostic coronary angiography. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Percutaneous (through the skin) coronary angiography and interventions have become a cornerstone in the diagnosis and treatment of coronary artery disease. A substantial proportion of the adverse effects associated with these procedures is related to access-site complications. The common femoral artery (a large artery in the groin) is still the most frequently used access site. After the procedure, closure of the artery access site is usually achieved by manual compression. Since the mid-1990s, however, vascular closure devices (VCDs) have been introduced into clinical practice with the aim of improving efficacy and safety. Different types of VCDs have been developed, including intravascular and extravascular. However, concern exists about the safety of VCDs in comparison with manual compression, according to background information in the article.

For this study, conducted at four centers in Germany, 4,524 patients undergoing coronary angiography via the common femoral artery were randomly assigned to receive an intravascular VCD (n = 1,509), extravascular VCD (n = 1,506), or manual compression (n = 1,509) to achieve hemostasis (defined as no bleeding or only light superficial bleeding and no expanding hematoma [a localized swelling filled with blood]). Before hospital discharge, imaging of the access site was performed in 4,231 (94 percent) patients.

The primary end point (the composite of access site-related vascular complications at 30 days after randomization with a two percent noninferiority margin) was observed in 208 patients (6.9 percent) assigned to receive a VCD and 119 patients (7.9 percent) assigned to manual compression (difference, -1.0 percent). In addition, the time to hemostasis was significantly shorter with VCD compared with manual compression; time to hemostasis was shorter with intravascular VCD vs extravascular VCD; and device failures were less frequent with intravascular VCD vs extravascular VCD.

The authors write that the results of this trial may represent an important development for the clinical use of these devices. “Overall, the increase in efficacy of VCD use, with no trade-off in safety, provides a sound rationale for the use of VCD over manual compression in daily routine.”
(doi:10.1001/jama.2014.15305; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was funded by the Deutsches Herzzentrum Munchen, Munich, Germany. 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: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact Giulio Conte, M.D., email giulioconte.cardio@gmail.com.

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Follow-up Testing Indicated After Initial Negative Test for Inherited Cardiac Syndrome That Can Cause Sudden Death

Giulio Conte, M.D., of the Heart Rhythm Management Centre, UZ Brussel-VUB, Brussels, Belgium and colleagues investigated the clinical significance of repeat testing after puberty in asymptomatic children with a family history of Brugada syndrome who had an initial negative test earlier in childhood. Brugada syndrome is a genetic disease that is characterized by abnormal electrocardiogram findings without structural heart disease and an increased risk of sudden cardiac death. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Brugada syndrome can present within the first months of life, although more typically in the fourth or fifth decade. Testing using ajmaline (an alkaloid) challenge is recommended, as it is an antiarrhythmic agent that can bring out the diagnostic electrocardiogram (ECG) pattern typical in patients suspected of having Brugada syndrome. Although screening of first-degree relatives is common, no evidence-based guidelines exist, particularly for children with normal ECGs, according to background information in the article.

The study included 53 asymptomatic individuals with a first-degree relative with Brugada syndrome and negative ajmaline test performed before 16 years of age between 1992 and 2010 who were seen at the university hospital of Brussels, Belgium (UZ Brussel­ VUB) and had an ECG repeated annually and were scheduled to repeat the test after puberty. Nine individuals were younger than 16 years and 1 presented with spontaneous Brugada type 1 ECG at age 16 years. The remaining 43 individuals repeated the ajmaline test, which unmasked type 1 ECG in 10 patients (23 percent).

“The ECG phenotype does not appear during childhood in most cases, but may develop later in response to hormonal, autonomic, or genetic factors,” the authors write.

“Screening of asymptomatic first-degree relatives of patients with Brugada syndrome is advisable, although the ideal timing is unknown. Relatives developing symptoms should always be investigated with ajmaline challenge even if they had a negative drug test performed before puberty. These findings support the need for repeat monitoring of family members of patients with Brugada syndrome, including those initially considered at low risk because of young age.”
(doi:10.1001/jama.2014.13752; 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: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact corresponding author Manesh R. Patel, M.D., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

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Study Examines Prevalence, Risk of Death of Type of Coronary Artery Disease in Heart Attack Patients

Duk-Woo Park, M.D., of the University of Ulsan College of Medicine, Seoul, Korea, and Manesh R. Patel, M.D., of the Duke Clinical Research Institute, Durham, N.C., and colleagues investigated the incidence, extent, and location of obstructive non-infarct-related artery (IRA) disease and compared 30-day mortality according to the presence of non-IRA disease in patients with ST-segment elevation myocardial infarction (STEMI; a certain pattern on an electrocardiogram following a heart attack). Obstructive non-IRA disease is blockage in arteries not believed to be the cause of a heart attack. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Acute STEMI is the leading cause of sudden cardiac death and typically arises from the blockage of a coronary artery. Because the presence of significant non-IRA disease in patients with STEMI has been found to be associated with recurrent angina, repeat revascularization, and worse prognosis, a comprehensive estimation of the extent and location of obstructive non-IRA disease may be clinically important information for physicians in the development of optimal treatment strategies, according to background information in the article.

The study included a sample of patients from eight international, randomized STEMI clinical trials published between 1993 and 2007. Among 68,765 patients enrolled in the trials, 28,282 patients with valid angiographic information were included in this analysis. Follow-up varied from 1 month to 1 year. To assess the generalizability of trial-based results, external validation was performed using observational data for patients with STEMI from the Korea Acute Myocardial Infarction Registry (KAMIR; n = 18,217) and the Duke Cardiovascular Databank (n = 1,812).

The researchers found that 53 percent of patients (n = 14,929) had non-IRA disease and there were no substantial differences in the extent and location of non-IRA disease according to the IRA territory (muscle or area served by the suspected heart attack artery with the blockage). The presence of non-IRA disease was significantly associated with increased 30-day mortality, compared to patients without non-IRA disease (3.3 percent vs 1.9 percent). The overall prevalence and association of non-IRA disease with 30-day mortality was consistent with findings from the KAMIR registry, but not with the Duke database.

“These findings require confirmation in prospectively designed studies, but raise questions about the appropriateness and timing of non­IRA revascularization in patients with STEMI,” the authors write.
(doi:10.1001/jama.2014.15095; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported in part by the John Bush Simson Fund. The statistical portion of the manuscript was funded by the Duke Clinical Research Institute. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact Lars H. Lund, M.D., Ph.D., email lars.lund@alumni.duke.edu. To contact editorial co-author Marc A. Pfeffer, M.D., Ph.D., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org.

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Use of Beta-Blockers by Patients with Certain Type of Heart Failure Associated With Improved Rate of Survival

Lars H. Lund, M.D., Ph.D., of the Karolinska Institutet, Stockholm, Sweden, and colleagues conducted a study to examine whether beta-blockers are associated with reduced mortality in heart failure patients with preserved ejection fraction (a measure of how well the left ventricle of the heart pumps with each contraction).The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Up to half of patients with heart failure have normal or near-normal ejection fraction, termed heart failure with preserved ejection fraction (HFPEF). The risk of death in HFPEF may be as high as in heart failure with reduced ejection fraction (HFREF), but there is no proven therapy. Beta-blockers improve outcomes in HFREF and may be beneficial in HFPEF, but data are sparse and inconclusive, and beta-blockers are currently not indicated for treating HFPEF, according to background information in the article.

The researchers used data from the Swedish Heart Failure Registry, which includes 67 hospitals with inpatient and outpatient units and 95 outpatient primary care clinics in Sweden. This analysis included 41,976 patients, 19,083 patients with HFPEF. Of these, 8,244 were matched 2:1 based on age and beta-blocker use, yielding 5,496 treated and 2,748 untreated patients with HFPEF. Another analysis involved 22,893 patients with HFREF, of whom 6,081were matched, yielding 4,054 treated with beta-blockers and 2,027 untreated patients.

In the matched HFPEF cohort, 5-year survival was 45 percent vs 42 percent for treated vs untreated patients, with 2,279 (41 percent) vs 1,244 (45 percent) total deaths, and a seven percent reduction in the risk of death. Beta-blockers were not associated with reduced combined mortality or heart failure hospitalizations: 3,368 (61 percent) vs 1,753 (64 percent) total for first events. In the matched HFREF cohort, beta-blockers were associated with reduced mortality and also with reduced combined mortality or heart failure hospitalization.

“In patients with HFPEF, use of beta-blockers was associated with lower all-cause mortality but not with lower combined all­cause mortality or heart failure hospitalization,” the authors write. “Beta-blockers in HFPEF should be examined in a large randomized clinical trial.”
(doi:10.1001/jama.2014.15241; 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: Searching for Treatments of Heart Failure with Preserved Ejection Fraction – Matching the Data to the Question

In an accompanying editorial, Susan Cheng, M.D., M.P.H., and Marc A. Pfeffer, M.D., Ph.D., of Brigham and Women’s Hospital, Boston, write that by design, administrative databases, such as the one used in this study, offer limited ability to provide complete information about potentially important confounders.

“Thus, an attempt to use administrative data to probe the potential efficacy of a therapy is a mismatch of the data to the question. However, for most questions in medicine, only incomplete data are available to guide diagnostic and therapeutic decisions, and observational studies may have a role in assisting with treatment options. As the authors also conclude, more definitive information about whether beta-blocker therapy is effective for preventing important outcomes in HFPEF requires well-designed and well­ conducted randomized clinical trials.”
(doi:10.1001/jama.2014.15358; 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: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact Vivek Y. Reddy, M.D., call Lauren Woods at 646-634-0869 or email Lauren.Woods@mountsinai.org.

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Implanted Device Shows Potential as Alternative to Warfarin for Stroke Prevention in Patients with Atrial Fibrillation

Vivek Y. Reddy, M.D., of the Icahn School of Medicine at Mount Sinai, New York, and colleagues examined the long-term efficacy and safety, compared to warfarin, of a device to achieve left atrial appendage closure in patients with atrial fibrillation. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

The left atrial appendage (LAA) is a pouch-like appendix located in the upper left chamber of the heart. Studies have suggested that the LAA is the major source of clots that block blood vessels in patients with atrial fibrillation (AF). This has led to the development of mechanical approaches (via percutaneous catheters) to close the LAA. Oral anticoagulation with warfarin has been the mainstay of treatment for prevention of cardioembolic stroke in AF. Although effective, warfarin is limited by a need for lifelong coagulation monitoring and multiple medication and food interactions, according to background information in the article.

This study included 707 patients with nonvalvular AF and at least 1 additional stroke risk factor who were randomly assigned to LAA closure with a device (WATCHMAN; Boston Scientific) (n = 463) or warfarin (n = 244). The study was conducted at 59 hospitals in the U.S. and Europe.

At an average follow-up of 3.8 years, there were 39 events (stroke, systemic embolism [blood clot], and cardiovascular death) among 463 patients (8.4 percent) in the device group, compared with 34 events among 244 patients (13.9 percent) in the warfarin group, with the difference in the event rate indicating that LAA closure met prespecified criteria for both noninferiority (not worse than) and superiority compared with warfarin. LAA closure reduced the relative risk of a composite of these events by 40 percent (1.5 percent absolute reduction) compared with warfarin anticoagulation.

Patients in the device group demonstrated lower rates of both cardiovascular death (3.7 percent vs 9.0 percent of patients) and all-cause death (12.3 percent vs 18.0 percent of patients), with the device-based strategy associated with a 60 percent relative risk reduction (1.4 percent absolute reduction) of cardiovascular death and 34 percent relative reduction (5.7 percent absolute reduction) in all-cause death. The authors note that these mortality end points are secondary end points, and due to multiplicity of data analysis, there is some uncertainty in the confidence of this conclusion.

Although the device implantation procedure was associated with early complications, the accumulation of complications related to chronic anticoagulation resulted in similar safety profiles for the two groups.
(doi:10.1001/jama.2014.15192; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by the manufacturer of the device, Atritech (now owned by Boston Scientific) which provided the LAA closure device used in this trial. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact Matthew D. Ritchey, D.P.T., call Kate Grusich at 770-488-3337 or email yhb3@cdc.gov.

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Overall Death Rate from Heart Disease Declines, Although Increase Seen for Certain Subtypes

Matthew D. Ritchey, D.P.T., of the Centers for Disease Control and Prevention (CDC), Atlanta, and colleagues examined the contributions of heart disease subtypes to overall heart disease mortality trends during 2000-2010. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Despite considerable information on overall heart disease (HD) and coronary HD (CHD) mortality trends, less is known about trends for other HD subtypes. The researchers analyzed mortality data from the CDC WONDER database, which contains death certificate information from every U.S. state and the District of Columbia. Deaths were included that occurred during 2000-2010 among U.S. residents 35 years or older with an underlying cause of death coded as CHD, heart failure, hypertensive HD (HHD), valvular HD, arrhythmia, pulmonary HD, or other HD.

During 2000-2010, there were 7,102,778 HD deaths. The mortality rates declined annually for total HD (-3.8 percent) and CHD (-5.1 percent). Mortality increased annually for HHD (1.3 percent) and arrhythmia (1.0 percent) and declined for most other subtypes. Although the HHD rate increased among non-Hispanic whites and was unchanged among non-Hispanic blacks, it remained much higher among non-Hispanic blacks in 2010. In 2010, excluding CHD and other HD, the leading cause of HD-related death was HHD among adults 35 to 54 years of age (12.1 percent) and those 55 to 74 years of age (6.7 percent); among those 75 years or older, it was heart failure (12.2 percent).

The authors write that although the proportions of HD deaths attributable to HHD and arrhythmia are relatively small, their mortality rate increases are notable. “Uncontrolled blood pressure and obesity among younger adults, especially non-Hispanic blacks, may be putting them at risk for developing HHD at an early age. … These increases might be linked to an aging population, the sequelae of persons living longer with heart failure, increases in chronic kidney disease and HHD prevalence, and possible changes in how arrhythmias are diagnosed and reported on death certificates.”

“Despite a continued decrease in overall HD mortality, considerable burden still exists. Public health and clinical communities should continue to develop and rigorously apply evidence-based interventions to prevent and treat CHD as well as other HD subtypes such as HHD and arrhythmia,” the authors conclude.
(doi:10.1001/jama.2014.11344; 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: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact corresponding author George A. Stouffer, M.D., call Tom Hughes at 984-974-1151 or email Tom.Hughes@unchealth.unc.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15236

Risk of Death May Be Higher if Heart Attack Occurs in a Hospital

Prashant Kaul, M.D., of the University of North Carolina, Chapel Hill, and colleagues conducted a study to define the incidence and treatment and outcomes of patients who experience a certain type of heart attack during hospitalization for conditions other than acute coronary syndromes. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Early restoration of blood flow with percutaneous coronary intervention (PCI; a procedure such as stent placement used to open narrowed coronary arteries) or administration of medication to dissolve a clot remains the primary goal in the initial treatment of eligible patients presenting to a hospital with ST-elevation myocardial infarction (STEMI; a certain pattern on an electrocardiogram following a heart attack). Over the last decade, recognition that this strategy is of critical importance has prompted the development of a number of regional and national initiatives to facilitate and improve systems of care for STEMI. These initiatives have focused exclusively on patients who develop STEMI outside of a hospital setting (outpatient-onset STEMI), and little is known about the incidence and outcomes of STEMI in patients hospitalized for non-acute coronary syndrome (ACS) conditions (inpatient­onset STEMI), according to background information in the article.

This study included an analysis of STEMIs occurring between 2008 and 2011 as identified in the California State Inpatient Database. Models were used to evaluate associations among location of onset of STEMI, resource utilization and outcomes. A total of 62,021 STEMIs were identified in 303 hospitals, of which 3,068 (4.9 percent) occurred in patients hospitalized for non-ACS indications.

The researchers found that patients developing inpatient-onset STEMI had more than 3-fold greater in-hospital mortality than those with outpatient-onset STEMI (33.6 percent vs 9.2 percent). Patients with inpatient-onset STEMI were less likely to be discharged home (33.7 percent vs 69.4 percent), and were less likely to undergo cardiac catheterization (33.8 percent vs 77.8 percent) or PCI (21.6 percent vs 65 percent). Average length of stay (13 days vs 5 days) and inpatient charges ($245,000 vs $129,000) were higher for inpatient-onset STEMI. Patients with inpatient-onset STEMI were older and more frequently female.

“The question of how to improve outcomes and define optimum treatment in hospitalized patients who experience a STEMI is an area that merits more attention and concern. Although there have been improvements in treatment times and clinical outcomes in outpatients who have onset of STEMI, few initiatives have focused on optimizing care of hospitalized patients with onset of STEMI after admission,” the authors write.
(doi:10.1001/jama.2014.15236; 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: 3:30 P.M. (CT) THURSDAY, NOVEMBER 13, 2014
Media Advisory: To contact co-author Alexander P. Reiner, M.D., call Kristen Lidke Woodward at 206-972-4333 or email kwoodwar@fredhutch.org.

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Sickle Cell Trait Among African Americans Associated With Increased Risk of Chronic Kidney Disease

In a study that included nearly 16,000 African Americans, those with sickle cell trait had an associated increased risk of chronic kidney disease and measures linked to poorer kidney function, according to a study appearing in JAMA. Sickle cell trait is a condition in which a person has only one copy of the gene for sickle cell but does not have sickle cell disease (which requires two copies of this gene). The study is being released to coincide with its presentation at the American Society of Nephrology’s annual Kidney Week meeting.

It is estimated that sickle cell trait (SCT) affects 1 in 12 African Americans and nearly 300 million people worldwide. The relationship of SCT to long-term functional impairment of the kidney has not been firmly established, according to background information in the article.

Using five large, U.S. population-based studies, Rakhi P. Naik, M.D., of Johns Hopkins University, Baltimore, and Vimal K. Derebail, M.D., of the University of North Carolina at Chapel Hill, and colleagues evaluated 15,975 self-identified African Americans (1,248 patients with SCT [SCT carriers] and 14,727 patients without SCT [noncarriers]) to examine the relationship between SCT and chronic kidney disease (CKD) and albuminuria (the presence of excessive protein in the urine, often a symptom of a kidney disorder). The studies included in the analysis were the Atherosclerosis Risk in Communities Study (ARIC); Jackson Heart Study (JHS); Coronary Artery Risk Development in Young Adults (CARDIA); Multi-Ethnic Study of Atherosclerosis (MESA); and the Women’s Health Initiative (WHI).

Chronic kidney disease (defined as a certain measure of estimated glomerular filtration rate [eGFR; the flow rate of filtered fluid through the kidney]) was present in 2,233 individuals (239 of 1,247 SCT carriers [19.2 percent) vs 1,994 of 14,722 noncarriers [13.5 percent]). A total of 20.7 percent of SCT carriers vs 13.7 percent of noncarriers experienced incident CKD. Sickle cell trait was significantly associated with a faster decline in eGFR; 22.6 percent of SCT carriers vs 19.0 percent of noncarriers from the 5 cohorts experienced eGFR decline; 31.8 percent of SCT carriers had albuminuria vs 19.6 percent of noncarriers.

“Our findings show an association of SCT with the development of CKD in African Americans,” the authors write.

The researchers add that the associations found in this study may offer an additional genetic explanation for the increased risk of CKD observed among African Americans compared with other racial groups. “Our study also highlights the need for further research into the renal complications of SCT. Because screening for SCT is already being widely performed, accurate characterization of disease associations with SCT is critical to inform policy and treatment recommendations.”
(doi:10.1001/jama.2014.15063; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 11, 2014
Media Advisory: To contact Adriaan J. van der Meer, M.D., Ph.D., email a.vandermeer@erasmusmc.nl.

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Study Examines Life Expectancy Among Patients With Chronic Hepatitis C Virus Infection and Cirrhosis

Patients with chronic hepatitis C virus infection and advanced fibrosis or cirrhosis who attained sustained virological response (SVR) had survival comparable with that of the general population, whereas patients who did not attain SVR had reduced survival, according to a study in the November 12 issue of JAMA.

Almost three million people in the United States are chronically infected with the hepatitis C virus (HCV). The life expectancy of patients with chronic HCV infection is reduced compared with the general population, largely attributable to the development of cirrhosis, liver failure and cancer. Studies have shown that the risk of all-cause death is lower among patients with chronic HCV infection and advanced hepatic (liver) fibrosis (development of excess fibrous connective tissue) if sustained virological response (SVR) is attained, but comparisons have been limited to those without SVR, according to background information in the article.

Adriaan J. van der Meer, M.D., Ph.D., of the Erasmus MC University Medical Center Rotterdam, the Netherlands, and colleagues compared overall survival of patients with chronic HCV infection and advanced fibrosis or cirrhosis before therapy (with and without SVR) with that of the general population. The researchers used data on patients from Europe and Canada with chronic HCV and advanced hepatic fibrosis from a previous study. Follow-up started 24 weeks after cessation of antiviral treatment, at which time achievement of SVR (defined as HCV RNA negativity in a blood sample) was determined. For each virological response group, the observed overall survival was compared with the expected survival from matched age-, sex- and calendar time–specific death rates of the general population in the Netherlands.

In total, 530 patients were followed for a median of 8.4 years; follow-up was complete in 454 patients (86 percent), 192 of whom attained SVR. Thirteen patients with SVR died, resulting in a cumulative 10-year overall survival of 91.1 percent, which did not differ significantly from the age- and sex-matched general population. In contrast, 100 patients without SVR died. The cumulative 10-year survival was 74.0 percent, which was significantly lower compared with the matched general population.

“The excellent survival among patients with advanced liver disease and SVR might be explained by the associations between SVR and regression of hepatic inflammation and fibrosis, reduced hepatic venous pressure gradient, reduced occurrence of hepatocellular carcinoma and liver failure, as well as reduced occurrence of diabetes mellitus, end-stage renal disease, and cardiovascular events. Even though patients with cirrhosis and SVR remain at risk for hepatocellular carcinoma, the annual hepatocellular carcinoma incidence is low and survival is substantially better compared with those without SVR,” the authors write.
(doi:10.1001/jama.2014.12627; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 11, 2014
Media Advisory: To contact Ziad Obermeyer, M.D., M.Phil., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org. To contact editorial co-author Joan M. Teno, M.D., M.S., call David Orenstein at 401-863-1862 or email david_orenstein@brown.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14950. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14949

Use of Hospice Care by Medicare Patients Associated With Lower Rate of Hospitalization, ICU Admission, Invasive Procedures and Costs

Medicare patients with poor­ prognosis cancers who received hospice care had significantly lower rates of hospitalization, intensive care unit (ICU) admissions and invasive procedures at the end of life, along with significantly lower health care expenditures during the last year of life, according to a study in the November 12 issue of JAMA.

Multiple studies have documented the high intensity of medical care at the end of life, and there is increasing consensus that such care can produce poor outcomes and conflict with patient preferences. The Institute of Medicine report Dying in America has drawn attention to the difficulties of promoting palliative care, including Medicare’s hospice program, the largest palliative care intervention in the United States, which covers all comfort­oriented care related to terminal illnesses from medications to home care to hospitalizations. More patients with cancer use hospice currently than ever before, but there are indications that care intensity outside of hospice is increasing, and length of hospice stay decreasing. Uncertainties regarding how hospice affects health care utilization and costs have hampered efforts to promote it, according to background information in the article.

Using data from Medicare beneficiaries with poor-prognosis cancers (e.g., brain, pancreatic, metastatic malignancies), Ziad Obermeyer, M.D., M.Phil., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues matched those enrolled in hospice before death to those who died without hospice care and compared utilization and costs at the end of life. The study included a nationally representative 20 percent sample of Medicare fee-for-service beneficiaries who died in 2011.

Among 86,851 patients with poor-prognosis cancers, 51,924 (60 percent) entered hospice before death. Matching patients based on various criteria produced a hospice and nonhospice group, each with 18,165 patients. Median hospice duration was 11 days.

The researchers found that nonhospice beneficiaries had significantly greater health care utilization, largely for acute conditions not directly related to cancer and higher overall costs. Rates of hospitalizations (65 percent vs 42 percent), ICU admissions (36 percent vs 15 percent), invasive procedures (51 percent vs 27 percent), and death in a hospital or nursing facility (74 percent vs 14 percent) were higher for nonhospice beneficiaries compared to hospice patients. Overall, costs during the last year of life were $62,819 for hospice beneficiaries and $71,517 for nonhospice beneficiaries.

“Our findings highlight the potential importance of frank discussions between physicians and patients about the realities of care at the end of life, an issue of particular importance as the Medicare administration weighs decisions around reimbursing physicians for advance care planning,” the authors write.
(doi:10.1001/jama.2014.14950; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by grants from the National Institutes of Health, National Cancer Institute, and Agency for Healthcare Research and Quality. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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

Editorial: Quality and Costs of End-of-Life Care

Joan M. Teno, M.D., M.S., and Pedro L. Gozalo, Ph.D., of the Brown University School of Public Health, Providence, R.I., comment on end-of-life care in an accompanying editorial.

“As financial incentives change in the U.S. health care system, valid measures of care quality are increasingly important for ensuring transparency and accountability. Obermeyer and colleagues assessed hospitalization rates, intensive care admissions, and invasive procedures, but additional measures must have evidence of their ability to discriminate the quality of care and must be responsive to change, easy to understand, and actionable. This will involve investing public dollars in the ‘quality’ of quality measures and their dissemination. If quality of care is not front and center, the momentum to improve end-of-life care in the United States could face a serious setback.”
(doi:10.1001/jama.2014.14949; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Teno is the recipient of a Robert Wood Johnson Foundation Health Policy Investigators Award grant. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 11, 2014
Media Advisory: To contact Elyse O. Kharbanda, M.D., M.P.H., email Patricia Lund at Patricia.A.Lund@healthpartners.com.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14825

Administration of Tdap Vaccine During Pregnancy Not Associated With Increased Risk of Preterm Delivery, Small Birth Size

Among approximately 26,000 women, receipt of the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine during pregnancy was not associated with increased risk of preterm delivery or small-for-gestational-age birth or with hypertensive disorders of pregnancy, although a small increased risk of being diagnosed with chorioamnionitis (an inflammation of the membranes that surround the fetus) was observed, according to a study in the November 12 issue of JAMA.

The Tdap vaccine was licensed in 2005 for use in nonpregnant adolescents and adults. Initially, postpartum administration of Tdap to parents and other caregivers was encouraged to prevent the transmission of pertussis to newborns. However, recent outbreaks, including infant deaths, have led to changing Tdap vaccine recommendations. In 2010, California became the first state to recommend Tdap be routinely administered during pregnancy. Tdap is now recommended by the Advisory Committee on Immunization Practices for all pregnant women, preferably between 27 and 36 weeks’ gestation. To date, there have been limited specific data on whether vaccination with Tdap during pregnancy adversely affects the health of mothers or their offspring, according to background information in the article.

Elyse O. Kharbanda, M.D., M.P.H., of the HealthPartners Institute for Education and Research, Minneapolis, and colleagues used administrative health care databases from 2 California Vaccine Safety Datalink sites to examine whether receipt of Tdap during pregnancy was associated with increased risks of selected adverse obstetric or birth outcomes. Included in the analysis were 123,494 women with pregnancies ending in a live birth between January 1, 2010 and November 15, 2012; 26,229 (21 percent) received Tdap during pregnancy and 97,265 did not.

The researchers found that receipt of Tdap during pregnancy was not associated with increased risk of preterm (<37 weeks’ gestation) or small-for-gestational-age (SGA) births. Among all pregnancies, 8.4 percent of those who received Tdap during pregnancy and 8.3 percent who were unexposed to the vaccine had an SGA birth. The rate of preterm delivery among women receiving Tdap during pregnancy at 36 weeks’ gestation or earlier was 6.3 percent, whereas the rate for unexposed women was 7.8 percent. Receipt of Tdap was not associated with increased risk of hypertensive disorders of pregnancy. Among women who received Tdap at any time during pregnancy, 6.1 percent were diagnosed with chorioamnionitis compared with 5.5 percent of unexposed women. In the subset of women vaccinated between 27 and 36 weeks’ gestation, this risk was still increased but less so. The authors note that these results should be interpreted with caution because the magnitude of the risk was small. “Given limited prior safety data, continued widespread pertussis transmission, and current recommendations to routinely vaccinate during pregnancy, our study provides important information on the safety of Tdap vaccination during pregnancy,” the authors write. (doi:10.1001/jama.2014.14825; Available pre-embargo to the media at https://media.jamanetwork.com) Editor’s Note: This study was funded through a contract from the CDC. Additional funding for chart reviews came from contracts from the CDC Vaccine Safety Datalink infrastructure task order. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc. [ama_toc_item id="29146"] # # #

Long-term Risks and Benefits of Bariatric Surgery
(For Immediate Release)

Bruce M. Wolfe, M.D., of the Oregon Health and Science University, Portland and Steven H. Belle, Ph.D., of the University of Pittsburgh Graduate School of Public Health, discuss the research challenges presented for determining long-term outcomes of bariatric surgery. They write that “metabolic/bariatric surgery offers the potential to address the morbidity and mortality of the obesity epidemic, but important research questions remain unresolved. No single study or research model will successfully address all of these questions. The substantial resources required for a clinical trial large enough with enough follow-up to address important research questions may be impractical, so extending follow-up of well-characterized and established cohorts, potentially with linkage to other data resources, may be the best hope to obtain the information needed to address long-term risks and benefits of bariatric surgery.”
(doi:10.1001/jama.2014.12966)

Behavioral Treatment of Obesity in Patients Encountered in Primary Care Settings
(Embargoed for Release: 3 p.m. CT Tuesday, November 4, 2014)

Thomas A. Wadden, Ph.D., of the University of Pennsylvania Perelman School of Medicine, Philadelphia, and colleagues conducted a systematic review of behavioral counseling for overweight and obese patients recruited from primary care, as delivered by primary care practitioners working alone or with trained interventionists (eg, medical assistants, registered dietitians), or by trained interventionists working independently. The researchers found that intensive behavioral counseling can induce clinically meaningful weight loss, but there is little research on primary care practitioners providing such care. They add that the “findings suggest that a range of trained interventionists, who deliver counseling in person or by telephone, could be considered for treating overweight or obesity in patients encountered in primary care settings.”
(doi:10.1001/jama.2014.14173)

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 4, 2014
Media Advisory: To contact Tsontcho Ianchulev, M.D., M.P.H., call Scott Maier at 415-476-3595 or email scott.maier@ucsf.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13754

Study Finds Google Glasses May Partially Obstruct Peripheral Vision

Testing of study participants who wore head-mounted display systems (Google glasses) found that the glasses created a partial peripheral vision obstruction, according to a study in the November 5 issue of JAMA.

Interest in wearable head-mounted display systems for general consumers is increasing, with multiple models in production. However, their effect on vision is largely unknown. Peripheral visual field is a main component of vision and essential for daily activities such as driving, pedestrian safety, and sports. Conventional spectacle frames can reduce visual field, sometimes causing absolute blind spots, and head­ mounted devices have even more pronounced frames, according to background information in the article.

Tsontcho Ianchulev, M.D., M.P.H., of the University of California, San Francisco, and colleagues compared performance on visual field tests with a head-mounted device vs regular eyewear to quantify their effect on visual function. Three healthy individuals with 20/20 best-corrected visual acuity and normal baseline visual fields were tested in April 2014. Participants used a wearable device (Google Glass, Google Inc.), following manufacturer’s instructions, for a 60-minute acclimation period. Perimetric visual testing (a measurement of the field of vision) was conducted first with the device, followed by a control frame (regular eyewear) of similar color and temple width.

In addition, to assess how the devices are worn by general consumers, photographs of people wearing the product and facing the camera, obtained from an Internet search, were analyzed. Photographs were assessed for prism position relative to the pupil.

Visual field testing demonstrated significant scotomas (blind spots) in all 3 participants while wearing the device, creating a clinically meaningful visual field obstruction in the upper right quadrant. Defects were induced by the Google Glass frame hardware design only and were not related to a distracting effect of software-related interference.

An analysis of 132 images indicated that many people wear the device near or overlapping their pupillary axis (a line perpendicular to the surface of the cornea, passing through the center of the pupil), which may induce scotomas and interfere with daily function.

The authors note that the study is limited by the small number of participants, who may not be representative of all users, and that a larger sample is needed to identify factors that influence scotoma size and depth.

“Additional studies are needed to understand the effects of these devices on visual function, particularly as their use becomes increasingly common,” the authors conclude.
(doi:10.1001/jama.2014.13754; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 4, 2014
Media Advisory: To contact F. Stephen Hodi, M.D., call Teresa Herbert at 617-632-5653 or email teresa_herbert@dfci.harvard.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13943

Combination Treatment for Metastatic Melanoma Results in Longer Overall Survival

Among patients with metastatic melanoma, treatment with a combination of the drugs sargramostim plus ipilimumab, compared with ipilimumab alone, resulted in longer overall survival and lower toxicity, but no difference in progression-free survival, according to a study in the November 5 issue of JAMA.

F. Stephen Hodi, M.D., of the Dana-Farber Cancer Institute, Boston, and colleagues conducted a phase 2 clinical trial in which 245 patients with unresectable (unable to be removed by surgery) stage Ill or IV melanoma were randomly assigned to receive ipilimumab (intravenously) on day 1 plus sargramostim (injected beneath the skin) on days 1 to 14 of a 21-day cycle (n = 123) or ipilimumab alone (n = 122). The researchers compared the effect of these treatments on length of overall survival, progression-free survival, response rate, safety, and tolerability.

Median follow-up was 13.3 months. The overall survival was significantly improved with the addition of sargramostim to ipilimumab. The median overall survival was 17.5 months for the ipilimumab plus sargramostim group and 12.7 months for the ipilimumab-only group. The 1-year overall survival was 68.9 percent for the combination treatment group and 52.9 percent for the ipilimumab-only group. There was no difference in progression-free survival. Adverse events were more common in the ipilimumab-only group. Toxicity was significantly lower in the ipilimumab plus sargramostim group than in the ipilimumab­only group.

“This randomized phase 2 study supports the evidence that the addition of sargramostim to ipilimumab therapy improved overall survival in patients with metastatic melanoma,” the authors write. “These findings require confirmation in larger sample sizes and with longer follow-up.”
(doi:10.1001/jama.2014.13943; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 4, 2014
Media Advisory: To contact Thomas M. Maddox, M.D., M.Sc., call Daniel Warvi at 303-393-5205 or email Daniel.Warvi@va.gov.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14681

Nonobstructive Coronary Artery Disease Associated With Increased Risk of Heart Attack, Death

In a study that included nearly 38,000 patients, those diagnosed with nonobstructive coronary artery disease (CAD) had a significantly increased risk of heart attack or death one year after diagnosis, according to a study in the November 5 issue of JAMA.

Nonobstructive coronary artery disease (CAD) is atherosclerotic plaque that would not be expected to obstruct blood flow or result in anginal symptoms (such as chest pain). Although such lesions are relatively common, occurring in 10 percent to 25 percent of patients undergoing coronary angiography, their presence has been characterized as “insignificant” or “no significant CAD” in the medical literature. However, this perception of nonobstructive CAD may be incorrect, because prior studies have noted that the majority of plaque ruptures and resultant myocardial infarctions (MIs; heart attacks) arise from nonobstructive plaques. Despite the prevalence of nonobstructive CAD identified by coronary angiography, little is known about its risk of adverse outcomes, according to background information in the article.

Thomas M. Maddox, M.D., M.Sc., of the VA Eastern Colorado Health Care System, Denver, and colleagues compared heart attack and mortality rates among patients with nonobstructive CAD, obstructive CAD, and no apparent CAD. The patients included in the study were all U.S. veterans who underwent elective coronary angiography for CAD between October 2007 and September 2012 in the Veterans Affairs health care system. Patients with prior CAD events were excluded. CAD extent was defined by degree of vessel narrowing and distribution (1, 2, or 3 vessel).

During the study period, 37,674 patients underwent elective coronary angiography for indications related to CAD; of those, 22.3 percent had nonobstructive CAD and 55.4 percent had obstructive CAD. Within 1 year, 845 patients died and 385 were rehospitalized for MI. The researchers found that the 1-year MI risk progressively increased by the extent of CAD, rather than abruptly increasing between nonobstructive and obstructive CAD. Patients with nonobstructive CAD had an associated risk of MI that was 2-to 4.5-fold greater than among those with no apparent CAD. Similar observations were seen with 1-year mortality and the combined outcome of 1-year MI and death.

“These findings highlight a need to recognize that nonobstructive CAD is associated with significantly increased risk for MI, consistent with prior biologic studies indicating that a majority of MIs are related to nonobstructive stenosis [narrowing of an artery]. Correspondingly, these results reveal the limitations of a dichotomous [divided into two parts] characterization of angiographic CAD into ‘obstructive’ and ‘nonobstructive’ to predict MI and highlight the importance of preventive strategies such as pharmacotherapy treatments and lifestyle modifications to mitigate these risks,” the authors write.
(doi:10.1001/jama.2014.14681; 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: 11:30 A.M. (CT) SATURDAY, NOVEMBER 1, 2014
Media Advisory: To contact Robert A. Fowler, M.D.C.M., M.S., call Laura Bristow at 416-480-4040 or email laura.bristow@sunnybrook.ca.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15101

Low-Molecular-Weight Heparin More Cost-Effective than Unfractionated Heparin for Preventing Blood Clots in Critically Ill Patients

From a health care payer perspective, prevention of venous thromboembolism (blood clot in a vein) with low-molecular-weight heparin dalteparin in critically ill patients was more effective and had similar or lower costs than the use of unfractionated heparin, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the Critical Care Canada Forum.

A recent randomized trial (PROTECT) comparing the effectiveness of the two most common strategies using drugs to prevent venous thromboembolism (VTE), the anticoagulants low-molecular-weight heparin (LMWH) dalteparin and unfractionated heparin (UFH), found no difference regarding deep-vein thrombosis but reduced rates of pulmonary embolus (clot) and heparin-induced thrombocytopenia (low platelet count) in the patients who received LMWH dalteparin. Drug acquisition costs have historically been higher for LMWH than for UFH. However, if the effects of these drugs on outcomes important to patients differs substantially, paying more may be worth it, which highlights the need for comparative economic and clinical effectiveness research to inform practice, according to background information in the article. Cost is cited as the most important barrier to using LWMH in a recent North American survey.

Robert A. Fowler, M.D.C.M., M.S., of the Sunnybrook Health Sciences Centre, University of Toronto, and colleagues evaluated the comparative cost-effectiveness of LMWH vs UFH for prevention against VTE in critically ill patients. The researchers conducted an economic evaluation concurrent with the PROTECT trial (May 2006 to June 2010), including measured costs among 2,344 patients in 23 centers in 5 countries and applied these costs to measured resource use and effects of all enrolled patients.

The researchers found that the median postrandomization hospital costs of care for patients who received UFH was greater ($40,805) compared with $39,508 for patients who received dalteparin, but the difference was not statistically significant. For 7 of 8 prespecified subgroups, using conventional cost metrics to prevent specific VTE-related events indicated that dalteparin was the most effective and least costly strategy to prevent all thrombotic events, pulmonary embolus, deep-vein thrombosis, major bleeding, and heparin-induced thrombocytopenia, given its lower cost combined with better effects.

Additional analyses indicated that a strategy using LMWH was most effective, least costly 78 percent of the time, and remained least costly unless the drug acquisition cost of dalteparin was to increase by more than 20-fold. There was no threshold in which lowering the acquisition cost of UFH favored prevention with UFH.

“These findings are important for the care of critically ill patients because they provide a cost-minimization rationale that complements clinical effectiveness knowledge from PROTECT. For example, if an ICU with 1,000 medical-surgical admissions per year uses UFH instead of LMWH for prevention of VTE, the annual incremental cost may be between $1,000,000 to $1,500,000 with similar or worse clinical outcomes, despite the individual drug cost of UFH being $4 to $5 less per day,” the researchers write.

The authors note that these findings were driven by lower rates of pulmonary embolus and heparin-induced thrombocytopenia and corresponding lower overall use of resources with LMWH.
(doi:10.1001/jama.2014.15101; 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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