EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 18, 2015

Media Advisory: To contact Adam M. Leventhal, Ph.D., call Leslie Ridgeway at 323-442-2823 or email lridgewa@usc.edu. To contact editorial author Nancy A. Rigotti, M.D., call Mckenzie Ridings at 617-726-0274 or email mridings@mgh.harvard.edu. To contact Viewpoint co-author Michele Barry, M.D., call Rosanne Spector at 650-725-5374 or email manishma@stanford.edu.

To place an electronic embedded link to this study, editorial and Viewpoint in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8950 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8382 This will be the link to the Viewpoint: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8676

Among high school students in Los Angeles, those who had ever used electronic cigarettes were more likely to report initiation of smokable (“combustible”) tobacco (such as cigarettes, cigars, and hookah) use over the next year compared with nonusers, according to a study in the August 18 issue of JAMA.

Combustible tobacco, which has well-known health consequences, has long been the most common nicotine-delivering product used. Electronic cigarettes (e-cigarettes), which are devices that deliver inhaled aerosol usually containing nicotine, are becoming increasingly popular, particularly among adolescents, including teens who have never used combustible tobacco. According to 2014 U.S. estimates, 16 percent of 10th graders reported use of e-cigarettes within the past 30 days, of whom 43 percent reported never having tried combustible cigarettes. Whether use of e-cigarettes is associated with risk of initiating combustible tobacco use has not been known, according to background information in the article.

Adam M. Leventhal, Ph.D., of the Keck School of Medicine of the University of Southern California, Los Angeles, and colleagues examined whether adolescents who reported ever using e-cigarettes were more likely to initiate the use of combustible tobacco (cigarettes, cigars, and hookah) during the subsequent year. The study included 2,530 students from ten public high schools in Los Angeles who reported never using combustible tobacco at study entry (fall 2013, 9th grade, average age = 14 years) and completed follow-up assessments at 6 months (spring 2014, 9th grade) or 12 months (fall 2014, 10th grade). At each time point, students completed self-report surveys on any use of combustible tobacco products.

The researchers found that e-cigarette users (n = 222) were more likely than never users (n = 2,308) to report past 6-month use of any combustible tobacco product at the 6-month follow-up (31 percent vs 8 percent) and at the 12-month follow-up (25 percent vs 9 percent). Baseline e-cigarette use was associated with a greater likelihood of use of any combustible tobacco product averaged across the 2 follow-up periods in the analyses adjusted for sociodemographic, environmental, and intrapersonal risk factors for smoking. In addition, relative to baseline e-cigarette never users, e-cigarette ever users were more likely to be using at least 1 more combustible tobacco product averaged across the 2 follow-up assessments.

“These data provide new evidence that e-cigarette use is prospectively associated with increased risk of combustible tobacco use initiation during early adolescence. Associations were consistent across unadjusted and adjusted models, multiple tobacco product outcomes, and various sensitivity analyses,” the authors write.

They add that “some teens may be more likely to use e-cigarettes prior to combustible tobacco because of beliefs that e-cigarettes are not harmful or addictive, youth-targeted marketing, availability of e-cigarettes in flavors attractive to youths, and ease of accessing e-cigarettes due to either an absence or inconsistent enforcement of restrictions against sales to minors.”

“Further research is needed to understand whether this association may be causal.”

(doi:10.1001/jama.2015.8950; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: E-Cigarette Use and Subsequent Tobacco Use by Adolescents

The report by Leventhal and colleagues is the strongest evidence to date that e-cigarettes might pose a health hazard by encouraging adolescents to start smoking conventional tobacco products, writes Nancy A. Rigotti, M.D., of Massachusetts General Hospital and Harvard Medical School, Boston,

“Regardless of whether e-cigarettes are a gateway to tobacco product initiation, there is no reason for adolescents to use a product for which the hypothesized public health benefit is harm reduction for adult smokers. However, there is ample evidence that e-cigarettes are marketed in ways that appeal to children and adolescents. Prompt, effective action is needed to protect youth and reduce the demand for e-cigarettes by nonsmokers of all ages. A rational approach is to extend to e-cigarettes the same sales, marketing, and use restrictions that apply to combustible cigarettes.”

(doi:10.1001/jama.2015.8382; 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.

Related Viewpoint: The Global Health Implications of e-Cigarettes

In an accompanying Viewpoint, Andrew Y. Chang, M.D., and Michele Barry, M.D., of the Stanford University School of Medicine, Stanford, Calif., discuss health considerations of e-cigarettes unique to low- and middle-income countries.

“Developing nations should not underestimate the availability and targeted marketing of electronic nicotine delivery systems (ENDS) within their borders and should place e-cigarettes under the purview of their medical and pharmaceutical regulatory boards. Low- and middle-income countries can feel empowered to exclude multinational tobacco companies from this regulatory process in accordance with Article 5.3 of WHO’s Framework Convention on Tobacco Control, which warns against the conflict of interest posed by the industry in this sphere.”

“International nongovernmental organizations such as the Gates Foundation and the Bloomberg Initiative to Reduce Tobacco Use should support these efforts to provide consistency in control and enforcement of ENDS legislation. Even though e-cigarettes may have a future as smoking cessation tools, evidence to support this indication is lacking. More rigorous studies must be conducted regarding the awareness, usage patterns, and potential for harm of these devices in low-income countries, particularly Africa and South Asia, where data are currently missing.”

(doi:10.1001/jama.2015.8676; 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: 11 A.M. (ET) TUESDAY, AUGUST 18, 2015

Media Advisory: To contact Melanie J. Davies, M.D., email melanie.davies@uhl-tr.nhs.uk.

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Among overweight and obese patients with type 2 diabetes, daily injection of the diabetes drug liraglutide with a modified insulin pen device, in addition to diet and exercise, resulted in greater weight loss over 56 weeks compared with placebo, according to a study in the August 18 issue of JAMA.

Obesity is a chronic disease and a significant global health challenge. Weight loss is recommended for patients with type 2 diabetes. Moderate weight loss (5 percent-10 percent) can improve glycemic control and other cardiometabolic risk factors and disorders. Weight loss is especially challenging for individuals with type 2 diabetes, who often experience a reduced response to weight-management pharmacotherapies compared with individuals without diabetes. Liraglutide is a medication approved for the treatment of type 2 diabetes (administered once daily at doses of 1.2 mg and 1.8 mg). Weight loss has also been observed with liraglutide at these doses, according to background information in the article.

Melanie J. Davies, M.D., of the University of Leicester, United Kingdom, and colleagues randomly assigned 846 overweight or obese study participants (age 18 years or older) with type 2 diabetes to once-daily injections of liraglutide (3.0 mg) (n = 423), liraglutide (1.8 mg) (n = 211), or placebo (n = 212) for 56 weeks. A 12-week “off-drug” follow-up period was included to assess treatment-cessation effects (total study length, 68 weeks). The study was conducted at 126 sites in 9 countries between June 2011 and January 2013. Participants were also instructed to follow a reduced-calorie diet and increase physical activity for weight management.

Average weight loss was 6.0 percent (14.1 lbs.) with liraglutide (3.0-mg dose), 4.7 percent (11 lbs.) with liraglutide (1.8-mg dose), and 2.0 percent (4.8 lbs.) with placebo. Weight loss of 5 percent or greater occurred in 54.3 percent with liraglutide (3.0 mg) and 40.4 percent with liraglutide (1.8 mg) vs 21.4 percent with placebo. Weight loss greater than 10 percent occurred in 25.2 percent with liraglutide (3.0 mg) and 15.9 percent with liraglutide (1.8 mg) vs 6.7 percent with placebo. More gastrointestinal disorders were reported with liraglutide (3.0 mg) vs liraglutide (1.8 mg) and placebo. Pancreatitis was not reported.

“To our knowledge, this is the first study specifically designed to investigate the efficacy of liraglutide for weight management in patients with type 2 diabetes and also the first study to investigate liraglutide at the higher 3.0-mg dose in a population with type 2 diabetes,” the authors write. “In the present trial, liraglutide (3.0 mg), as an adjunct to a reduced-calorie diet and increased physical activity, was effective and generally well tolerated and was significantly better than placebo on all 3 co-primary weight-related end points.”

“Further studies are needed to evaluate longer-term efficacy and safety.”

(doi:10.1001/jama.2015.9676; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by Novo Nordisk. Liraglutide is a Novo Nordisk A/S proprietary compound. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 18, 2015

Media Advisory: To contact Agnes Y. Y. Lee, M.D., M.Sc., call Heather Amos at 604-822-3213 or email heather.amos@ubc.ca.

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Among patients with active cancer and acute symptomatic venous thromboembolism (VTE; blood clots in the deep veins), the use of the low molecular-weight heparin tinzaparin daily for 6 months compared with warfarin did not significantly reduce recurrent VTE and was not associated with reductions in overall death or major bleeding, but was associated with a lower rate of clinically relevant nonmajor bleeding, according to a study in the August 18 issue of JAMA.

Venous thromboembolism is a major cause of illness and death in patients with cancer. Treatment with low-molecular-weight heparin is effective and is recommended over warfarin by clinical practice guidelines. These recommendations are largely based on results from a single, large randomized trial with supportive evidence from additional smaller studies that were conducted over a decade ago in academic centers primarily in North America and Western Europe, according to background information in the article.

Agnes Y. Y. Lee, M.D., M.Sc., of the University of British Columbia, Vancouver, and colleagues randomly assigned 900 adult patients with active cancer and documented deep vein thrombosis or pulmonary embolism to tinzaparin once daily for 6 months vs conventional therapy with tinzaparin once daily for 5 to 10 days followed by warfarin at a dose adjusted to maintain the international normalized ratio (INR) within the therapeutic range for 6 months. The patients, enrolled in 164 centers in Asia, Africa, Europe, and North, Central, and South America between August 2010 and November 2013, were followed up for 180 days and for 30 days after the last study medication dose for collection of safety data.

Recurrent VTE occurred in 31 of 449 patients treated with tinzaparin and 45 of 451 patients treated with warfarin (6-month cumulative incidence, 7.2 percent for tinzaparin vs 10.5 percent for warfarin). There were no differences in major bleeding (12 patients for tinzaparin vs 11 patients for warfarin) or overall mortality (150 patients for tinzaparin vs 138 patients for warfarin).

Tinzaparin significantly reduced the risk of clinically relevant nonmajor bleeding (included bleeding that required any medical or surgical intervention but was not fatal; did not occur in a critical area or organ; or did not cause a fall in hemoglobin of greater than 2 g/dL or lead to a transfusion of 2 or more units of whole blood or red cells) compared with warfarin (49 of 449 patients for tinzaparin vs 69 of 451 patients for warfarin). “Together with the adverse events data, [this trial] demonstrated that tinzaparin, even when given at a full therapeutic dose for up to 6 months, is safe in a broad oncology population,” the authors write.

“Further studies are needed to assess whether the efficacy outcomes would be different in patients at higher risk of recurrent VTE.”

(doi:10.1001/jama.2015.9243; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was sponsored and funded by LEO Pharma and had research support from the Sondra and Stephen Hardis Endowed Chair in Oncology Research and the Scott Hamilton CARES Initiative. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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

Media Advisory: To contact Rachel E. Patzer, Ph.D., M.P.H., call Holly Korschun at 404-727-3990 or email Hkorsch@emory.edu. To contact editorial co-author Dorry L. Segev, M.D., Ph.D., email Ekaterina Pesheva at epeshev1@jhmi.edu.

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Only about one in four patients with end-stage renal disease in Georgia were referred for kidney transplant evaluation within 1 year of starting dialysis between 2005 and 2011, although there was substantial variability in referral among dialysis facilities, according to a study in the August 11 issue of JAMA.

For most of the more than 600,000 patients in the United States with end-stage renal disease (ESRD), kidney transplantation represents the optimal treatment, providing longer survival, better quality of life, and substantial cost savings compared with dialysis. Dialysis facilities in the United States are required to educate patients with ESRD about all treatment options, including kidney transplantation. Patients receiving dialysis typically require a referral for kidney transplant evaluation at a transplant center to begin the transplantation process, but the proportion of dialysis patients referred for transplantation has been unknown, according to background information in the article.

Rachel E. Patzer, Ph.D., M.P.H., of the Emory University School of Medicine, Atlanta, and colleagues examined variation in dialysis facility-level referral for kidney transplant evaluation and factors associated with referral among patients initiating dialysis in Georgia, the U.S. state with the lowest kidney transplantation rates. The study included data from the United States Renal Data System for 15,279 adult (18-69 years) patients with ESRD from 308 Georgia dialysis facilities from January 2005 to September 2011, followed up through September 2012, and linked to kidney transplant referral data collected from adult transplant centers in Georgia in the same period.

The median within-facility percentage of patients referred within 1 year of starting dialysis at 308 Georgia dialysis facilities was 24 percent. There were 15 facilities (5 percent) that referred zero patients within 1 year of starting dialysis; the maximum referral in a year was 75 percent. Facilities in the lowest tertile of referral (<19 percent) were more likely to treat patients living in high-poverty neighborhoods, had a higher patient to social worker ratio, and were more likely nonprofit compared with facilities in the highest tertile of referral (>31 percent).

Factors associated with lower referral for transplantation, such as white race, older age, and nonprofit facility status, were not necessarily the same as those associated with lower waitlisting, the researchers write. “Results of this study suggest that referral for transplantation among Georgia dialysis facilities is not uniform and that national surveillance data measuring waitlisting and transplantation, but not referral, may be inadequate to assess and intervene on disparities in access to kidney transplantation.”

“These findings may have implications for health policy makers, researchers, clinicians, and patients. Low facility-level referral for transplantation, as well as the variability in referral across Georgia facilities, suggests that standardized guidelines are needed for the content and duration of a patient-clinician educational discussion regarding treatment options at start of dialysis. Socioeconomic status factors were significant barriers to both referral and waitlisting in this study; national policies, such as Medicaid expansion, could help to alleviate disparities,” the authors write.

“Researchers should continue to develop, test, and implement pragmatic interventions to improve knowledge of transplantation among both clinicians and patients. In Georgia, such interventions could focus on those dialysis facilities with the lowest proportions of patients with ESRD referred for kidney transplantation.”

(doi:10.1001/jama.2015.8897; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by a National Institute on Minority Health and Health Disparities grant. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Improving Access to Kidney Transplantation

“In summary, this important report by Patzer et al has established that major barriers in access to transplantation exist even after a patient has been referred to a transplant center, with 80 percent of referred patients not joining the transplant waitlist within 1 year of referral,” writes Dorry L. Segev, M.D., Ph.D., and colleagues with the Johns Hopkins University School of Medicine, Baltimore, in an accompanying editorial.

“Furthermore, the initial rates of referral were likely low and varied widely between dialysis centers, suggesting that some facilities may have been underreferring patients. Future research to better understand and target post-referral barriers, as well as interventions to identify and improve referral rates in the context of comprehensive transplant education, will be crucial for improving access to kidney transplantation for patients with ESRD.”

(doi:10.1001/jama.2015.8932; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors are supported, in part, by grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. 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: 11 A.M. (ET) TUESDAY, AUGUST 11, 2015

Media Advisory: To contact Shalender Bhasin, M.B.B.S., call Haley Bridger at 617-525-6383 or email hbridger@partners.org.

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Among older men with low testosterone levels, testosterone administration for 3 years compared with placebo did not result in a significant difference in the rates of change in atherosclerosis (thickening and hardening of artery walls), nor was it associated with improved overall sexual function or health-related quality of life, according to a study in the August 11 issue of JAMA. The authors note that because this trial was only powered to evaluate atherosclerosis progression and not cardiovascular events, these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men such as those enrolled in this trial.

Testosterone sales have increased substantially, particularly among older men, during the past decade. However, the benefits and risks of long-term testosterone administration to older men with age-related decline in testosterone levels remain poorly understood. Although some studies have reported an association of low testosterone levels with increased risk of diabetes, metabolic syndrome, cardiovascular disease (CVD), and mortality, other studies have not shown a consistent association between testosterone levels and incident CVD. The long-term consequences of testosterone supplementation on atherosclerosis in older men remain unknown, according to background information in the article.

Shalender Bhasin, M.B.B.S., of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues randomly assigned 308 men 60 years or older with low or low-normal testosterone levels to receive 7.5 g of 1 percent testosterone (n = 156) or placebo (n = 152) gel packets daily for 3 years. The dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL. Characteristics were similar between groups at study entry: patients were an average age of 68 years; 42 percent had hypertension; 15 percent, diabetes; 15 percent, cardiovascular disease; and 27 percent, obesity.

The researchers found that the rates of subclinical atherosclerosis progression, as measured by changes in common carotid artery intima-media thickness or coronary artery calcium, did not differ significantly between men assigned to the testosterone or placebo groups. Changes in intima-media thickness or calcium scores were not associated with change in testosterone levels among individuals assigned to receive testosterone.

Sexual desire, erectile function, overall sexual function scores, partner intimacy, and health-related quality of life did not differ significantly between groups. Hematocrit (a measure of red blood cells) and prostate-specific antigen levels increased more in testosterone group.

The authors write that this trial was not designed to determine the effects of testosterone on CVD events, and that a substantially larger trial would be needed to determine this.

(doi:10.1001/jama.2015.8881; 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 A.M. (ET) TUESDAY, AUGUST 11, 2015

Media Advisory: To contact Joseph S. Ross, M.D., M.H.S., call Ziba Kashef at 203-436-9317 or email Ziba.kashef@yale.edu.

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Of high-risk therapeutic devices approved via the Food and Drug Administration (FDA) Premarket Approval (PMA) pathway between 2010 and 2011, there has been wide variation in both the number and quality of premarket and postmarket studies, with approximately 13 percent of initiated postmarket studies completed between 3 and 5 years after FDA approval, according to a study in the August 11 issue of JAMA.

In the United States, the FDA predominantly grants marketing approval through the PMA pathway for high-risk medical devices, which are defined as those that support or sustain human life, prevent illness, or present potential, unreasonable risk to patients. The PMA pathway requires premarket clinical evidence providing reasonable assurance of device safety and effectiveness and permits supplemental applications whenever postapproval changes are made to the device. Recently, concerns have been raised that the clinical studies supporting FDA approval of these devices lack adequate rigor and are prone to bias, according to background information in the article.

Joseph S. Ross, M.D., M.H.S., of the Yale University School of Medicine, New Haven, Conn., and colleagues examined the clinical evidence generated for high-risk therapeutic devices over the total product life cycle (premarket and postmarket). The analysis included all clinical studies of high-risk therapeutic devices receiving initial market approval via the PMA pathway in 2010 and 2011 identified through ClinicalTrials.gov and publicly available FDA documents as of October 2014. Studies were characterized by type (pivotal, studies that served as the basis of FDA approval; FDA-required postapproval studies [PAS]; or manufacturer/investigator-initiated); premarket or postmarket; status (completed, ongoing, or terminated/unknown); and design features, including enrollment, comparator, and longest duration of primary effectiveness end point follow-up.

In 2010 and 2011, 28 high-risk therapeutic devices received initial marketing approval via the PMA pathway. The researchers identified 286 clinical studies of these devices: 82 (29 percent) premarket and 204 (71 percent) postmarket, among which 18 percent were nonpivotal premarket studies, 10.5 percent pivotal premarket studies, 11.5 percent FDA-required PAS, and 60 percent manufacturer/investigator-initiated postmarket studies. Six of 33 (18 percent) PAS and 12 percent of manufacturer/investigator-initiated postmarket studies were reported as completed. No postmarket studies were identified for 18 percent of devices; 3 or fewer were identified for 46 percent of devices overall.

Premarket clinical studies of high-risk therapeutic devices were limited in number and quality. Nearly all devices were cleared on the basis of 2 studies: 1 nonpivotal and 1 pivotal study.

Approximately half of all studies used no comparator. Median duration of primary effectiveness end point follow-up was 3 months, 9 months, and 12 months for pivotal, completed postmarket, and ongoing postmarket studies, respectively.

“Our characterization of the clinical studies examining high-risk therapeutic medical devices initially approved via the FDA PMA pathway between 2010 and 2011 demonstrates that the amount and quality of evidence generated over the total product life cycle varies widely. Some devices are currently being evaluated through ongoing studies that, if completed, will provide evidence on clinical outcomes for large numbers of patients with planned follow-up of a year or longer. However, most devices have been or will be evaluated through only a few studies, which often focus on surrogate markers of disease in small numbers of patients followed up over short periods of time and study indications that differ from the original FDA-approved indication,” the authors write.

(doi:10.1001/jama.2015.8761; 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 A.M. (ET) TUESDAY, AUGUST 11, 2015

Media Advisory: To contact Vitaly A. Kushnir, M.D., email Mat Probasco at mprobasco@thechr.com.

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Compared to using fresh oocytes (eggs) for in vitro fertilization, use of cryopreserved (frozen) donor oocytes in 2013 was associated with lower live birth rates, according to a study in the August 11 issue of JAMA.

Use of oocytes donated for in vitro fertilization (IVF) has increased in recent years. Donated fresh oocytes traditionally have been used immediately, creating embryos for transfer into the uterus, with extra embryos being cryopreserved for later use. In January 2013, the American Society for Reproductive Medicine declared the technique of oocyte cryopreservation (egg freezing) no longer experimental, although it called for “more widespread clinic-specific data on the safety and efficacy of oocyte cryopreservation … before universal donor oocyte banking can be recommended.” Based on data that IVF outcomes with cryopreserved and fresh donor oocytes are comparable, some IVF centers established frozen donor egg banks. However, data reflecting IVF outcomes in routine clinical practice with cryopreserved donor oocytes have not previously been published, according to background information in the article.

Vitaly A. Kushnir, M.D., of the Center for Human Reproduction, New York, and colleagues used data from the 2013 annual report of U.S. IVF center outcomes published by the Society for Assisted Reproductive Technology to compare live birth and cycle cancellation (started IVF cycles which do not reach egg retrieval and/or embryo transfer) rates using either fresh or cryopreserved donor oocytes. This data set is based on center-specific voluntarily reported outcomes from 380 of 467 (81 percent) U.S.­ based fertility centers, which in 2013 collectively performed 92 percent of all IVF cycles.

Of 11,148 oocyte donation cycles, 2,227 (20 percent) involved use of cryopreserved donor oocytes. Initiated cycles were canceled in 12 percent of fresh oocyte cycles vs 8.5 percent of cryopreserved oocyte cycles. Per started recipient cycle, the live birth rates were 50 percent with fresh vs 43 percent with cryopreserved oocytes. Per embryo transfer, the live birth rates were 56 percent with fresh vs 47 percent with cryopreserved oocytes.

The authors write that the reasons for lower live birth rates with use of cryopreserved oocytes remain to be established. “One possible explanation is less opportunity for proper embryo selection due to smaller starting numbers of oocytes, leading to fewer embryos available for transfer. Alternatively, oocyte quality may be negatively affected by cryopreservation and thawing.” They add that the added convenience and lower cycle costs with use of cryopreserved oocytes must be balanced against the lower live birth rates.

The researchers note that these findings need to be viewed with caution because they are based on anonymized aggregate outcomes, which do not allow adjustments for confounding patient characteristics, such as donor and recipient ages, infertility diagnosis, and embryo stage.

(doi:10.1001/jama.2015.7556; 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 A.M. (ET) TUESDAY, AUGUST 11, 2015

Media Advisory: To contact Christian F. Poets, M.D., email christian-f.poets@med.uni-tuebingen.de. To contact editorial author Lex W. Doyle, M.D., email lwd@unimelb.edu.au.

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Among extremely preterm infants, prolonged episodes of hypoxemia (abnormally low levels of oxygen in the blood, which leads to shortness of breath) during the first 2 to 3 months after birth were associated with an increased risk of disability or death at 18 months, according to a study in the August 11 issue of JAMA.

Almost all extremely preterm infants (those born at < 28 weeks’ gestation) experience intermittent hypoxemia and bradycardia (a slow heart rate) during their stay in the neonatal intensive care unit. The relationship between neonatal hypoxemia or bradycardia and later neurodevelopment in this population of high-risk preterm infants is uncertain, according to background information in the article.

Christian F. Poets, M.D., of Tuebingen University Hospital, Tuebingen, Germany, and colleagues examined the association between intermittent hypoxemia or bradycardia and death or disability. The study included 1,019 infants with gestational ages of 23 weeks 0 days through 27 weeks 6 days who were born between December 2006 and August 2010 and survived to a postmenstrual age of 36 weeks. Follow-up assessments occurred between October 2008 and August 2012. The researchers used data from infants who were part of the Canadian Oxygen Trial (25 hospitals in Canada, the United States, Argentina, Finland, Germany, and Israel).

Average percentages of recorded time with hypoxemia for the least and most affected 10 percent of infants were 0.4 percent and 13.5 percent, respectively. Corresponding values for bradycardia were 0.1 percent and 0.3 percent. The primary outcome (a composite of death after 36 weeks’ postmenstrual age, motor impairment, cognitive or language delay, severe hearing loss, or blindness at 18 months) was ascertained for 972 infants and present in 414 (43 percent). Hypoxemic episodes were associated with an estimated increased risk of late death or disability at 18 months of 56.5 percent in the highest decile (one of 10 groups) of hypoxemic exposure vs 37 percent in the lowest decile. This association was significant only for prolonged hypoxemic episodes lasting at least 1 minute.

Relative risks for all secondary outcomes (motor impairment, cognitive or language delay, and severe retinopathy of prematurity [a disorder of the retina]) were similarly increased after prolonged hypoxemia.

“If these observations are confirmed in future studies, further research on the prevention of such episodes will be needed,” the authors write.

The researchers note that intermittent bradycardia did not significantly add to the risk of adverse outcomes, suggesting that bradycardia in the absence of concurrent hypoxemia may not be of prognostic importance. In addition, the severity of intermittent hypoxemia added little prognostic value to the simpler measure of the percentage of time spent with hypoxemia.

The authors add that should the observation be confirmed in future research that episodes of hypoxemia lasting less than 1 minute are not associated with adverse outcomes in extremely preterm infants, this would be important information for both clinicians and parents.

(doi:10.1001/jama.2015.8841; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded exclusively by a Canadian Institutes of Health Research grant. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Hypoxemic Episodes and Adverse Neurodevelopmental Outcome in Extremely Preterm Infants

“If hypoxemia is proven to cause adverse neurodevelopment, any future interventions to reduce prolonged hypoxemic episodes, such as doxapram [a respiratory stimulant] or higher doses of caffeine, as suggested by Poets et al, must be evaluated in rigorous randomized clinical trials to minimize exposure to therapies that are useless or even harmful,” writes Lex W. Doyle, M.D., of the University of Melbourne, Parkville, Victoria, Australia, in an accompanying editorial.

“Such trials should have long-term developmental outcome as the primary end point, rather than short-term end points, such as a reduction in the number or duration of hypoxemic episodes. Neonatal intensive care is littered with examples of treatments that were introduced based on observational data or even no data, only to be proven to be disastrous when tested properly in randomized clinical trials. In the meantime, other treatments known from randomized clinical trials to improve long-term neurodevelopmental outcome for extremely preterm infants, such as magnesium sulfate before birth, regular doses of caffeine, or developmental care interventions after discharge, should be maximized.”

(doi:10.1001/jama.2015.9136; 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: 11 A.M. (ET) TUESDAY, AUGUST 4, 2015

Media Advisory: To contact Melissa A. Polusny, Ph.D., call Ralph Heussner at 612-467-3012 or email Ralph.heussner@va.gov. To contact editorial co-author David J. Kearney, M.D., call Chad Hutson at 206-764-2589 or email Chad.Hutson@va.gov.

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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8361 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7522

In a randomized trial that included veterans with posttraumatic stress disorder (PTSD), those who received mindfulness-based stress reduction therapy showed greater improvement in self-reported PTSD symptom severity, although the average improvement appears to have been modest, according to a study in the August 4 issue of JAMA, a violence/human rights theme issue.

Posttraumatic stress disorder affects 23 percent of veterans returning from Afghanistan and Iraq. Left untreated, PTSD is associated with high rates of other disorders, disability, and poor quality of life. Evidence suggests that mindfulness-based stress reduction, an intervention that teaches individuals to attend to the present moment in a nonjudgmental, accepting manner, can result in reduced symptoms of depression and anxiety. By encouraging acceptance of thoughts, feelings, and experiences without avoidance, mindfulness-based interventions target experiential avoidance, a key factor in the development and maintenance of PTSD, and may be an acceptable type of intervention for veterans who have poor adherence to existing treatments for PTSD, according to background information in the article.

Melissa A. Polusny, Ph.D., of the Minneapolis Veterans Affairs Health Care System, and colleagues randomly assigned 116 veterans with PTSD to receive nine sessions of mindfulness-based stress reduction therapy (n = 58) or present-centered group therapy (n = 58), an active-control condition consisting of nine weekly group sessions focused on current life problems. Outcomes were assessed before, during, and after treatment and at 2-month follow-up.

Participants in the mindfulness-based stress reduction group demonstrated greater improvement in self-reported PTSD symptom severity during treatment and at 2-month follow-up. Although participants in the mindfulness-based stress reduction group were more likely to show clinically significant improvement in self-reported PTSD symptom severity (49 percent vs 28 percent with present-centered group therapy) at 2-month follow-up, there was no difference in rates of loss of PTSD diagnosis at posttreatment (42 percent vs 44 percent) or at 2-month follow-up (53 percent vs 47 percent).

“Findings from the present study provide support for the efficacy of mindfulness-based stress reduction for the treatment of PTSD among veterans,” the researchers write. “However, the magnitude of the average improvement suggests a modest effect.”

(doi:10.1001/jama.2015.8361; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This material is the result of work supported with resources and the use of facilities at the Minneapolis VA Health Care System. This research was supported by a VA grant to Dr. Lim. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Broadening the Approach to Posttraumatic Stress Disorder and the Consequences of Trauma

David J. Kearney, M.D., and Tracy L. Simpson, Ph.D., of the VA Puget Sound Health Care System, Seattle, comment on the findings of this study in an accompanying editorial.

“The rate of clinically significant PTSD symptom reduction of 49 percent for those randomized to mindfulness-based stress reduction (MBSR) is similar to that reported for empirically supported treatment approaches to PTSD … and consistent with the rate of clinically significant improvement in PTSD symptoms of 48 percent found in a before-and-after study of MBSR among veterans. Although the results reported by Polusny et al are promising, the short duration of follow-up calls into question whether the effects of MBSR persist over time; thus, additional studies of MBSR and other mindfulness-based interventions for PTSD are warranted.”

(doi:10.1001/jama.2015.7522; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This material is based on work supported by the U.S. Department of Veterans Affairs Office of Research and Development. 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: 11 A.M. (ET) TUESDAY, AUGUST 4, 2015

Media Advisory: To contact Steven A. Sumner, M.D., M.Sc., call Courtney Lenard at 404-639-3286 or email clenard@cdc.gov.

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Even though homicide and assault rates have decreased in the U.S. in recent years, the number of these and other types of violent acts remains high, according to a report in the August 4 issue of JAMA, a violence/human rights theme issue. The authors write that multiple strategies exist to improve interpersonal violence prevention efforts, and health care providers are an important part of this solution.

Interpersonal violence is a pervasive public health, social, and developmental threat that affects millions of U.S. residents each year. It is a leading cause of death in the U.S., particularly among children, adolescents and young adults. Exposure to violence can cause immediate physical wounds that clinicians recognize and treat but can also result in long-lasting mental and physical health conditions that are often less apparent to health care providers. Surveillance systems, programs, and policies to address violence often lack broad, cross-sector collaboration, and there is limited awareness of effective strategies to prevent violence, according to background information in the article.

Steven A. Sumner, M.D., M.Sc., of the Centers for Disease Control and Prevention, Atlanta, and colleagues examined the burden of interpersonal violence in the United States and challenges to violence prevention efforts and sought to identify prevention opportunities. The researchers reviewed data from various health and law enforcement surveillance systems (listed at the end of this news release).

The researchers found that homicide rates have decreased from a peak of 10.7 per 100,000 persons in 1980 to 5.1 per 100,000 in 2013. Aggravated assault rates have decreased from a peak of 442 per 100,000 in 1992 to 242 per 100,000 in 2012. Despite the decrease in these rates, annually there are more than 16,000 homicides and 1.6 million nonfatal assault injuries requiring treatment in emergency departments. More than 12 million adults experience intimate partner violence annually and more than 10 million children younger than 18 years of age experience some form of maltreatment from a caregiver, ranging from neglect to sexual abuse, but only a small percentage of these violent incidents are reported to law enforcement, health care clinicians, or child protective agencies.

The researchers write that exposure to violence increases vulnerability to a broad range of mental and physical health problems over the life course; for example, meta-analyses indicate that exposure to physical abuse in childhood is associated with a 54 percent increased odds of depressive disorder, a 78 percent increased odds of sexually transmitted illness or risky sexual behavior, and a 32 percent increased odds of obesity.

Rates of violence vary by age, geographic location, sex, and race/ethnicity, and significant disparities exist. Homicide is the leading cause of death for non-Hispanic blacks from age 1 through 44 years, whereas it is the fifth most common cause of death among non-Hispanic whites in this age range. Additionally, efforts to understand, prevent, and respond to interpersonal violence have often neglected the degree to which many forms of violence are interconnected at the individual level, across relationships and communities, and even intergenerationally.

The authors write that the most effective violence prevention strategies include parent and family-focused programs, early childhood education, school-based programs, therapeutic or counseling interventions, and public policy. For example, a systematic review of early childhood home visitation programs found a 39 percent reduction in episodes of child maltreatment in intervention participants compared with control participants.

“The scientific literature indicates quite clearly that preventing interpersonal violence is strategic from a health and public health perspective. It is strategic because of the consistently documented high levels of violence to which young children, adolescents, and young adult women and men are exposed. Furthermore, exposure to violence plays an important role, not just in causing physical injuries and homicide, but also in the etiology of mental illness, chronic disease, and infectious diseases such as HIV. Thus, preventing exposure to violence can have downstream effects on a broad range of health problems.”

“Finally, there is a substantial and rapidly growing evidence base on what works to prevent violence. This evidence suggests that priority should be given to interventions that can affect multiple forms of violence, particularly those that seek to prevent violence among children and youth. The effects of violence and the probability of involvement in future violence are dose dependent; thus, considerable gains can be made by early intervention,” the authors write.

(doi:10.1001/jama.2015.8371; 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.

For this report, the researchers reviewed data from health and law enforcement surveillance systems including the National Vital Statistics System, the Federal Bureau of Investigation’s Uniform Crime Reports, the U.S. Justice Department’s National Crime Victimization Survey, the National Survey of Children’s Exposure to Violence, the National Child Abuse and Neglect Data System, the National Intimate Partner and Sexual Violence Survey, the Youth Risk Behavior Surveillance System, and the National Electronic Injury Surveillance System-All Injury Program.

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Media Advisory: To contact Karin V. Rhodes, M.D., M.S., call Katie Delach at 215-349-5964 or email katie.delach@uphs.upenn.edu.

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A brief motivational intervention delivered during an emergency department visit did not improve outcomes for women with heavy drinking involved in abusive relationships, according to a study in the August 4 issue of JAMA, a violence/human rights theme issue.

There is a strong and reciprocal association between two highly prevalent public health problems: intimate partner violence (IPV) and heavy drinking. Each risk individually represents major costs to individuals, families, and society. The emergency department (ED) visit is conceptualized as a sensitive period or window of time when exposure to motivational health promotion might have an influence on behaviors. Integrated brief interventions for IPV and heavy drinking have not been tested, according to background information in the article.

Karin V. Rhodes, M.D., M.S., of the University of Pennsylvania, Philadelphia, and colleagues randomly assigned 600 IPV-involved female ED patients who exceeded safe drinking limits to brief intervention (n = 242), assessed control (n = 237), or no-contact control (n = 121). All received social service referrals. The brief intervention was a 20- to 30-minute manual-guided motivational intervention delivered by master’s-level therapists with a follow-up telephone booster. The assessed control group received the same number of assessments as the brief intervention group but no intervention; the no-contact control group was assessed only once at 3 months.

Incidents of heavy drinking and IPV were assessed weekly for 12 weeks using an interactive voice response system. Of 600 participants, 80 percent were black women with an average age of 32 years. Retention among study participants was 89 percent for 2 or more interactive voice response system calls. Seventy-eight percent of women completed the 3-month interview, 79 percent at 6 months, and 71 percent at 12 months.

During the 12-week period following the brief motivational intervention, there were no significant differences between the intervention group and the assessed control group on weekly assessments for experiencing IPV or heavy drinking. From baseline to 12 weeks, the number of women with any IPV in the past week decreased from 57 percent in the intervention group to 43 percent and from 63 percent in the assessed control group to 41 percent (absolute difference of 8 percent; not statistically significant). From baseline to 12 weeks, the number of women with past week heavy drinking decreased from 51 percent in the intervention group to 43 percent and from 46 percent in the assessed control group to 41 percent (absolute difference of 3 percent).

At 12 months, 43 percent of the intervention group and 47 percent of the assessed control group reported no IPV during the previous 3 months and 19 percent of the intervention group and 24 percent of the control group had reduced their alcohol consumption to sex-specific National Institute on Alcohol Abuse and Alcoholism safe drinking levels.

“We did find that over time, reports of experiencing and perpetrating IPV and days of heavy drinking decreased significantly within the intervention and the control groups alike. However, there was no evidence that these outcomes were influenced by the intervention,” the authors write.

The researchers note that integrated interventions that address multiple risk factors in the context of violence exposure may require a more in-depth approach than can be feasibly provided in an ED setting.

“These findings do not support a brief motivational intervention in this setting.”

(doi:10.1001/jama.2015.8369; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was funded by an award from the National Institute on Alcohol Abuse and Alcoholism. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Sommers reported receiving book royalties from FA Davis. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 4, 2015

Media Advisory: To contact Joanne Klevens, M.D., Ph.D., call Courtney Lenard at 404-639-3286 or email clenard@cdc.gov.

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Screening women for partner violence and providing a resource list did not influence the number of hospitalizations, emergency department, or outpatient care visits compared with women only receiving a resource list or receiving no intervention over 3 years, according to a study in the August 4 issue of JAMA, a violence/human rights theme issue.

The U.S. Preventive Services Task Force recommends women of reproductive age be screened for partner violence. However, others, such as the World Health Organization conclude there is insufficient evidence for this recommendation. Joanne Klevens, M.D., Ph.D., of the U.S. Centers for Disease Control and Prevention, Atlanta, and colleagues had conducted a randomized clinical trial that allocated women seeking care in outpatient clinics to 1 of 3 study groups: computerized partner violence screening and provision of a local resource list, universal provision of a partner violence resource list without screening, or a no screen/no resource list control group. No differences were found in women’s quality of life, days lost from work or housework, use of health care and partner violence services, or the recurrence of partner violence after 1 year.

In this report, the authors examined women’s use of health services over 3 years. Participants’ electronic medical records were searched for outpatient care visits, emergency department visits, and hospitalizations. Of 2,708 women randomized, 8 were unenrolled, leaving 2,700 women with electronic medical records; 15 percent reported partner violence in the year before enrollment. The average age was 39 years; 55 percent of participants were black and 37 percent Latina.

For the full sample, adjusted estimates showed no statistically significant differences between study groups in the average number of hospitalizations (0.2), emergency department visits (0.7), or outpatient care visits (12.2) in the 3 years following enrollment. No differences in these outcomes were found among the subgroup of women who reported experiencing partner violence in the year before enrollment.

“Our data do not support providing a partner violence resource list with or without computerized screening of women in urban health care settings to improve health outcomes,” the authors write.

“The consistency of the results at 1 year and 3 years contributes to greater confidence in the findings. These null findings are consistent with other trials in primary care settings. Research should focus on more intensive interventions among women already identified as abused.”

(doi:10.1001/jama.2015.6755; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by the U.S. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Division of Violence Prevention. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 4, 2015

Media Advisory: To contact Jay G. Silverman, Ph.D., call Heather Buschman at 619-543-6163 or email hbuschman@ucsd.edu.

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More than 1 in 4 female sex workers in the northern Mexico cities of Tijuana and Ciudad Juarez reported entering the sex trade as minors, and entering the sex trade as an adolescent vs as an adult was associated with a greater risk for HIV infection, according to a study in the August 4 issue of JAMA, a violence/human rights theme issue.

Adolescents migrating from Central America and Mexico to the United States are at risk for being trafficked into the sex industry in Mexico’s northern border cities. Research from other regions indicates that those entering the sex trade as adolescents (vs as adults) are more likely to experience sexual violence and to become infected with HIV. Apart from 1 study among injection drug users, no research exists on the prevalence of minors in the sex industry in Latin America or their subsequent risk for violence and HIV infection, according to background information in the article.

Jay G. Silverman, Ph.D., of the University of California–San Diego, La Jolla, Calif., and colleagues studied female sex workers age 18 years or older from Tijuana and Ciudad Juarez. Indoor and street sex work venues were randomly sampled based on mapping of all venues. Confidential computer-assisted surveys were completed to assess prevalence of adolescent (ages 16-17 years) and early adolescent (ages <16 years) entry to the sex trade and associations of age at entry with violence to force commercial sex, high-client volume (>10 clients/day), and no condom use during the initial 30 days after entry.

Of 1,041 individuals screened, 614 were eligible and 603 participated. The average age was 34 years; 25.4 percent reported entering the sex trade before the age of 18 years and 11.8 percent reported entry before the age of 16 years. Compared with those entering sex work as adults, those entering the sex trade as adolescents were more likely to report experiencing violence to force commercial sex (19.7 percent among those aged <16 years vs 8.7 percent among adults), high client volume (21.1 percent for <16 years; 19.5 percent for 16-17 years; 9.6 percent for adults), and never use of condoms with clients (35.2 percent for <16 years vs 8 percent for adults) during their first 30 days in the sex industry. Those reporting entering the sex trade as adolescents were more likely to be infected with HIV compared with those entering as adults (5.9 percent for age <18 years vs 1.6 percent for adults).

“Entering the sex trade as an adolescent vs as an adult was associated with a greater risk for HIV infection, which may relate to elevated risks for violence to force participation in commercial sex, higher numbers of clients, and condom nonuse during initiation to the sex industry. Efforts to effectively protect adolescents vulnerable to sex trade entry and assist adolescents in the sex industry are needed,” the authors write.

(doi:10.1001/jama.2015.7376; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was supported via funding from the National Institute on Drug Abuse and the University of California–San Diego AIDS Research Institute via the National Institute of Allergy and Infectious Diseases. 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: 11 A.M. (ET) TUESDAY, JULY 28, 2015

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

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Among Medicare fee-for-service beneficiaries age 65 years or older, all-cause mortality and hospitalization rates, along with inpatient expenditures per beneficiary, decreased from 1999 to 2013, according to a study in the July 28 issue of JAMA, a theme issue on Medicare and Medicaid at 50. There has also been a decrease in recent years in total hospitalizations and inpatient expenditures for the last 6 months of life.

In recent decades, the United States has experienced a period of dynamic change in health care technology, health care delivery, and health behaviors. Given these changes, which could provide benefit or cause unintended harm, there is a need to assess the results that are being achieved. The Medicare fee-for-service program is ideally positioned to provide information on trends in mortality, hospitalizations, and hospitalization outcomes during this period in health care. A comprehensive analysis of national hospital trends in the Medicare fee-for-service population can provide an assessment of past performance and targets for future interventions, according to background information in the article.

Harlan M. Krumholz, M.D., S.M., of the Yale University School of Medicine, New Haven, Conn., and colleagues examined national trends between 1999 and 2013 in all-cause mortality for all Medicare beneficiaries and trends in all-cause hospitalization and hospitalization-associated outcomes and expenditures for fee-for-service beneficiaries. The analyses included adults 65 years of age or older. Geographic variation, stratified by key demographic groups, and changes in the intensity of care for fee-for-service beneficiaries in the last 1, 3, and 6 months of life were also assessed.

The sample consisted of 68,374,904 Medicare beneficiaries (fee-for-service and Medicare Advantage). The annual all-cause mortality rate across the Medicare population declined from 5.3 percent in 1999 to 4.5 percent in 2013. Among hospitalized fee-for-service beneficiaries, in-hospital mortality declined, as did 30-day and 1-year mortality.

Among fee-for-service beneficiaries (n = 60,056,069), the total number of hospitalizations decreased between 1999 and 2013, as did the number of hospitalizations that involved major surgical procedures. The median hospital length of stay for beneficiaries who had at least 1 hospitalization declined from 5 to 4 days. Average inflation-adjusted inpatient expenditures per Medicare fee-for-service beneficiary declined from $3,290 to $2,801.

Among fee-for-service beneficiaries in the last 6 months of life, the number of hospitalizations decreased from 131 to 103 per 100 deaths. The percentage of beneficiaries with 1 or more hospitalizations decreased from 70.5 to 57 per 100 deaths, while the inflation-adjusted inpatient expenditure per death increased from $15,312 in 1999 to $17,423 in 2009 and then decreased to $13,388 in 2013. Findings were consistent across geographic and demographic groups.

The researchers also found that patients were increasingly discharged to rehabilitation and nursing facilities or with home health care, whereas the proportion of patients discharged to home without care decreased steadily.

“Even though it is difficult to disentangle the specific reasons for improvement, it is clear that over the past 15 years there have been marked reductions in mortality, hospitalization, and adverse hospital outcomes among the Medicare population aged 65 years or older,” the authors write.

(doi:10.1001/jama.2015.8035; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at the embargo time at https://broadcast.jamanetwork.com/.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 28, 2015

Media Advisory: To contact Benjamin D. Sommers, M.D., Ph.D., call Veronica Jackson at 202-690-5488 or email veronica.jackson@hhs.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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8421

Results of a national survey that included more than half a million adults indicates significant improvements in trends for self-reported insurance coverage, access to a personal physician and medications, affordability and health after the Affordable Care Act’s (ACA’s) first and second open enrollment periods, according to a study in the July 28 issue of JAMA, a theme issue on Medicare and Medicaid at 50. Analyses also demonstrated that the largest improvements in coverage and access to medicine occurred among racial/ethnic minorities, suggesting that the ACA may be associated with reductions in long-standing disparities in access to care.

The ACA’s Medicaid expansion and new subsidized private coverage from insurance marketplaces have entered their second year. The law’s first 2 open enrollment periods are complete, the most recent finishing February 15, 2015. How coverage expansion is affecting access to care and health remains an important question, according to background information in the article.

Benjamin D. Sommers, M.D., Ph.D., of the Harvard T. H. Chan School of Public Health and Brigham and Women’s Hospital, Boston, and U.S. Department of Health and Human Services, Washington, D.C., and colleagues analyzed results of the 2012-2015 Gallup-Healthways Well-Being Index, a daily national telephone survey. Using methods to adjust for pre-ACA trends and sociodemographics, the researchers examined changes in outcomes for the U.S. adult population age 18 through 64 years (n = 507,055) since the first open enrollment period began in October 2013. Pre-ACA (January 2012-September 2013) and post-ACA (January 2014-March 2015) changes for adults with incomes below 138 percent of the poverty level in Medicaid expansion states (n = 48,905 among 28 states and Washington, D.C.) vs nonexpansion states (n = 37,283 among 22 states) were compared.

Among the 507,055 adults in the survey, pre-ACA trends were significantly worsening for all outcomes. Compared with the pre-ACA trends, by the first quarter of 2015, the adjusted proportions who were uninsured decreased by 7.9 percentage points; who lacked a personal physician, -3.5 percentage points; who lacked easy access to medicine, -2.4 percentage points; who were unable to afford care, -5.5 percentage points; who reported fair/poor health, -3.4 percentage points; and the percentage of days with activities limited by health, -1.7 percentage points.

Coverage changes were largest among minorities; for example, the decrease in the uninsured rate was larger among Latino adults (-11.9 percentage points) than white adults (-6.1 percentage points). Medicaid expansion was associated with significant reductions among low-income adults in the uninsured rate, lacking a personal physician, and difficulty accessing medicine. “As states continue to debate whether to expand Medicaid under the ACA, these results add to the growing body of research indicating that such expansions are associated with significant benefits for low-income populations,” the authors write.

The researchers add that from a clinical perspective, positive trends were detected for self-reported health and functional status among individuals with chronic medical conditions, who may potentially benefit most from expanded coverage. “These results might reflect changes in the management of chronic conditions, peace of mind from gaining insurance, or factors unrelated to the ACA.”

The authors note that whether the changes found in this study are related directly to the ACA’s coverage expansions is not possible to determine with this type of study design. “For instance, the economic recovery may have also influenced the study outcomes, though the analysis did adjust for several potential confounders including income, individual employment, and state unemployment rates.”

(doi:10.1001/jama.2015.8421; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by the authors’ employment at the U.S. Department of Health and Human Services and did not receive any external grants or corporate funding. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 28, 2015

Media Advisory: To contact Karl Y. Bilimoria, M.D., M.S., email Bret Coons at bcoons@nm.org.

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Hospitals that were penalized more frequently in the Hospital-Acquired Condition (HAC) Reduction Program offered advanced services, were major teaching institutions and had better performance on other publicly reported process-of-care and outcome measures, according to a study in the July 28 issue of JAMA, a theme issue on Medicare and Medicaid at 50. These findings suggest that penalization in this program may not reflect poor quality of care but rather may be due to measurement and validity issues of the HAC program component measures.

The Affordable Care Act (ACA) established the HAC program in an effort to reduce the incidence of preventable adverse events that occur during hospitalizations in the United States. This program reduces payments to the lowest-performing hospitals. However, it is uncertain whether the program accurately measures quality and fairly penalizes hospitals, according to background information in the article.

Karl Y. Bilimoria, M.D., M.S., of the Feinberg School of Medicine, Northwestern University, Chicago, and colleagues evaluated the characteristics and performance of hospitals penalized in the HAC Reduction Program. Data for hospitals participating in this program for FY2015 were obtained from CMS’ Hospital Compare and combined with the 2014 American Hospital Association Annual Survey and FY2015 Medicare Impact File. The authors examined the association between hospital characteristics and HAC program penalization.

An 8-point hospital quality summary score was created using hospital characteristics related to clinical volume, accreditations, and offering of advanced care services. Publicly reported process-of-care and outcome measures were examined from 4 clinical areas (surgery, acute heart attack, heart failure, pneumonia).

Of the 3,284 hospitals participating in the HAC program, 721 (22 percent) were penalized. Hospitals were more likely to be penalized if they were accredited by the Joint Commission (24 percent accredited, 14 percent not accredited); they were major teaching hospitals (42 percent) or very major teaching hospitals (62 percent vs nonteaching hospitals, 17 percent); they cared for more complex patient populations based on case mix index; or they were safety-net hospitals vs non-safety-net hospitals (28 percent vs 20 percent).

Hospitals with higher quality summary scores had significantly better performance on 9 of 10 publicly reported process and outcomes measures compared with hospitals that had lower quality scores. However, hospitals with the highest quality score of 8 were penalized significantly more frequently than hospitals with the lowest quality score of 0 (67 percent [37/55] vs 13 percent [53/422]).

The researchers speculate that one explanation for these findings may be that these component measures are affected by surveillance bias, where differences in clinical practice result in varying rates of identifying an adverse outcome. “Hospitals that look more for adverse events frequently identify more events and incorrectly appear to have worse performance.”

In addition, hospital-to-hospital differences in information technology may also result in differences in the detection of adverse events.

The authors conclude that “these paradoxical findings suggest that the approach for assessing hospital penalties in the HAC Reduction Program merits reconsideration to ensure it is achieving the intended goals.”

(doi:10.1001/jama.2015.8609; 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 A.M. (ET) TUESDAY, JULY 28, 2015

Media Advisory: To contact Drew Altman, Ph.D., call Amy Jeter at 650-854-9400 or email amyj@kff.org.

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Although Medicare and Medicaid are playing a role in health care payment and delivery reform innovation, it will be difficult to enact large-scale program changes because of the conflicting priorities of beneficiaries, health practitioners and organizations, and policy makers, according to an article in the July 28 issue of JAMA, a theme issue on Medicare and Medicaid at 50.

Medicare and Medicaid are the nation’s two largest public health insurance programs, serving the elderly, those with disabilities, and mostly lower-income populations. Drew Altman, Ph.D., of the Kaiser Family Foundation, Menlo Park, Calif., and William H. Frist, M.D., former U.S. Senate majority leader, analyzed the roles of Medicare and Medicaid in the health system using publicly available data and private surveys of the public and beneficiaries.

Together, Medicare (n = 55 million) and Medicaid (n = 66 million) provide health coverage to about 111 million people, or 1 in 3 Americans, including 10 million dual-eligible people covered by both programs. That number is projected to reach 139 million people by 2025. The programs accounted for approximately $1 trillion in total spending in 2013 (Medicare, $585.7 billion; Medicaid, $449.4 billion). Together, they constitute 39 percent of national health spending, account for 23 percent of the federal budget, and generate 43 percent of hospital revenues.

Spending on the two programs for 2013 to 2023 is projected to increase at an average rate of 3.7 percent per year, which is slower than the projected growth for private health insurance, despite that Medicare and Medicaid generally serve populations with more illness and health problems.

The authors note that future issues confronting both programs include whether they will remain open-ended entitlements, the degree to which the programs may be privatized, the scope of their cost-sharing structures for beneficiaries, and the roles the programs will play in payment and delivery reform.

“While public attention has focused on the Affordable Care Act (ACA), Medicare and Medicaid remain the core of the nation’s public health insurance system. Together these programs serve more than a hundred million of the nation’s most vulnerable people—low-income children and adults, people with disabilities, and older persons. Because beneficiaries, health practitioners and organizations, and policy makers all have different interests in these programs, it is difficult to reconcile their conflicting perspectives and priorities and enact large-scale program changes. Few policies can simultaneously constrain spending, improve reimbursement rates, and protect and strengthen benefits. Reaching bipartisan agreement on policy change is especially challenging in the current polarized political environment.”

The authors add that both Medicare and Medicaid are changing their roles in the health care system to become more proactive forces for payment and delivery reform. “The goal of moving 90 percent of traditional Medicare reimbursements to alternative value-based payment arrangements by 2016 signals a new effort to use Medicare’s purchasing power to promote quality and reform the delivery of care. While it gets less attention, payment and delivery reform in Medicaid is also under way in virtually every state. Medicaid programs have also been increasingly aggressive purchasers of drugs.”

Together, Medicare and Medicaid have more than $1 trillion a year in purchasing power, “and they are now pursuing common strategies in the form of accountable care organizations, medical homes, managed care for chronically ill persons, and a variety of value-based payment options.”

“The private sector is generally regarded as the engine of innovation in the United States, but on the 50th anniversary of Medicare and Medicaid, health care’s 2 largest public health insurance programs are playing a much larger role in innovation in payment and delivery reform and reshaping the delivery of care for the future.”

(doi:10.1001/jama.2015.7811; 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.

Please Note: A podcast interview on this report will be available at JAMA.com at the embargo time.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 28, 2015

Media Advisory: To contact Sonja M. Swenson, B.A., call Adam Gorlick at 650-724-9842 or email agorlick@stanford.edu.

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In an analysis of expenditures for outpatient pharmacy products used by publicly insured children with serious chronic illness in California, treating hemophilia accounted for about 40 percent of expenditures but included just 0.4 percent of the group studied, suggesting a need to improve pricing for this and other effective yet high-cost medications, according to a study in the July 28 issue of JAMA.

Children with serious chronic conditions are increasingly likely to survive infancy, intensifying demands on health care delivery. Medication is one driver of their health care costs; high-cost drugs threaten cost-containment efforts. Sonja M. Swenson, B.A., of Stanford University, Stanford, Calif., and colleagues analyzed paid claims for children (ages, 0-21 years) using the California Children’s Services (CCS) paid claims data set (2010-2012). CCS provides insurance coverage, care coordination, and a regionalized system of pediatric specialty care facilities for approximately 180,000 publicly insured children with serious chronic illness. The data set includes age, sex, race/ethnicity, county of residence, enrollment dates, primary and secondary eligible diagnoses, claim diagnoses, and procedures for every enrollee. This study included children enrolled through fee-for-service care for at least 6 continuous months.

The analysis examined records of 34,330 children. Outpatient pharmacy expenditures totaled $475,718,130 (20 percent of total health care expenditures); per-child pharmacy expenditures ranged from $0.16 to $56,849,034, and average and median per-child expenditures were $13,857 and $791, respectively.

The product class of blood formation, coagulation, and thrombosis agents accounted for the greatest share (42 percent) of outpatient pharmacy expenditures, and antihemophilic factor (a protein that is essential to normal blood clotting and is lacking or deficient in persons having hemophilia A) represented 98 percent of this class’s expenditures or 41 percent of total pharmacy expenditures. Children with an antihemophilic factor paid claim were 0.4 percent of the cohort. The average per-child expenditure for antihemophilic factor was $1,343,262. Among children with antihemophilic factor claims and enrolled for all 3 years, the average and median per-child annualized expenditures were $634,054 and $152,280, respectively. The next largest percentage of total pharmacy expenditures was 9.2 percent for central nervous system agents, with an average expenditure of $1,869 per child.

“Antihemophilic factor is highly efficacious and essential in caring for children with hemophilia, putting pressure on public programs to seek improved pricing mechanisms for antihemophilic factor and other highly efficacious, high-cost medications,” the authors write.

“Our study underscores the potential effect of new, expensive but efficacious pharmaceuticals on public insurance programs for children with chronic illness. These findings may inform efforts to enhance value in these programs, particularly as new insurance frameworks, such as accountable care organizations, are considered.”

(doi:10.1001/jama.2015.7169; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The work was funded by a grant from the California HealthCare Foundation. 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: 11 A.M. (ET) TUESDAY, JULY 21, 2015

Media Advisory: To contact Shinji Nakahara, M.D., Ph.D., email snakahara-tky@umin.net. To contact Carolina Malta Hansen, M.D., call Samiha Khanna at 919-419-5069 or email samiha.khanna@duke.edu. To contact editorial co-author Graham Nichol, M.D., M.P.H., F.R.C.P., call Susan Gregg at 206-616-6730 or email sghanson@uw.edu.

To place an electronic embedded link to these studies and editorial in your story This link to the 1^st study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8068 This link to the 2nd study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7938 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7519

Two studies in the July 21 issue of JAMA find that use of interventions such as cardiopulmonary resuscitation and automated external defibrillators by bystanders and first responders have increased and were associated with improved survival and neurological outcomes for persons who experienced an out-of-hospital cardiac arrest.

Out-of-hospital cardiac arrest (OHCA) is an increasing health concern worldwide, with poor prognoses. Shinji Nakahara, M.D., Ph.D., of the Kanagawa University of Human Services, Yokosuka, Japan, and colleagues examined the associations between bystander interventions and changes in neurologically intact survival among patients with OHCA in Japan. The researchers used data from Japan’s nationwide OHCA registry, which started in January 2005. The registry includes all patients with OHCA transported to the hospital by emergency medical services (EMS) and recorded patients’ characteristics, prehospital interventions (including defibrillation using public-access automated external defibrillators [AEDs] and chest compression) and outcomes.

The study included 167,912 patients with bystander-witnessed OHCA between January 2005 and December 2012. The researchers found that during this time period, the number of these events increased and the rate of bystander chest compression, bystander-only defibrillation, and bystander defibrillation combined with EMS defibrillation also increased. In addition, likelihood of neurologically intact survival improved (age-adjusted proportion, 3.3 percent to 8.2 percent), but remained quite low. The increase in neurologically intact survival was associated with bystander defibrillation and chest compressions.

The authors write that further increases in use of chest compression by bystanders should be promoted. “In Japan it is used in just 50 percent of patients and is increasing slowly. Simplifying the basic life support procedure by omitting mouth-to-mouth breathing may have reduced hesitancy and increased its use. Facilitating chest compression has an economic advantage over deployment of expensive public-access AEDs. Fire departments provide training to more than 1,400,000 citizens every year to increase the prevalence of skills in basic resuscitation procedures, including chest compression and AED use. This effort should be further strengthened.”

(doi:10.1001/jama.2015.8068; 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.

Carolina Malta Hansen, M.D., of the Duke Clinical Research Institute, Durham, N.C., and colleagues examined the outcomes and changes in bystander and first-responder resuscitation efforts for cardiac arrest patients before arrival of the EMS following statewide initiatives to improve these efforts in North Carolina.

Out-of-hospital cardiac arrest is a major public health issue, associated with low survival and accounting for approximately 200,000 deaths per year in the United States. Early cardiopulmonary resuscitation (CPR) and defibrillation can improve outcomes if more widely adopted, according to background information in the article.

This study included 4,961 patients with out-of-hospital cardiac arrest for whom resuscitation was attempted and who were identified through the Cardiac Arrest Registry to Enhance Survival (2010-2013). First responders included police officers, firefighters, rescue squad, or life-saving crew trained to perform basic life support until arrival of the EMS. Statewide initiatives to improve bystander and first-responder interventions included training members of the general population in CPR and in use of AEDs, training first responders in team-based CPR including AED use and high-performance CPR, and training dispatch centers in recognition of cardiac arrest.

The combination of bystander CPR and first-responder defibrillation increased from 14 percent (51 of 362) in 2010 to 23 percent (104 of 451) in 2013. Survival with favorable neurological outcome increased from 7 percent in 2010 to 10 percent in 2013 and was associated with bystander-initiated CPR. Bystander and first-responder interventions were associated with higher survival to hospital discharge. Survival following EMS-initiated CPR and defibrillation was 15 percent compared with 34 percent following bystander-initiated CPR and defibrillation; 24 percent following bystander CPR and first-responder defibrillation; and 25 percent following first-responder CPR and defibrillation

“Our study presents novel findings indicating that improvements in bystander and first-responder CPR and defibrillation are both associated with increased survival,” the authors write. “Our findings suggest the possibility of improving outcomes by strengthening first-responder programs, in addition to increasing the number of bystanders who could then provide CPR, including those assisted by emergency dispatchers, and by improving EMS systems. This is particularly important for cardiac arrests that occur in residential areas and in areas with a long EMS response time, where public access defibrillation programs are unlikely to be implemented.”

(doi:10.1001/jama.2015.7938; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by the HeartRescue Project, which is funded by the Medtronic Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Bystander Interventions Can Improve Outcomes From Out-of-Hospital Cardiac Arrest

“Despite increased knowledge and use of bystander CPR as well as improved survival over time, ongoing efforts are needed to improve outcomes after OHCA,” write Graham Nichol, M.D., M.P.H., F.R.C.P., and Francis Kim, M.D., of the University of Washington, Seattle, in an accompanying editorial.

“Mortality after resuscitation from cardiac arrest continues to be high in many communities. Further improvements in outcomes will require additional coordinated efforts to improve resuscitation care. The Institute of Medicine has released a report that describes multiple steps to improve outcomes after cardiac arrest. Key recommendations of this report include simple, sustainable high-quality efforts to measure and improve the process and outcome of care, as well as increased training of EMS personnel and leadership and funding for resuscitation research. The current studies by Malta Hansen et al and by Nakahara et al demonstrate the potential benefit these changes can have on resuscitation outcomes. Lay persons can improve outcomes after cardiac arrest in their community by participating in their system of care as well as supporting increased measurement and resuscitation research.”

(doi:10.1001/jama.2015.7519; 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: 11 A.M. (ET) TUESDAY, JULY 21, 2015

Media Advisory: To contact Assiamira Ferrara, M.D., Ph.D., call Janet Byron at 510-891-3115 or email Janet.L.Byron@kp.org. To contact editorial co-author Joshua M. Sharfstein, M.D., call Barbara Benham at 410-614-6029 or email bbenham1@jhu.edu. To contact editorial co-author Phil B. Fontanarosa, M.D., M.B.A., call Jim Michalski at 312-464-5785 or email Jim.Michalski@jamanetwork.org.

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Although some previous studies have suggested an increased risk of bladder cancer with use of the diabetes drug pioglitazone, analyses that included nearly 200,000 patients found no statistically significant increased risk, however a small increased risk could not be excluded, according to a study in the July 21 issue of JAMA. Additional analyses with another large group found that use of pioglitazone was associated with an increase in the risk of prostate and pancreatic cancer, although further investigation is needed to assess whether the associations are causal or due to other factors.

Assiamira Ferrara, M.D., Ph.D., of Kaiser Permanente Northern California, Oakland, and colleagues studied with several groups of persons with diabetes: a bladder cancer cohort that followed 193,099 persons (40 years or older in 1997-2002) until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders (factors that can influence outcomes that may improperly skew the results); and a cohort analysis of 10 additional cancers included 236,507 persons (40 years or older in 1997-2005) and followed until June 2012. The additional cancers were prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. All cohorts were from Kaiser Permanente Northern California.

Among the persons in the bladder cancer cohort, 34,181 (18 percent) received pioglitazone (median duration, 2.8 years) and 1,261 had incident bladder cancer. Ever use of pioglitazone was not associated with bladder cancer risk. Results were similar in case-control analyses (pioglitazone use: 19.6 percent among case patients and 17.5 percent among controls).

In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer and pancreatic cancer. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose.

“These studies were conducted to address safety concerns related to the risk of cancer after treatment with pioglitazone,” the authors write.

“There was no statistically significant increased risk of bladder cancer associated with pioglitazone use. However, a small increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether the observed associations are causal or due to chance, residual confounding, or reverse causality.”

(doi:10.1001/jama.2015.7996; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was funded by a grant from Takeda Development Center Americas Inc. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: The Safety of Prescription Drugs

Joshua M. Sharfstein, M.D., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and Aaron S. Kesselheim, M.D., J.D., M.P.H., of Brigham and Women’s Hospital, Boston, comment on the findings of this study in an accompanying editorial.

“That these data from the report by Lewis et al shed new light on the safety of pioglitazone reflects the dynamic nature of many drug safety questions. As in this case, caution and further review are the appropriate responses to many safety signals. But when emerging available data—clinical, laboratory, observational, and even population-based studies— create a compelling picture of risk in excess of potential benefit to patients, the FDA should act to protect the public.”

(doi:10.1001/jama.2015.7151; 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.

Editorial: Evaluating Research on the Safety of Medical Therapies

In an accompanying editorial, Phil B. Fontanarosa, M.D., M.B.A., Executive Deputy Editor, JAMA, Chicago, and colleagues discuss the responsibility of medical journals to the health of the public in reviewing studies evaluating the potential relationship between drugs, devices, or vaccines and adverse outcomes.

“The findings of the study by Lewis et al demonstrating no statistically significant association between the use of pioglitazone and the risk of bladder cancer are important because of the prevalence of type 2 diabetes, fairly widespread use of pioglitazone, and safety concerns about this drug.”

“Even though no observational study examining the relationship between an exposure and an outcome can definitively establish ‘positive’ cause-and-effect results, and no observational study can definitively prove ‘negative’ results, each study adds to the totality of evidence regarding the safety of drugs, devices, and vaccines. By publishing the results of these studies, JAMA will continue to provide information physicians can use in discussions with patients and regulatory bodies can use in policy decisions about the benefits and risks of various therapies.”

(doi:10.1001/jama.2015.8232; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 21, 2015

Media Advisory: To contact Lisa A. Jackson, M.D., M.P.H., call Joan DeClaire at 206-287-2653 or email declaire.j@ghc.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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7916

In a phase 2 trial that included nearly 1,000 adults, the AS03 and MF59 adjuvants (a component that improves immune response of inactivated influenza vaccines) increased the immune responses to two doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest amount of antibody response, according to a study in the July 21 issue of JAMA.

In March 2013 the first human infections with the avian influenza A(H7N9) virus were reported in China, and since that time hundreds of cases have been documented. While most infections are believed to result from exposure to infected poultry, the potential for viral adaptation that would facilitate person-to-person transmission is a major concern. Previous experience with an inactivated H7N7 influenza vaccine indicated that hemagglutinin (a substance on the outer coat of the influenza virus) H7 is poorly immunogenic, necessitating evaluation of adjuvanted H7N9 vaccines, according to background information in the article.

Lisa A. Jackson, M.D., M.P.H., of Group Health Research Institute, Seattle, and colleagues randomly assigned 980 adults (19 through 64 years or age) to receive the H7N9 vaccine on days 0 and 21 at doses of 3.75 µg, 7.5 µg, 15 µg, and 45 µg of hemagglutinin with or without AS03 or MF59 adjuvant. The study was conducted at 5 U.S. sites from September 2013 through November 2013; safety follow-up was completed in January 2015.

Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an hemagglutination inhibition antibody (HIA) titer of 40 or higher was 2 percent without adjuvant (n = 94), 84 percent with AS03 adjuvant (n = 96), and 57 percent with MF59 adjuvant (n = 92).

The two schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean (average) titers (GMTs) than the group induced by two AS03-adjuvanted formulations but higher GMTs than two doses of MF59-adjuvanted formulation. Older age and prior administration of seasonal influenza vaccine were independently associated with a decreased antibody response.

“These results imply that, of the options currently available utilizing adjuvants included in the national stockpile, based on the immune response data, AS03 should be considered a first-line adjuvant for strategies incorporating an inactivated H7N9 vaccine in adults,” the authors write.

“This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs.”

(doi:10.1001/jama.2015.7916; 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 A.M. (ET) TUESDAY, JULY 21, 2015

Media Advisory: To contact Anton Pottegard, M.Sc.Pharm., Ph.D., email apottegaard@health.sdu.dk.

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Researchers have found an association between treatment with the antibiotic dicloxacillin and a decrease in international normalized ratio (INR; a measure of blood coagulation) levels among patients taking the vitamin K antagonists warfarin or phenprocoumon, according to a study in the July 21 issue of JAMA.

A challenge in the use of vitamin K antagonists (VKAs) is the potential for drug-drug interactions, resulting in insufficient or excessive anticoagulation. Solid data are lacking for most alleged interactions. In case reports, the commonly used antibiotic dicloxacillin has been reported to lower the anticoagulant effect of warfarin, the most used VKA, according the background information in the article.

Anton Pottegard, M.Sc.Pharm., Ph.D., of the University of Southern Denmark, Odense, and colleagues identified patients currently taking warfarin via the anticoagulant database Thrombobase, a clinical database of all VKA-treated patients (n = 7,400) followed up by 3 outpatient clinics and 50 general practitioners in Funen, Denmark. The researchers included all patients who filled a prescription for dicloxacillin while receiving warfarin therapy between March 1998 and November 2012. INR results were grouped by the week relative to dicloxacillin exposure. The last INR measurement before dicloxacillin exposure was compared with the first measurement within weeks 2 to 4 after dicloxacillin exposure. The authors also assessed the use of dicloxacillin among patients taking another VKA, phenprocoumon.

Of 519 patients taking warfarin and initiating treatment with dicloxacillin, 236 met inclusion criteria. The average INR level prior to dicloxacillin exposure was 2.6 compared with 2, 2 to 4 weeks after dicloxacillin exposure, an average decrease of 0.6. In total, 61 percent (n = 144) experienced sub-therapeutic INR levels (<2.0) within 2 to 4 weeks after dicloxacillin treatment.

Among patients taking phenprocoumon (n = 64), average INR levels were 2.6 before exposure to dicloxacillin compared with 2.3 after exposure, an average decrease of 0.3. The proportion with sub-therapeutic INR levels after dicloxacillin exposure was 41 percent (n = 26).

“Physicians should be aware that dicloxacillin treatment may cause a significant decrease in INR levels among patients taking VKAs,” the authors write.

(doi:10.1001/jama.2015.6669; 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 A.M. (ET) TUESDAY, JULY 14, 2015

Media Advisory: To contact Udo Hoffmann, M.D., M.P.H., call McKenzie Ridings at 617-726-0274 or email mridings@partners.org. To contact Ankur Pandya, Ph.D., call Marge Dwyer at 617-432-8416 or email mhdwyer@hsph.harvard.edu. To contact editorial co-author Philip Greenland, M.D., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu.

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An examination of the 2013 guidelines for determining statin eligibility, compared to guidelines from 2004, indicates that they are associated with greater accuracy and efficiency in identifying increased risk of cardiovascular disease (CVD) events and presence of subclinical coronary artery disease, particularly in individuals at intermediate risk, according to a study in the July 14 issue of JAMA.

The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of blood cholesterol represent a shift in the treatment approach for the primary prevention of CVD, from focusing on the treatment of traditional risk factors, including the management of low-density lipoprotein cholesterol levels, to absolute cardiovascular risk as estimated by the 10-year atherosclerotic CVD (ASCVD) score for statin treatment. It has been unclear whether this approach improves identification of adults at higher risk of cardiovascular events, according to background information in the article.

Udo Hoffmann, M.D., M.P.H., of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues conducted a study determine whether the ACC/AHA guidelines improve identification of individuals who develop incident CVD and/or have coronary artery calcification (CAC) compared with the National Cholesterol Education Program’s Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) guidelines. The study included participants from the offspring and third-generation cohorts of the Framingham Heart Study. Participants underwent multi-detector computed tomography for CAC between 2002 and 2005 and were followed up for a median of 9 years for new CVD.

The study population consisted of 2,435 participants not taking lipid-lowering therapy. The average age was 51 years; 56 percent were women. There were a total of 74 (3 percent) incident CVD events (40 nonfatal heart attacks, 31 nonfatal strokes, and 3 with fatal coronary heart disease [CHD]) and 43 (2 percent) incident CHD events (40 non­fatal heart attacks and 3 with fatal CHD).

The researchers found that overall, more participants were eligible for statin treatment when applying the 2013 ACC/AHA guidelines compared with the 2004 ATP III guidelines (39 percent vs 14 percent). Among those eligible for statin treatment by the ATP III guidelines, 7 percent developed incident CVD compared with 2 percent among noneligible participants. Applying the ACC/AHA guidelines, among those eligible for statin treatment, 6 percent developed incident CVD compared with only 1 percent among those not eligible. The hazard ratio (risk) of having incident CVD among statin-eligible vs noneligible participants was also higher when applying the ACC/AHA guidelines’ statin eligibility criteria compared with the ATP III guidelines. “This finding is consistent across subgroups and particularly important in participants at intermediate CVD risk on the Framingham Risk Scores, the most challenging group in clinical practice for whom to decide to initiate statin therapy.”

Participants with CAC were more likely to be statin eligible by ACC/AHA than by ATP III.

The authors write that extrapolating their findings to the approximately 10 million U.S. adults who are newly eligible for statins, an estimated 41,000 to 63,000 incident CVD events would be prevented over a 10-year period by adopting the ACC/AHA guidelines. They note that the absolute cardiovascular event risk of statin-noneligible adults is not much lower with the ACC/AHA guidelines (1 percent) compared with the ATP III guidelines (2.4 percent), and the larger benefit may be that the ACC/AHA guidelines identify many more statin-eligible participants with a similarly high event rate as the ATP III guidelines (6.3 percent vs 6.9 percent).

The researchers add that a risk-benefit analysis considering costs and potential adverse effects of statins, especially in patients with prediabetes and in lower-risk patients, is needed to provide a complete assessment of the effects of the change in statin eligibility guidelines on the health care system.

(doi:10.1001/jama.2015.7515; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study. Dr. Pursnani was supported by a National Institutes of Health grant. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

A microsimulation model-based analyses suggests that the health benefits associated with the 10-year atherosclerotic cardiovascular disease risk threshold of 7.5 percent or higher used in the 2013 ACC-AHA cholesterol guidelines are worth the additional costs required to achieve these health gains, and that a more lenient threshold might also be cost-effective, according to a study in the July 14 issue of JAMA.

In November 2013 the American College of Cardiology and the American Heart Association (ACC/AHA) released new recommendations to guide statin treatment initiation for the primary prevention of cardiovascular disease. These guidelines established 4 categories for statin treatment eligibility for adults 40 to 75 years of age, including 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 7.5 percent or higher. It has been estimated that based on the new ASCVD risk threshold that 8.2 million additional adults in the U.S. would be recommended for statin treatment compared with previous recommendations. This expansion of statin treatment eligibility has been controversial, with some critics arguing that the guidelines substantially overestimate risk, and when taken in conjunction with more lenient treatment thresholds, millions of adults in the U.S. would be exposed to unnecessary statin treatment costs and risks, according to background information in the article.

Ankur Pandya, Ph.D., of the Harvard T.H. Chan School of Public Health, Boston, and colleagues performed a cost-effectiveness analysis of the ACC/AHA cholesterol treatment guidelines. With use of a microsimulation model, hypothetical individuals from a representative U.S. population 40 to 75 years of age received statin treatment, experienced ASCVD events, and died from ASCVD-related or non-ASCVD-related causes based on ASCVD natural history and statin treatment parameters. Data sources for model parameters included National Health and Nutrition Examination Surveys, large clinical trials and meta-analyses for statin benefits and treatment, and other published sources.

The researchers found that the current ASCVD threshold of 7.5 percent or higher, which was estimated to be associated with 48 percent of adults treated with statins, had an incremental cost-effectiveness ratio (ICER) of $37,000/quality-adjusted life-year (QALY) compared with a 10 percent or higher threshold. More lenient ASCVD thresholds of 4.0 percent or higher (61 percent of adults treated) and 3.0 percent or higher (67 percent of adults treated) had ICERs of $81,000/QALY and $140,000/QALY, respectively.

Shifting from the 7.5 percent or higher threshold to 3.0 percent or higher to 4.0 percent or higher was associated with an estimated additional 125,000 to 160,000 CVD events averted.

The optimal ASCVD threshold was sensitive to patient preferences for taking a pill daily, changes to statin price, and the risk of statin-induced diabetes.

“The decision to initiate statin treatment for adults without CVD should ultimately be informed by both evidence-based policies and patient preferences,” the authors write.

(doi:10.1001/jama.2015.6822; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work is supported by a grant to the Harvard School of Public Health from the National Heart, Lung, and Blood Institute (Dr. Gaziano). Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Please Note: A podcast interview on this study is available at https://media.jamanetwork.com.

Editorial: Cholesterol Lowering in 2015

“Based on available evidence, including the 2 reports in this issue of JAMA, answers to the questions of in whom and how regarding cholesterol lowering are now more clear than they were just 18 months ago,” write Philip Greenland, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, and Senior Editor, JAMA, and Michael S. Lauer, M.D., of the National Heart, Lung, and Blood Institute, Bethesda, Md., in an accompanying editorial.

“Available evidence indicates that statins are both effective and cost-effective for primary prevention even among low-risk individuals. Although lifestyle interventions must be employed across all segments of the population, for many people a statin drug will also be required to minimize risk. Where to set the treatment threshold and how to determine the individual’s level of risk are also becoming progressively clarified.”

“There is no longer any question as to whether to offer treatment with statins for patients for primary prevention, and there should now be fewer questions about how to treat and in whom. Rather, the next phase of research should be directed at better ways of applying lifestyle and drug treatments to the millions, and possibly billions, worldwide who could potentially benefit from a cost-effective approach to primary prevention of ASCVD.”

(doi:10.1001/jama.2015.7434; 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: 11 A.M. (ET) TUESDAY, JULY 14, 2015

Media Advisory: To contact George L. Bakris, M.D., call John Easton at 773-795-5225 or email John.easton@uchospitals.edu. To contact editorial author Wolfgang C. Winkelmayer, M.D., Sc.D., call Julia Parsons at 713-798-4738 or email Julia.Parsons@bcm.edu.

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Among patients with diabetic kidney disease and hyperkalemia (elevated potassium levels in the blood), a potentially life-threatening condition, those who received the new drug patiromer, twice daily for four weeks, had significant decreases in potassium levels which lasted through one year, according to a study in the July 14 issue of JAMA.

Patients at the highest risk for hyperkalemia are those taking renin-angiotensin-aldosterone system (RAAS) inhibitors with stage 3 or greater chronic kidney disease (CKD) who also have diabetes mellitus, heart failure, or both. Because of the limited utility of current options to manage hyperkalemia, particularly over the long term, clinicians frequently must either avoid using RAAS inhibitors or use them at lower than recommended doses, according to background information in the article. Use of RAAS can help further slow progression of renal disease among patients with diabetes.

Patiromer is an orally administered drug being investigated for the treatment of hyperkalemia. The active portion, patiromer, is a non-absorbed polymer that binds potassium throughout the gastrointestinal tract, thus increasing excretion of potassium in the stool and lowering serum potassium levels. Prior patiromer clinical trials have demonstrated the drug’s utility in treating hyperkalemia in other at-risk populations for periods ranging from a few days to up to 12 weeks.

George L. Bakris, M.D., of University of Chicago Medicine, Chicago, and colleagues randomly assigned 306 outpatients with type 2 diabetes and an elevated serum potassium level to 1 of 3 starting doses of patiromer twice daily. All patients received RAAS inhibitors prior to and during study treatment. The phase 2 trial was conducted at 48 sites in Europe from June 2011 to June 2013.

The researchers found that patiromer significantly reduced serum potassium levels across dose groups (8.4 – 33.6 g/d) through week 4 in patients with a varying severity of hyperkalemia, and consistently maintained normal serum potassium levels over 52 weeks. Over this period, patiromer use demonstrated high adherence, low risk of hypokalemia (abnormally low level of potassium in the blood), and minimal discontinuations because of adverse events.

Over the 52 weeks, hypomagnesemia (abnormally low level of magnesium in the blood; 7 percent) was the most common treatment-related adverse event, mild to moderate constipation (6 percent) was the most common gastrointestinal adverse event, and hypokalemia occurred in 6 percent of patients.

The authors note that based on the findings of this study, a phase 3 study was performed in which patiromer demonstrated consistent efficacy as shown in this study. “The consistency of results across the secondary end points [including average change in serum potassium level through 52 weeks] supports the conclusions regarding long-term efficacy.”

(doi:10.1001/jama.2015.7446; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Treatment of Hyperkalemia

In an accompanying editorial, Wolfgang C. Winkelmayer, M.D., Sc.D., of the Baylor College of Medicine, Houston, and Associate Editor, JAMA, comments on the findings of this study.

“Once hyperkalemia drugs are approved based on trials of the surrogate of potassium concentration, it is uncertain if the manufacturers will be motivated to conduct such crucial trials of the hard end points that patients care about (reduced progression of CKD and deferral of dialysis; better heart failure outcomes), especially if the alternative is to spend the same dollars on marketing and company-sponsored and -directed contract research of their already-approved product. Thus, as part of the approval process, the FDA and other agencies should consider mandating a sizeable postmarketing trial and safety surveillance program to clearly establish whether the assumptions underlying the value proposition of chronic hyperkalemia treatments actually hold.”

(doi:10.1001/jama.2015.7521; 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: 11 A.M. (ET) TUESDAY, JULY 14, 2015

Media Advisory: To contact Jason L. Schwartz, Ph.D., M.B.E., call Min Pullan at 609-258-9045 or email mpullan@princeton.edu.

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An examination of state vaccination requirements for adolescents finds that the human papillomavirus (HPV) vaccine is currently required in only two states, many fewer than another vaccine associated with sexual transmission (hepatitis B) and another primarily recommended for adolescents (meningococcal conjugate), according to a study in the July 14 issue of JAMA.

Eight years after HPV vaccines were first recommended in the United States, vaccination coverage is substantially below the Healthy People 2020 target of 80 percent. Data from the U.S. Centers for Disease Control and Prevention (CDC) show that 38 percent of adolescent girls and 14 percent of adolescent boys had completed the 3-dose series in 2013. Recent efforts to address these deficits emphasize that HPV vaccines should not be viewed or treated differently than other routinely recommended vaccines, according to background information in the article.

Jason L. Schwartz, Ph.D., M.B.E., and Laurel A. Easterling, of Princeton University, Princeton, N.J., examined the presence and timing of state requirements for vaccines with particular relevance to adolescent health and compared those findings to the implementation of HPV vaccines. Vaccines studied were those used by the CDC to evaluate adolescent vaccination that were added to the recommended schedule since 1990 and protected against new disease targets: hepatitis B, varicella, meningococcal conjugate, and HPV. The researchers identified the earliest date that a requirement, if applicable, took effect for each vaccine in every state and the District of Columbia (D.C.) for any childhood, adolescent, or college-aged population.

Vaccination requirements were more common for hepatitis B vaccine (47 states and D.C.), varicella vaccine (50 states and D.C.), and meningococcal conjugate vaccine (29 states and D.C.) than for HPV vaccine (2 states and D.C.). Through March 2015, only Virginia and D.C. required HPV vaccination, and each includes broad, vaccine-specific exemption procedures. A third requirement will take effect in Rhode Island in August 2015.

In a comparison of requirements eight years after publication of a routine Advisory Committee on Immunization Practices recommendation, hepatitis B vaccine was required in 36 states and D.C., varicella vaccine in 38 states and D.C., meningococcal conjugate vaccine in 21 states and D.C., and HPV vaccine in 1 state and D.C.

“Why HPV vaccine requirements have not been more widely implemented is unclear, but may reflect reluctance among states to revisit the contentious political climate surrounding requirement proposals in 2006-2007. The novelty of the 3-dose HPV vaccine series in the adolescent schedule may present additional challenges. The recent approval and recommendation of a 9-valent HPV vaccine offers a new opportunity to consider all strategies shown to promote high vaccination rates, including school requirements,” the authors write.

(doi:10.1001/jama.2015.6041; 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: 4 P.M. (ET) MONDAY, JULY 13, 2015

Media Advisory: To contact Diana W. Bianchi, M.D., call Jeremy Lechan at 617-636-0104 or email JLechan@tuftsmedicalcenter.org. To contact editorial co-author Roberto Romero, M.D., D.Med.Sci., call 301-496-5133 or email Bob Bock (bockr@mail.nih.gov) or Katie Rush (katie.rush@nih.gov).

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In preliminary research, a small number of occult (hidden) malignancies were subsequently diagnosed among pregnant women whose noninvasive prenatal testing results showed chromosomal abnormalities but the fetal karyotype was subsequently shown to be normal, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the 19th International Conference on Prenatal Diagnosis and Therapy in Washington, D.C.

Understanding the relationship between aneuploidy detection (an abnormal number of chromosomes) on noninvasive prenatal testing (NIPT) and occult maternal malignancies may explain abnormal NIPT results that are discordant with the actual fetal karyotype (the chromosomal characteristics of a cell) and improve maternal clinical care. Many professional societies have recommended that NIPT be offered to pregnant women at high risk for having a fetus with autosomal (pertaining to a chromosome that is not a sex chromosome) aneuploidy, with follow-up diagnostic testing (amniocentesis or chorionic villus sampling) recommended to confirm a positive test result, according to background information in the article.

Diana W. Bianchi, M.D., of Tufts Medical Center, Boston, and colleagues examined DNA sequencing data in a series of pregnant women with abnormal NIPT results involving aneuploidies of certain chromosomes, who were diagnosed with cancer after prenatal testing occurred. The case patients were identified from 125,426 samples submitted between February 2012 and September 2014 from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening.

Among the clinical samples, 3,757 (3 percent) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. These were reported to the ordering physician with recommendations for further evaluation. From this set of 3,757 samples, 10 cases of maternal cancer were identified. Detailed clinical and sequencing data were obtained in 8. Maternal cancers most frequently occurred with the rare NIPT finding of more than 1 aneuploidy detected (7 known cancers among 39 cases of multiple aneuploidies by NIPT, 18 percent). In 1 case, blood was sampled after completion of treatment for colorectal cancer and the abnormal pattern was no longer evident.

“Here we have shown that occult maternal malignancies may provide a biological explanation for some discordant NIPT results. This is presumably due to the cell-free DNA that is released into maternal circulation from apoptotic [death of cells] malignant cells,” the authors write.

The researchers add that these data underscore the necessity of performing a diagnostic procedure to determine the true fetal karyotype whenever NIPT results reveal chromosomal abnormalities. “When there is discordance between the fetal karyotype and NIPT result, occult maternal malignancy, although very uncommon, may be an explanation for the findings. Based on the results of the study, we estimate there is between a 20 percent and 44 percent risk of maternal cancer if multiple aneuploidies are detected. However, until further studies are done to assess the clinical implications of discordant NIPT and fetal karyotype results, it is not clear what, if any, follow-up clinical evaluation is appropriate.”

(doi:10.1001/jama.2015.7120; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Funding for the study was provided by Illumina. Sponsored research funding from Illumina that is administered through Tufts Medical Center paid for the time that Dr. Bianchi spent working with the full-time Illumina employees to design the study, analyze the data, and prepare the manuscript. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Please Note: There will be a video and audio report for this study. It will be posted at 4 p.m. ET Monday, July 13 at https://broadcast.jamanetwork.com/, and include broadcast-quality downloadable video and audio files, B-roll, scripts, and other images. Please email JAMAReport@synapticdigital.com with any questions.

Editorial: Noninvasive Prenatal Testing and Detection of Maternal Cancer

“At this time, there is insufficient evidence about the benefits, risks, and costs of reporting the incidental findings, as Bianchi et al mention,” write Roberto Romero, M.D., D.Med.Sci., of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md., and Maurice J. Mahoney, M.D., J.D., of the Yale University School of Medicine, New Haven, Conn., in an accompanying editorial.

“As the authors correctly recommend, the data emphasize the need for performing a diagnostic procedure to determine the fetal karyotype in all situations in which there is an abnormal NIPT result. Given that it is likely that NIPT will increase in the coming years, an active dialogue among stakeholders (obstetricians, patients, laboratories, ethicists, policy makers, etc.) needs to take place to provide informed advice to potentially affected pregnant women and to guide the care of such patients.”

(doi:10.1001/jama.2015.7523; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported (in part) by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, OHHS. Please see the article for additional information, including financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 7, 2015

Media Advisory: To contact Deborah A. Levine, M.D., M.P.H., call Kara Gavin at 734-764-2220 or email kegavin@umich.edu. To contact editorial co-author Philip B. Gorelick, call Sarina Gleason at 517-355-9742 or email sarina.gleason@cabs.msu.edu.

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Stroke Associated With Both Immediate and Long-Term Decline in Cognitive Function

In a study that included nearly 24,000 participants, those who experienced a stroke had an acute decline in cognitive function and also accelerated and persistent cognitive decline over 6 years, according to an article in the July 7 issue of JAMA.

Each year, approximately 795,000 U.S. residents experience a stroke. In 2010, almost 7 million adults were stroke survivors. Cognitive decline is a major cause of disability in stroke survivors. The magnitude of survivors’ cognitive changes after stroke has been uncertain, according to background information in the article.

Deborah A. Levine, M.D., M.P.H., of the University of Michigan Medical School and Ann Arbor VA Health System, and colleagues examined the changes in cognitive function among survivors of incident stroke, controlling for their pre-stroke cognitive trajectories. The study included 23,572 U.S. participants 45 years or older without cognitive impairment at study entry (2003-2007), and followed up through March 2013. Over a median follow-up of 6.1 years, 515 participants (306 white, 209 black) survived incident stroke and 23,057 remained stroke free. Participants are in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.

The researchers found that stroke survivors had a significantly faster rate of incident cognitive impairment after stroke compared with the pre-stroke rate, controlling for the odds of developing cognitive impairment before or acutely after the event. Incident stroke was associated with accelerated and persistent declines in global cognition and executive function (cognitive process that regulates an individual’s ability to organize thoughts and activities, prioritize tasks, manage time and make decisions), after accounting for individuals’ cognitive changes before and acutely after the event. In addition, there were significant, acute declines in new learning and verbal memory after stroke but no acceleration of pre-stroke rates of change in these functions.

“Our study has potential implications for clinical practice, research, and health care policy. Although clinical practice guidelines and quality improvement programs recommend cognitive assessments be performed for patients with stroke before hospital discharge and also in the postacute settings, our results suggest that stroke survivors also warrant monitoring for mounting cognitive impairment over the years after the event,” the authors write.

“Moreover, our results suggest that long-term cognitive dysfunction is a potential domain for evaluating acute stroke therapies. As adults increasingly survive stroke, cases of post-stroke cognitive impairment will multiply. Given that post-stroke cognitive impairment increases mortality, morbidity, and health care costs, health systems and payers will need to develop cost-effective systems of care that will best manage the long-term needs and cognitive problems of this increasing and vulnerable stroke survivor population.”

(doi:10.1001/jama.2015.6968; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by a cooperative agreement from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services. Additional funding was provided by a grant from the National Institute on Aging (Dr. Levine). Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Stroke and Cognitive Decline

“Clinicians should remain alert for the presence of clinically manifest stroke or silent stroke identified incidentally on neuroimaging study, because these findings may be harbingers of future major complications such as recurrent stroke, cognitive impairment, and disability,” write Philip B. Gorelick, M.D., M.P.H., and David Nyenhuis, Ph.D., of the Michigan State University College of Human Medicine, Grand Rapids, in an accompanying editorial.

“Information gained from cognitive screening can be used to plan for daily management of patient care based on cognitive performance and need for possible formal neuropsychological testing. In addition, intensification of vascular risk management may be indicated for patients at risk of cognitive impairment in an attempt to prevent subsequent stroke, myocardial infarction, loss of cognitive vitality, and overall disability.”

(doi:10.1001/jama.2015.7149; 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: 11 A.M. (ET) TUESDAY, JULY 7, 2015

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Life Expectancy Substantially Lower With Combination of Diabetes, Stroke, or Heart Attack

In an analysis that included nearly 1.2 million participants and more than 135,000 deaths, mortality associated with a history of diabetes, stroke, or heart attack was similar for each condition, and the risk of death increased substantially with each additional condition a patient had, according to a study in the July 7 issue of JAMA.

The prevalence of cardiometabolic multimorbidity (defined in this study as a history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction [MI; heart attack]) is increasing rapidly. Considerable evidence exists about the mortality risk of having any 1 of these conditions alone. However, evidence is sparse about life expectancy among people who have 2 or 3 cardiometabolic conditions at the same time, according to background information in the article.

John Danesh, F.Med.Sci., of the University of Cambridge, England, and colleagues estimated reductions in life expectancy associated with cardiometabolic multimorbidity. Age- and sex-adjusted mortality rates and hazard ratios (HR) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The hazard ratios from this study population were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7,995 deaths).

Among the primary findings:

• Compared to participants who did not have a history of any of these conditions (diabetes mellitus, stroke, heart attack), participants who had 1 condition had about twice the rate of death; 2 conditions, about 4 times the rate of death; and all 3 conditions, about 8 times the rate of death. “Our results emphasize the importance of measures to prevent cardiovascular disease in people who already have diabetes, and, conversely, to avert diabetes in people who already have cardiovascular disease,” the authors write.

• The results suggest that estimated reductions in life expectancy associated with cardiometabolic multimorbidity are of similar magnitude to those previously noted for exposures of major concern to public health, such as lifelong smoking (10 years of reduced life expectancy) and infection with the human immunodeficiency virus (11 years of reduced life expectancy). For example, at the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. The researchers estimated even greater reductions in life expectancy in patients with multimorbidity at younger ages, such as 23 years of life lost in patients with 3 conditions at the age of 40 years.

• Modification by sex of associations between cardiometabolic multimorbidity and mortality were noted. For men, the association between baseline cardiovascular disease (i.e., a history of stroke or MI) and reduced survival was stronger than for women, whereas the association between baseline diabetes and reduced survival was stronger for women. Consequently, about 60 percent of the years of life lost from cardiometabolic multimorbidity can be attributed to cardiovascular deaths for men compared with only about 45 percent for women. “Nevertheless, for both men and women, our findings indicate that associations of cardiometabolic multimorbidity extend beyond cardiovascular mortality. Future work will seek to elucidate explanations for these interactions by sex.”

The authors write that their results highlight the need to balance the primary prevention and secondary prevention of cardiovascular disease. “About 1 percent of the participants in the cohorts we studied had cardiometabolic multimorbidity compared with an estimate of 3 percent from recent surveys in the United States. There are currently an estimated 10 million adults in the United States and the European Union with cardiometabolic multimorbidity. Nevertheless, an overemphasis on the substantial reductions in life expectancy estimated for the subpopulation with multimorbidity could divert attention and resources away from population-wide strategies that aim to improve health for the large majority of the population.”

(doi:10.1001/jama.2015.7008; 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 A.M. (ET) TUESDAY, JULY 7, 2015

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Benefit of Extending Anticoagulation Therapy Lost After Discontinuation of Therapy

Among patients with a first episode of pulmonary embolism (the obstruction of the pulmonary artery or a branch of it leading to the lungs by a blood clot) who received 6 months of anticoagulant treatment, an additional 18 months of treatment with warfarin reduced the risk of additional blood clots and major bleeding, however, the benefit was not maintained after discontinuation of anticoagulation therapy, according to a study in the July 7 issue of JAMA.

When anticoagulant therapy is stopped after 3 to 6 months of treatment, patients with a first episode of unprovoked (no major risk factor) venous thromboembolism (blood clot within a vein) have a much higher risk of recurrence than those with venous thromboembolism provoked by a transient risk factor (e.g., surgery). In this high-risk population, extending anticoagulation beyond 3 to 6 months is associated with a reduction in the risk of recurrence as long as treatment is continued. However, whether this benefit is maintained thereafter has been uncertain because most previous studies did not include follow-up of patients after discontinuation of treatment, according to background information in the article.

Francis Couturaud, M.D., Ph.D., of the Universite de Bretagne Occidentale, Brest, France, and colleagues conducted a study that included 371 adult patients who had experienced a first episode of symptomatic unprovoked pulmonary embolism (i.e., with no major risk factor for a blood clot) and had been treated initially for 6 uninterrupted months with a vitamin K antagonist. The patients were randomly assigned to warfarin or placebo for 18 months; median follow-up was 24 months. The trial was conducted at 14 French centers.

After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event. During the 18-month treatment period, the primary outcome (the composite of recurrent venous thromboembolism or major bleeding at 18 months after randomization) occurred in 6 of 184 patients (3 percent) in the warfarin group and in 25 of 187 patients (13.5 percent) in the placebo group, resulting in a relative risk reduction of 78 percent in favor of warfarin. This result was driven by a reduction in the risk of recurrent venous thromboembolism, with the risk of bleeding increasing to a minimal extent.

This benefit of anticoagulation was lost after anticoagulation was discontinued. During the 42-month entire study period (including the study treatment and follow-up periods), the composite outcome occurred in 33 patients (21 percent) in the warfarin group and in 42 (24 percent) in the placebo group. Rates of recurrent venous thromboembolism, major bleeding, and unrelated death did not differ between groups.

The authors note that their results suggest that patients such as those who participated in this study require long-term secondary prevention measures. “Whether these should include systematic treatment with vitamin K antagonists, new anticoagulants or aspirin, or be tailored according to patient risk factors needs further investigation.”

(doi:10.1001/jama.2015.7046; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was supported by grants from the Programme Hospitalier de Recherche Clinique (French Department of Health), and the sponsor was the University Hospital of Brest. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Please Note: There is related content in this issue of JAMA on this topic. These articles, along with a podcast, are available to the media at https://media.jamanetwork.com.

Long-term vs Short-term Therapy With Vitamin K Antagonists for Symptomatic Venous Thromboembolism

Computed Tomographic Pulmonary Angiography for Pulmonary Embolism

Edoxaban (Savaysa) – The Fourth New Oral Anticoagulant

Treatment Duration for Pulmonary Embolism

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 7, 2015

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Findings Suggest Improvement in Management of Localized Prostate Cancer

After years of overtreatment for patients with low-risk prostate cancer, rates of active surveillance/ watchful waiting increased sharply in 2010 through 2013, and high-risk disease was more often treated appropriately with potentially curative local treatment rather than androgen deprivation alone, according to a study in the July 7 issue of JAMA.

Matthew R. Cooperberg, M.D., M.P.H., and Peter R. Carroll, M.D., M.P.H., of the University of California, San Francisco, conducted a study to examine recent trends in community-based practice patterns of the management of localized prostate cancer. The researchers analyzed data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a national registry accruing men with prostate cancer diagnosed at 45 urology practices across the United States since 1995. All but 3 are community-based practices and 28 states across all regions are represented. The study included men with tumors classified as stage cT3aNoMo or lower managed with prostatectomy, radiation, androgen deprivation monotherapy, or active surveillance/watchful waiting between 1990 and 2013.

The analysis included 10,472 men; average age, 66 years. Surveillance use for low-risk disease remained low from 1990 through 2009 (varying from 7 percent to 14 percent), but increased sharply in 2010 through 2013 (to 40 percent). Conversely, treatment with androgen deprivation for intermediate-risk and high-risk tumors, which had been increasing steadily from 1990 (10 percent and 30 percent, respectively), decreased sharply (to 4 percent and 24 percent, respectively).

Among men 75 years or older, the rate of surveillance was 54 percent from 1990 through 1994, declined to 22 percent from 2000 through 2004, and increased to 76 percent from 2010 through 2013. There was an increase in the use of surgery for men 75 years or older with low-risk cancer to 9.5 percent and intermediate­risk cancer to 15 percent; however, there was not an increase in use for those with high-risk cancer, among whom androgen deprivation still accounted for 67 percent of treatment.

Substantial variation persisted in treatment patterns across individual practices, as observed previously.

“The magnitude and speed of the changes suggest a genuine change in the management of patients with prostate cancer in the United States, which could accelerate as more clinicians begin to participate in registry efforts. Given that overtreatment of low-risk disease is a major driver of arguments against prostate cancer screening efforts, these observations may help inform a renewed discussion regarding early detection policy in the United States,” the authors write.

(doi:10.1001/jama.2015.6036; 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: 11 A.M. (ET) TUESDAY, JULY 7, 2015

Media Advisory: To contact Aung Ko Win, M.B.B.S., Ph.D., M.P.H., email awin@unimelb.edu.au.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6789

Study Examines Association Between Certain Genetic Condition, Hormonal Factors, and Risk of Endometrial Cancer

For women with Lynch syndrome, an association was found between the risk of endometrial cancer and the age of first menstrual cycle, having given birth, and hormonal contraceptive use, according to a study in the July 7 issue of JAMA. Lynch syndrome is a genetic condition that increases the risk for various cancers.

Endometrial cancer is the most common type of gynecologic cancer in developed countries. Between 2 percent and 5 percent of all endometrial cancer cases are associated with a hereditary susceptibility to cancer, mainly Lynch syndrome, which is caused by a germline mutation in one of the DNA mismatch repair (MMR) genes. Depending on the mutated gene, cumulative risk of developing endometrial cancer by age 70 years for women is thought to be between 15 percent and 30 percent. Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with an MMR gene mutation. Studies in the general population have shown that hormonal factors are associated with endometrial cancer risk, according to background information in the article.

For Lynch syndrome, the association between hormonal factors and endometrial cancer risk has not been clear. Aung Ko Win, M.B.B.S., Ph.D., M.P.H., of the University of Melbourne, Victoria, Australia, and colleagues conducted a study that included 1,128 women with an MMR gene mutation identified from the Colon Cancer Family Registry. Participants were recruited between 1997 and 2012 from centers across the United States, Australia, Canada, and New Zealand.

Endometrial cancer was diagnosed in 133 women. The researchers found that later age at menarche (first menstrual cycle, age 13 or older), parity (has had one or more live births), and hormonal contraceptive use (for one year or longer) were associated with a lower risk of endometrial cancer. There was no statistically significant association between endometrial cancer and age at first and last live birth, age at menopause, and postmenopausal hormone use.

“In this study, an inverse association was observed between the risk of endometrial cancer for women with an MMR gene mutation and later age of menarche, increased parity, and use of hormonal contraceptives. The directions of the observed associations are similar to those that have been reported for the general population, suggesting a possible protective effect of these factors,” the authors write.

“If replicated, these findings suggest that women with an MMR gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk.”

(doi:10.1001/jama.2015.6789; 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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Please Note: The JAMA paper and news release previously posted on this website on dosing of edible medical marijuana products, embargoed for 11 a.m. ET Tuesday, June 23, contained an error.

In the following sentence, “Of 75 products purchased (47 different brands), 17 percent were accurately labeled, 23 percent were overlabeled, and 60 percent were underlabeled with respect to THC content,” the corrected portion should read “… 23 percent were underlabeled, and 60 percent were overlabeled with respect to THC content.”

JAMA regrets the error.

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 23, 2015

Media Advisory: To contact Sean D. Pokorney, M.D., M.B.A., call Samiha Khanna at 919-419-5069 or email samiha.khanna@duke.edu. To contact editorial author Robert G. Hauser, M.D., email Gloria O’Connell at gloria.oconnell@allina.com.

Implantable Cardioverter-Defibrillators Underused Among Older Patients After Heart Attack

Among Medicare patients who experienced a heart attack from 2007 to 2010, fewer than 1 in 10 eligible patients with low ejection fraction (a measure of how well the left ventricle of the heart pumps blood with each beat) received an implantable cardioverter-defibrillator (ICD) within 1 year after the heart attack, even though ICD implantation was associated with a lower risk of death at 2 years after implantation, according to a study in the June 23/30 issue of JAMA.

More than 350,000 people experience sudden cardiac death in the United States annually. Clinical trials have established the benefit of primary prevention ICDs among patients with low ejection fraction (EF). ICDs are not recommended within 40 days of a myocardial infarction (MI; heart attack). Given this need to wait, ICD consideration is susceptible to errors of omission during the transition of post-MI care between inpatient and outpatient care teams. In addition, uncertainties regarding ICD effectiveness, along with other considerations of treatment goals and procedural risk, may discourage ICD implantation among older adults, according to background information in the article.

Sean D. Pokorney, M.D., M.B.A., of the Duke University Medical Center, Durham, N.C., and colleagues examined ICD implantation rates and associated mortality among Medicare beneficiaries with an EF of 35 percent or less after MI, treated at 441 U.S. hospitals between 2007 and 2010. Follow-up data were available through December 2010.

The final study population included 10,318 post-MI patients (median age, 78 years) who were potentially eligible for primary prevention ICD implantation. The cumulative 1-year ICD implantation rate among the patients was 8.1 percent. Patients who received an ICD within 1 year after MI were younger and were more likely to be male; to have larger infarcts (area of damage in heart caused by impaired circulation), prior coronary artery bypass graft procedures (31 percent vs 20 percent), and evidence of cardiogenic shock (shock due to low blood output by the heart) during index hospitalization (13 percent vs 8 percent), relative to patients who did not receive an ICD within 1 year.

Implantation of ICD was associated with a 36 percent lower risk of death at two years. The rate of early cardiology follow-up within 2 weeks after discharge was higher among patients who did vs did not receive an ICD within 1 year (30 percent vs 20 percent).

“Additional research is needed to determine evidence-based approaches to increase ICD implantation among eligible patients,” the authors write.

(doi:10.1001/jama.2015.6409; 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: Underutilization of Implantable Cardioverter-Defibrillators in Older Patients

“Even if the ICD implantation rate were twice what Pokorney et al found, it is concerning that so few potentially ICD-eligible elderly patients are undergoing implantation, especially considering that ICDs significantly improve survival,” writes Robert G. Hauser, M.D., of the Minneapolis Heart Institute, Abbott Northwestern Hospital, Allina Health, Minneapolis, in an accompanying editorial.

“Even though the use of ICDs for primary prevention may not seem to make as much sense for an 80-year-old patient as it does for a patient in his or her 50s or 60s, an older patient at risk for sudden cardiac death should have the same opportunity to choose potentially lifesaving therapy. The report by Pokorney et al provides important data on the utilization of ICDs and the clinical outcomes related to ICD therapy after MI, so physicians and their patients can be better informed during discussions about the risks and benefits of ICDs in older persons.”

(doi:10.1001/jama.2015.6408; 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: 11 A.M. (ET) TUESDAY, JUNE 23, 2015

Media Advisory: To contact Stacy Loeb, M.D., M.Sc., call David March at 212-404-3528 or email david.march@nyumc.org.

Drug Used in Erectile Dysfunction Medications Associated With Small Increased Risk of Malignant Melanoma

Among men in Sweden, use of erectile dysfunctions drugs with phosphodiesterase type 5 inhibitors was associated with a modest but significant increased risk of malignant melanoma, although the pattern of association raises questions about whether this association is causal, according to a study in the June 23/30 issue of JAMA.

Phosphodiesterase type 5 (PDE5; an enzyme), the target of oral erectile dysfunction (ED) drugs, is part of a pathway that has been implicated in the development of malignant melanoma. This has raised questions whether PDE5 inhibitors used to treat ED may promote malignant melanoma. An increased risk of melanoma of the skin following use of the ED drug sildenafil was recently reported in a study based on 14 cases of malignant melanoma among men taking PDE5 inhibitors. PDE5 inhibitors are the most commonly prescribed medications used for treatment of ED. Given the frequency with which these medications are used, further support for a causal association with the development of malignant melanoma would have important implications, according to background information in the article.

Stacy Loeb, M.D., M.Sc., of New York University, New York, and colleagues examined the association between use of PDE5 inhibitors and malignant melanoma risk. The study included data from the Swedish Prescribed Drug Register, the Swedish Melanoma Register, and other health care registers and demographic databases in Sweden; the researchers identified melanoma cases diagnosed from 2006 through 2012.

Of 4,065 melanoma cases, 435 men (11 percent) had filled prescriptions for PDE5 inhibitors (sildenafil, vardenafil or tadalafil), as did 1,713 men of 20,325 controls (8 percent). Analysis indicated a modest but statistically significant increased risk of melanoma in men taking PDE5 inhibitors. The most pronounced increase in risk was observed in men who had filled a single prescription, but was not significant among men with multiple filled prescriptions.

PDE5 inhibitors were significantly associated for low-stage but not for high-stage melanoma. PDE5 inhibitor use was also associated with an increased risk of basal cell carcinoma (9 percent for cases vs 8 percent for controls).

The associated increased risk was similar for short­ and long-acting PDE5 inhibitors; risk estimates were similar for sildenafil, vardenafil or tadalafil. Men taking PDE5 inhibitors had a higher educational level and annual income, factors that were also significantly associated with melanoma risk.

The authors note that overall, the pattern of association (e.g., the lack of association with multiple filled prescriptions) raises questions about whether this association is causal. “Rather, the observed association may reflect confounding [other factors that can influence outcomes] by lifestyle factors associated with both PDE5 inhibitor use and low-stage melanoma.”

(doi:10.1001/jama.2015.6604; 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 A.M. (ET) TUESDAY, JUNE 23, 2015

Media Advisory: To contact Jean­Christophe Roze, M.D., Ph.D., email jcroze@chu-nantes.fr.

Early Screening for Vascular Disorder Among Extremely Preterm Infants Associated With Lower Risk of In-Hospital Death

Among extremely preterm infants, early screening for the vascular disorder patent ductus arteriosus before day 3 of life was associated with a lower risk of in-hospital death and pulmonary hemorrhage, but not with differences in other severe complications, according to a study in the June 23/30 issue of JAMA.

The ductus arteriosus is a blood vessel in a fetus that bypasses pulmonary circulation by connecting the pulmonary artery directly to the ascending aorta. It usually closes within 72 hours of birth in most normal-term infants. However, failure to close is common in extremely premature infants, resulting in patent (open) ductus arteriosus (PDA), which can result in serious complications. There is currently no consensus for the screening and treatment of PDA. Some neonatologists perform early screening echocardiography (imaging of the heart with ultrasound) for PDA, which allows for diagnosis and treatment at a preclinical stage, according to background information in the article.

Jean­Christophe Roze, M.D., Ph.D., of Nantes University Hospital, Nantes, France, and colleagues compared outcomes for preterm infants who received early screening echocardiography before day 3 of life vs. those not screened. The study included infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011.

The final analysis included 847 infants who were screened (“exposed” group) for PDA and 666 who were not; 605 infants from each group could be paired. The proportion of infants who received a treatment for PDA at any time during their hospitalization was significantly lower in the nonexposed group than in the exposed group (43 percent vs 55 percent). Exposed infants had a lower hospital death rate (14 percent vs 18.5 percent). The number of infants needed to be screened to prevent 1 death was 23. Exposed infants also had a lower rate of pulmonary hemorrhage (6 percent vs 9 percent), a life-threatening complication.

No significant differences were observed in rates of necrotizing enterocolitis (severe inflammation due to decreased blood flow that occurs in the intestines of premature infants), severe bronchopulmonary dysplasia (a chronic lung disorder in infants), and severe cerebral (brain) lesions.

The authors note that additional analysis resulted in some ambiguity regarding the interpretation of the results (whether the reduced mortality finding was statistically significant), and longer-term evaluation is needed to provide clarity.

(doi:10.1001/jama.2015.6734; 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 A.M. (ET) TUESDAY, JUNE 23, 2015

Media Advisory: To contact Penny F. Whiting, Ph.D., email penny.whiting@bristol.ac.uk. To contact editorial co-author Deepak Cyril D’Souza, M.B.B.S., M.D., email William Hathaway at william.hathaway@yale.edu.

Mixed Findings Regarding Quality of Evidence Supporting Benefit of Medical Marijuana

In an analysis of the findings of nearly 80 randomized trials that included about 6,500 participants, there was moderate-quality evidence to support the use of cannabinoids (chemical compounds that are the active principles in cannabis or marijuana) for the treatment of chronic pain and lower-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, sleep disorders, and Tourette syndrome, according to a study in the June 23/30 issue of JAMA.

Medical cannabis refers to the use of cannabis or cannabinoids as medical therapy to treat disease or alleviate symptoms. In the United States, 23 states and Washington, D.C., have introduced laws to permit the medical use of cannabis; many other countries have similar laws. Despite the wide us of cannabis and cannabinoid drugs for medical purposes, their efficacy for specific indications is not clear, according to background information in the article.

Penny F. Whiting, Ph.D., of the University of Bristol, Bristol, United Kingdom, and colleagues evaluated the evidence for the benefits and adverse events (AEs) of medical cannabinoids by searching various databases for randomized clinical trials of cannabinoids for a variety of indications. The researchers identified 79 trials (6,462 participants) that met criteria for inclusion in the review and meta-analysis.

The researchers found that most studies suggested that cannabinoids were associated with improvements in symptoms, but these associations did not reach statistical significance in all studies. There was moderate-quality evidence to suggest that cannabinoids may be beneficial for the treatment of chronic neuropathic or cancer pain and spasticity due to multiple sclerosis (sustained muscle contractions or sudden involuntary movements). There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV, sleep disorders, and Tourette syndrome; and very low-quality evidence for an improvement in anxiety. There was low-quality evidence for no effect on psychosis and very low-level evidence for no effect on depression.

There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. There was no clear evidence for a difference in association (either beneficial or harmful) based on type of cannabinoids or mode of administration. Only 2 studies evaluated cannabis. There was no evidence that the effects of cannabis differed from other cannabinoids.

“Further large, robust, randomized clinical trials are needed to confirm the effects of cannabinoids, particularly on weight gain in patients with HIV/AIDS, depression, sleep disorders, anxiety disorders, psychosis, glaucoma, and Tourette syndrome are required. Further studies evaluating cannabis itself are also required because there is very little evidence on the effects and AEs of cannabis,” the authors write.

(doi:10.1001/jama.2015.6358; 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: Medical Marijuana

“If the states’ initiative to legalize medical marijuana is merely a veiled step toward allowing access to recreational marijuana, then the medical community should be left out of the process, and instead marijuana should be decriminalized,” write Deepak Cyril D’Souza, M.B.B.S., M.D., and Mohini Ranganathan, M.D., of the Yale University School of Medicine, New Haven, Conn., in an accompanying editorial.

“Conversely, if the goal is to make marijuana available for medical purposes, then it is unclear why the approval process should be different from that used for other medications. Evidence justifying marijuana use for various medical conditions will require the conduct of adequately powered, double-blind, randomized, placebo/active controlled clinical trials to test its short- and long-term efficacy and safety. The federal government and states should support medical marijuana research. Since medical marijuana is not a life-saving intervention, it may be prudent to wait before widely adopting its use until high-quality evidence is available to guide the development of a rational approval process.”

(doi:10.1001/jama.2015.6407; 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: 11 A.M. (ET) TUESDAY, JUNE 23, 2015

Media Advisory: To contact Ryan Vandrey, Ph.D., email Shawna Williams (shawna@jhmi.edu) or Vanessa McMains (vmcmain1@jhmi.edu).

Study Finds Inaccuracy in Dosing of Edible Medical Marijuana Products

An analysis of edible medical marijuana products from 3 major metropolitan areas found that many had lower amounts of key substances than labeled, which may not produce the desired medical benefit, while others contained significantly more of a certain substance than labeled, placing patients at risk of experiencing adverse effects, according to a study in the June 23/30 issue of JAMA.

As the use of cannabis (marijuana) for medical purposes has expanded, a variety of edible products for oral consumption has been developed. An estimated 16 percent to 26 percent of patients using medical cannabis consume edible products. Even though oral consumption lacks the harmful by-products of smoking, difficult dose titration (a process that involves determining the concentration of a substance) can result in overdosing or underdosing, highlighting the importance of accurate product labeling. Regulation and quality assurance for edible product cannabinoid (chemical compounds that are the active principles in cannabis or marijuana) content and labeling are generally lacking, according to background information in the article.

Ryan Vandrey, Ph.D., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues investigated the label accuracy of edible cannabis products. An Internet directory of dispensaries, with a menu of products available at each, was used to determine purchase locations in San Francisco, Los Angeles and Seattle. A list of dispensaries was generated, with individual businesses randomly selected that offered at least 1 edible cannabis product from each of 3 common categories (baked goods, beverages, candy or chocolate) with package labels that provided, at minimum, specific measures of Δ⁹-tetrahydrocannabinol (THC; along with cannabidiol [CBD], typically the most concentrated chemical components of cannabis and believed to primarily drive therapeutic benefit). Between August and October 2014, edible cannabis products were obtained from the dispensaries and the contents analyzed. Studies suggest improved clinical benefit and fewer adverse effects with a THC:CBD ratio of 1:1.

Products were considered accurately labeled if the measured THC and CBD content was within 10 percent of the labeled values, underlabeled if the content was more than 10 percent above the labeled values, and overlabeled if the content was more than 10 percent below the labeled values. Of 75 products purchased (47 different brands), 17 percent were accurately labeled, 23 percent were underlabeled, and 60 percent were overlabeled with respect to THC content. The greatest likelihood of obtaining overlabeled products was in Los Angeles and underlabeled products in Seattle. Non-THC content was generally low.

Forty-four products (59 percent) had detectable levels of CBD; only 13 had CBD content labeled. Four products were overlabeled and 9 were underlabeled for CBD. The median THC:CBD ratio of products with detectable CBD was 36:1; 7 had ratios of less than 10:1; and only 1 had a 1:1 ratio.

“Edible cannabis products from 3 major metropolitan areas, though unregulated, failed to meet basic label accuracy standards for pharmaceuticals,” the authors write. “Because medical cannabis is recommended for specific health conditions, regulation and quality assurance are needed.”

(doi:10.1001/jama.2015.6613; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was funded by Johns Hopkins University School of Medicine except for the cost of analytical testing, which was covered by Werc Shop Laboratories. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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On Tuesday, June 23, from 2 p.m. – 3:30 p.m. (ET) in Washington, D.C., Dr. Christopher Murray, Director of the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, will present findings form IHME’s Financing Global Health 2014 report, “Shifts in Funding as the MDG Era Closes,” and results published June 16 by JAMA: “Sources and Focus of Health Development Assistance, 1990–2014.”

Dr. Murray will highlight how funding patterns have shifted across time and identify where funding gaps persist. Following Dr. Murray’s presentation, there will be a roundtable discussion, moderated by Talia Dubovi, Deputy Director of the CSIS Global Health Policy Center that will feature: Dr. Christopher Murray, Dr. Howard Bauchner, Editor-in-Chief, JAMA, and Dr. Jennifer Kates, Vice President and Director of Global Health and HIV Policy at the Kaiser Family Foundation. The roundtable discussion will focus on the policy implications of IHME’s report.

Members of the media can RSVP here. The event will be webcast live at Smartglobalhealth.org/live.

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