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.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7811

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.

# # #

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.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7169

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.

# # #

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: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8068 This link to the 2nd study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7938 This will be the link to the editorial: http://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.

# # #

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.

To place an electronic embedded link to this study and editorials in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7996 This will be the link to the 1^st editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7151 This will be the link to the 2^nd editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8232

 
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.

# # #

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: http://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.

# # #

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.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6669

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.

# # #

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.

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: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7515 This link to the 2^nd study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6822 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7434

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.

# # #

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.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7446

This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7521

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.

# # #

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.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6041

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.

# # #

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).

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7120. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7523.

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 http://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.

# # #

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.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6968 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7149

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.

# # #

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

Media Advisory: To contact co-author Emanuele Di Angelantonio, M.D., email erfc@phpc.cam.ac.uk.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7008

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.

# # #

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

Media Advisory: To contact Francis Couturaud, M.D., Ph.D., email francis.couturaud@chu-brest.fr.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7046

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

# # #

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

Media Advisory: To contact Matthew R. Cooperberg, M.D., M.P.H., call Elizabeth Fernandez at 415-514-1592 or email Elizabeth.Fernandez@UCSF.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6036

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.

# # #

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: http://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.

# # #

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.

# # #

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.

# # #

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.

# # #

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.

# # #

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.

# # #

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.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 16, 2015

Media Advisory: To contact Paulina Salminen, M.D., Ph.D., email paulina.salminen@tyks.fi. To contact Edward Livingston, M.D., call Jim Michalski at 312-464-5785 or email jim.michalski@jamanetwork.org.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6154

This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6266

Trial Compares Antibiotics vs Appendectomy for Treatment of Appendicitis

Among patients with uncomplicated appendicitis, antibiotic treatment did not meet a prespecified level of effectiveness compared with appendectomy, although most patients who received antibiotic therapy did not require an appendectomy, and for those who did, they did not experience significant complications, according to a study in the June 16 issue of JAMA.

Appendectomy has been the standard treatment for acute appendicitis for over a century. More than 300,000 of these procedures are performed annually in the United States. Although appendectomy is generally well tolerated, it is a major surgical intervention and can be associated with postoperative complications. An increasing amount of evidence supports the use of antibiotics instead of surgery for treating patients with uncomplicated acute appendicitis, according to background information in the article.

Paulina Salminen, M.D., Ph.D., of Turku University Hospital, Turku, Finland, and colleagues randomly assigned 530 patients with uncomplicated acute appendicitis (confirmed by a computed tomography [CT] scan) to receive antibiotic therapy for 10 days or a standard appendectomy. The researchers tested the hypothesis that antibiotic treatment was noninferior (not worse than) to appendectomy, and assumed that there would be sufficient benefits from avoiding surgery and that a 24 percent failure rate in the antibiotic group would be acceptable.

Of the 273 patients randomized to the surgical group, all but 1 underwent successful appendectomy, resulting in a success rate of 99.6 percent. Of the 256 patients available for 1-year follow-up in the antibiotic group, 186 (72.7 percent) did not require appendectomy. Seventy patients (27.3 percent) in the antibiotic group underwent surgical intervention within 1 year of initial presentation for appendicitis. The intention-to-treat analysis yielded a difference in treatment efficacy between groups of -27.0 percent. Given the prespecified noninferiority margin of 24 percent, the researchers were unable to demonstrate noninferiority of antibiotic treatment relative to surgery.

There were no intra-abdominal abscesses or other major complications associated with delayed appendectomy inpatients assigned to antibiotic treatment.

“Antibiotic treatment of patients with uncomplicated acute appendicitis was not shown to be noninferior to appendectomy for uncomplicated appendicitis within the first year of observation following initial presentation of appendicitis. Nevertheless, the majority (73 percent) of patients with uncomplicated acute appendicitis were successfully treated with antibiotics,” the authors write. “These results suggest that patients with CT-proven uncomplicated acute appendicitis should be able to make an informed decision between antibiotic treatment and appendectomy. Future studies should focus both on early identification of complicated acute appendicitis patients needing surgery and to prospectively evaluate the optimal use of antibiotic treatment in patients with uncomplicated acute appendicitis.”

(doi:10.1001/jama.2015.6154; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This trial was supported by a government research grant (EVO Foundation) awarded to Turku University Hospital. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Treating Appendicitis Without Surgery

Edward Livingston, M.D., Deputy Editor, JAMA, Chicago, and Corrine Vons, M.D., Ph.D., of the Jean­ Verdier Hospital, Bondy, France, comment on the findings of this study in an accompanying editorial.

“These findings suggest that for CT-diagnosed uncomplicated appendicitis, an initial trial of antibiotics is reasonable followed by elective appendectomy for patients who do not improve with antibiotics or present with recurrent appendicitis.”

“The time has come to consider abandoning routine appendectomy for patients with uncomplicated appendicitis. The operation served patients well for more than 100 years. With development of more precise diagnostic capabilities like CT and effective broad-spectrum antibiotics, appendectomy may be unnecessary for uncomplicated appendicitis, which now occurs in the majority of acute appendicitis cases.”

(doi:10.1001/jama.2015.6266; 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.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 16, 2015

Media Advisory: To contact Reinier G.S. Meester, M.Sc., email r.meester@erasmusmc.nl.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6251

Higher Quality Screening Colonoscopies Associated With Lower Risk of Colorectal Cancer Death, Without Higher Overall Costs

An analysis that included information from more than 57,000 screening colonoscopies suggests that higher adenoma detection rates may be associated with up to 50 percent to 60 percent lower lifetime colorectal cancer incidence and death without higher overall costs, despite a higher number of colonoscopies and potential complications, according to a study in the June 16 issue of JAMA.

Screening colonoscopy reduces colorectal cancer death risk through detection and treatment of early cancerous or precancerous lesions (adenomas) but its effectiveness depends on examination quality, which is measured by adenoma detection rates (ADRs). This rate varies widely among physicians, with unknown consequences for the cost and benefits of screening programs, according to background information in the article.

Reinier G.S. Meester, M.Sc., of Erasmus MC University Medical Center, Rotterdam, the Netherlands, and colleagues estimated the lifetime benefits, complications, and costs of an initial colonoscopy screening program at different levels of adenoma detection. The researchers performed microsimulation modeling with data from a large, community-based health care system (Kaiser Permanente Northern California) on ADR variation and cancer risk among 57,588 patients examined by 136 physicians from 1998 through 2010. For this study, no screening was compared with screening initiation with colonoscopy according to ADR quintiles (divided into five groups). Adenoma detection rates, the proportion of a physician’s screening colonoscopies that detect at least 1 histologically confirmed adenoma, ranged from 7.4 percent to 53 percent, with the rates increasing from quintile 1 to quintile 5.

The model estimated that among unscreened patients the lifetime colorectal cancer risk was 34.2 per 1,000, the lifetime colorectal cancer mortality risk was 13.4 per 1,000. The modeled risks were inversely related to the level of adenoma detection. The simulated lifetime risk of colorectal cancer per 1,000 was 26.6 for patients of physicians in quintile 1 and was lower for subsequent quintiles; in quintile 5, the lifetime colorectal cancer risk was 12.5. The model estimated that lifetime incidence and mortality risks averaged 11 percent to 13 percent lower for every 5-point higher ADR, which translates to overall differences of 53 percent to 60 percent between the lowest and highest quintiles.

Simulated risk of complications increased from 6 of 2,777 colonoscopies in quintile 1 to 8.9 complications of 3,376 colonoscopies in quintile 5. Estimated net screening costs were lower from quintile 1 ($2.1 million) to quintile 5 ($1.8 million) due to averted cancer treatment costs.

“By evaluating the costs for screening, surveillance, screening-associated complications and cancer care, our model suggested that ADR is not associated with higher overall costs,” the authors write.

“Future research is needed to assess why adenoma detection rates vary and whether increasing adenoma detection would be associated with improved patient outcomes.”

(doi:10.1001/jama.2015.6251; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 16, 2015

Media Advisory: To contact Joseph L. Dieleman, Ph.D., email Rhonda Stewart at stewartr@uw.edu. To contact editorial author Andy Haines, M.D., M.B., B.S., email andy.haines@lshtm.ac.uk.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5825

This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5790

Development Assistance for Health Has Increased Substantially Since 1990 for Low-Income Countries

Funding for health in developing countries has increased substantially since 1990, with a focus on HIV/AIDS, maternal health, and newborn and child health, and limited funding for noncommunicable diseases, according to a study in the June 16 issue of JAMA.

Among children born in low-income countries in 2013, the estimated rate of death before age 5 was 12 times higher than that in the U.S.; the rate of death in these countries for women due to complications from childbirth was 21 times higher than in the U.S. The majority of these deaths were preventable, but the health systems in resource­scarce settings are, in many cases, unable to provide services that could prevent these outcomes. The governments of high-income countries and private organizations have provided financial resources to the health sectors of developing countries to improve these systems and support interventions that can prevent premature death and disability, according to background information in the article.

Joseph L. Dieleman, Ph.D., of the Institute for Health Metrics and Evaluation, Seattle, and colleagues examined the amount of development assistance that countries and organizations provided for health for developing countries and the health areas that received these funds. The researchers analyzed budget, revenue, and expenditure data of the primary agencies and organizations (n = 38) that provided resources to developing countries (n = 146-183, depending on the year) for health from 1990 through 2014. Development assistance for health was divided into 11 mutually exclusive health focus areas.

Between 1990 and 2014, $458 billion was disbursed from the major channels (the international agency or organization that directed the resources toward the implementing institution or government) in high-income countries to developing countries to maintain or improve health. Annual disbursements increased substantially over time. In 1990, donors disbursed $6.9 billion for health. In 2014, they disbursed $35.9 billion. From 1990 to 2014, the U.S. government was the largest source of development assistance for health, providing $143.1 billion or 31.2 percent of the total. The U.S. government disbursed $12.4 billion in 2014. The UK government was the second largest public source and provided $32.6 billion or 7.1 percent of the total between 1990 and 2014. Of resources that originated with the U.S. government during this same period, 71 percent were provided through U.S. government agencies, and 41 percent were allocated for HIV/AIDS.

The second largest source of development assistance for health was private philanthropic donors, including the Bill and Melinda Gates Foundation and other private foundations, which provided $69.9 billion between 1990 and 2014, including $6.2 billion in 2014. These resources were provided primarily through private foundations and nongovernmental organizations and were allocated for a diverse set of health focus areas.

Since 1990, 28 percent of all development assistance for health was allocated for maternal health and newborn and child health; 23 percent for HIV/AIDS, 4 percent for malaria, 3 percent for tuberculosis, and 2 percent for noncommunicable diseases. Between 2000 and 2010, development assistance for health increased 11 percent annually. However, since 2010, total development assistance for health has not increased as substantially.

“Understanding how funding patterns have changed across time and the priorities of sources of international funding across distinct channels, recipients, and health focus areas may help identify where funding gaps persist and where cost-effective interventions could save lives,” the authors write.

(doi:10.1001/jama.2015.5825; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the Bill and Melinda Gates Foundation. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Development Assistance for Health

In an accompanying editorial, Andy Haines, M.D., M.B., B.S., of the London School of Hygiene and Tropical Medicine, London, asks how funding assistance for health for developing countries can be sustained and increased in the face of austerity as well as ensuring efficient use of funding that is available.

“The UN aid spending target of 0.7 percent of gross domestic product on international aid has only been met by a few countries. … Although renewed progress on reaching this target is necessary, innovative financing mechanisms should be exploited, such as the airline or carbon taxes that fund UNITAID and the potential for recycling fossil fuel subsidies to support universal health coverage. New major emerging economies of Brazil, Russia, India, China, and South Africa could become increasingly prominent contributors. For example, between 2005 and 2010, Brazil and India increased their foreign aid expenditure by more than 20 percent and China and South Africa by about 10 percent, often using different approaches to Western donors, based on their own recent experience of scaling up access to health care. Other potential sources of funding include various climate change funds to support adaptation or mitigation efforts, some of which have potential benefits to health.”

“Work such as that described in the study by Dieleman et al should be supported and expanded. Additional data are needed to provide better evidence for decision making and strengthen the case for funding to address the health problems of poor populations living in low-income countries that cannot fund the provision of essential health care for their own populations in the near future.”

(doi:10.1001/jama.2015.5790; 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. He reports being an advisor on a grant funded by the Bill and Melinda Gates Foundation and a member of the Research Advisory Group for the UK Department for International Development.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 16, 2015

Media Advisory: To contact Elizabeth E. Foglia, M.D., call Katie Delach at 215-349-5964 or email katie.delach@uphs.upenn.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5734

Extremely Preterm Infants Enrolled in RCTs Do Not Experience Worse Outcomes Compared to Infants Not Enrolled

In a group of more than 5,000 extremely preterm infants, important in-hospital outcomes were neither better nor worse in infants enrolled in randomized clinical trials (RCTs) compared with eligible but nonenrolled infants, findings that may provide reassurance regarding concerns about performing RCTs in this vulnerable population, according to a study in the June 16 issue of JAMA.

It has been unknown whether participation in a neonatal RCT is independently associated with differences in outcomes. Elizabeth E. Foglia, M.D., of the University of Pennsylvania, Philadelphia, and colleagues compared in-hospital outcomes between extremely premature infants enrolled in RCTs and those who were eligible but not enrolled in RCTs conducted by the National Institute of Child Health and Human Development Neonatal Research Network between January 1999 and December 2012.

Six RCTs met the inclusion criteria. Of 5,389 eligible infants, 3,795 were enrolled in at least 1 RCT and 1,594 were not enrolled in any RCT. The researchers found that the primary outcome (a composite of death; bronchopulmonary dysplasia [a chronic lung disorder in infants]; severe brain injury; or severe retinopathy of prematurity [a sight-threatening abnormality of the eye]) did not differ significantly between groups (68 percent in enrolled group vs 69 percent in eligible but not enrolled group).There were no differences in the secondary outcomes (individual components of the primary outcome, culture-proven late-onset sepsis, and necrotizing enterocolitis (severe inflammation due to decreased blood flow that occurs in the intestines of premature infants) in the adjusted analysis. In addition, the primary outcome did not differ between groups when analyzed by individual trial.

“The present study did not find differences in mortality or neonatal morbidity between trial participants and nonparticipants. Similarly, meta-analyses of studies of adults and older children have demonstrated no significant differences in outcomes between trial participants and nonparticipants who were treated similarly outside trials,” the authors write.

(doi:10.1001/jama.2015.5734; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development provided grant support for the Neonatal Research Network’s Generic Database Study via cooperative agreements. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 9, 2015

Media Advisory: To contact Nitin B. Jain, M.D., M.S.P.H., email Craig Boerner at craig.boerner@Vanderbilt.Edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6250

Overall Rate of Traumatic Spinal Cord Injury Remains Stable in U.S.

Although Increase Seen Among Older Adults

Between 1993 and 2012, the incidence rate of acute traumatic spinal cord injury remained relatively stable in the U.S., although there was an increase among older adults, mostly associated with an increase in falls, according to a study in the June 9 issue of JAMA, a theme issue on the Americans with Disabilities Act.

Traumatic spinal cord injury leads to chronic impairment and disability. Despite the substantial effects of this injury on health-related quality of life and health care spending, contemporary data on trends in incidence, causes, and medical care are limited, according to background information in the article.

Nitin B. Jain, M.D., M.S.P.H., of the Vanderbilt University School of Medicine, Nashville, Tenn., and colleagues analyzed survey data from the U.S. Nationwide Inpatient Sample (NIS) databases for 1993-2012 to examine trends in incidence, causes, health care utilization, and mortality for acute traumatic spinal cord injury.

The total study sample consisted of 63,109 patients with acute traumatic spinal cord injury. The actual number of cases in the NIS database increased from 2,659 in 1993 to 3,393 in 2012. The incidence rate for acute traumatic spinal cord injury remained relatively stable: the estimated rate was 53 cases per 1 million persons in 1993 and 54 cases per 1 million persons in 2012.

Incidence rates among the younger male population declined. For both the male and female populations, a high rate of increase in spinal cord injury incidence from 1993 to 2012 was observed in elderly persons. Although overall in-hospital mortality increased from 6.6 percent in 1993-1996 to 7.5 percent in 2010-2012, mortality decreased significantly from 24 percent in 1993-1996 to 20 percent in 2010-2012 among persons 85 years or older.

The percentage of spinal cord injury associated with falls increased significantly from 28 percent in 1997-2000 to 66 percent in 2010-2012 in those 65 years or older. “This is a major public health issue and it likely represents a more active 65- to 84-year-old U.S. population currently compared with the 1990s, which increases the risk of falls in this age group. This issue may be further compounded in the future because of the aging population in the United States,” the authors write.

(doi:10.1001/jama.2015.6250; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 9, 2015

Media Advisory: To contact Levi J. Hargrove, Ph.D., call Molly Reynolds at 312-541-9300 (ext. 107) or email Molly.Reynolds@sikich.com.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4527

Control System Shows Potential for Improving Function of Powered Prosthetic Leg

A control system that incorporated electrical signals generated during muscle contractions and gait information resulted in improved real-time control of a powered prosthetic leg for different modes of walking (such as on level ground or descending stairs), according to a study in the June 9 issue of JAMA, a theme issue on the Americans with Disabilities Act.

Most prosthetic lower limbs are mechanically passive (cannot provide power) and so do not restore full function. Leg prostheses that provide power are becoming available; however, different ambulation modes require very different control sequences for operating powered prosthetic limbs. Transitioning currently available powered limbs between different ambulation modes requires patients to slow down, stop, press buttons on an electronic key fob, or perform unrelated body movements. To maximize benefit from these devices and ensure patient safety, control systems must automatically identify which ambulation mode the patient is using and provide the correct prosthesis response, according to background information in the article.

Electromyographic (EMG) signals—electrical signals generated during muscle contractions—are routinely used to control powered arm prostheses. Advanced pattern recognition algorithms can decode the unique EMG signal patterns generated by multiple muscles during specific movements, thus determining user intent and providing intuitive prosthesis control.

Levi J. Hargrove, Ph.D., of the Rehabilitation Institute of Chicago, and colleagues assessed the effect of including EMG data from residual muscles with mechanical sensor data in a real-time control system on ambulation performance using a powered prosthetic leg. The trial included 7 patients with single-sided above-knee (n = 6) or knee-disarticulation (n = 1; separation at the knee joint) amputations. All patients were capable of ambulation within their home and community using a passive prosthesis (i.e., one that does not provide external power).

The researchers used pattern recognition algorithms to predict ambulation mode for the next stride. Electrodes were placed over 9 residual limb muscles and EMG signals were recorded as patients ambulated and completed 20 trials involving level­ground walking and stair and ramp ascent and descent. Data were acquired simultaneously from 13 mechanical sensors embedded on the prosthesis. Two real-time pattern recognition algorithms, using either (1) mechanical sensor data alone or (2) mechanical sensor data in combination with EMG data and historical information from earlier in the gait cycle were evaluated.

The order in which patients used each configuration was randomly assigned. The primary measured outcome for the trial was classification error for each real-time control system (defined as the percentage of steps incorrectly predicted by the control system).

The authors found that including EMG signals and historical information in the real-time control system resulted in significantly lower classification error (average, 7.9 percent) across an average of 683 steps compared with using mechanical sensor data only (average, 14.1 percent) across an average of 692 steps.

“This preliminary study is, to our knowledge, the first clinical evaluation of the ability of individuals with above-knee amputations to control a powered knee-ankle prosthesis across different ambulation modes and the first time EMG signals have been incorporated into a real-time control system for a powered lower limb prosthesis,” the researchers write. “This control system allowed for automatic, natural transitions between ambulation modes, in contrast to current control systems that require the patient to use an electronic key fob or perform a set of exaggerated movements to transition between modes.”

The authors note that the study had limitations that should be considered, including a small sample size, and experiments were only performed by patients who could already ambulate freely in a variety of environments. “Additional work needs to be completed to determine if patients with more limited ambulation capabilities could benefit from the proposed system.”

“These preliminary findings, if confirmed, have the potential to improve the control of powered leg prostheses.”

(doi:10.1001/jama.2015.4527; 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.

Editor’s Note: A related article, “Advanced Prosthetics Provide More Functional Limbs,” from JAMA’s Medical News & Perspectives section, is available to the media at https://media.jamanetwork.com.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 9, 2015

Media Advisory: To contact Cynthia A. Searcy, Ph.D., call Brooke Bergen at 202-828-0419 or email bbergen@aamc.org.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5511

MCAT Predicts Differently for Students Who Test with Extra Time; Suggests Need for Supportive Learning Environments

Among applicants to U.S. medical schools, those with disabilities who obtained extra test administration time for the Medical College Admission Test in use from 1991 to January 2015 had no significant difference in rate of medical school admission but had lower rates of passing the United States Medical Licensing Examination Step examinations and of medical school graduation, according to a study in the June 9 issue of JAMA, a theme issue on the Americans with Disabilities Act.

Individuals with documented mental and physical disabilities may receive testing accommodations on the Medical College Admission Test (MCAT) and other admissions tests in accordance with professional testing standards and federal law. Testing accommodations (such as extra testing time) are alterations to standard test administration procedures designed to enable test takers to show their proficiencies rather than the extent of their disabilities. Whether such accommodations are associated with MCAT scores, medical school admission, and medical school performance has been unclear, according to background information in the article.

Cynthia A. Searcy, Ph.D., of the Association of American Medical Colleges, Washington, D.C., and colleagues investigated the comparability of MCAT scores in relation to medical school admission and subsequent performance for individuals who had scores obtained with standard vs extra time. The study included applicants to U.S. medical schools for the 2011-2013 entering classes who reported MCAT scores obtained with standard time (n = 133,962) vs extra time (n = 435), and of students admitted to U.S. medical schools from 2000-2004 who reported MCAT scores obtained with standard time

(n = 76,262) vs extra time (n = 449).

Acceptance rates were not significantly different for applicants who had MCAT scores obtained with standard vs extra time (45 percent vs 44 percent). Students who tested with extra time passed the United States Medical Licensing Examination (USMLE) Step examinations on first attempt at significantly lower rates: Step 1, 82% vs 94%; Step 2 CK, 86% vs 95%; Step 2 CS, 92% vs 97%. They also graduated from medical school at lower rates at different times: 4 years, 67 percent vs 86 percent; 5 years, 82 percent vs 94 percent; 6 years, 85 percent vs 96 percent; 7 years, 88 percent vs 96 percent; and 8 years, 88 percent vs 97 percent. These differences remained after controlling for MCAT scores and undergraduate grade point averages.

More than 10 percent of students who tested with extra time did not graduate within the time frame of the study, compared with approximately 3 percent of students who tested with standard time.

The recently redesigned MCAT increases “the amount of time per question . . . to reduce potential time barriers that may make it difficult for examinees to demonstrate their proficiency.  Providing more working time may decrease the need for extra testing time and reduce the differences in predictive meaning between scores obtained under standard vs. extra time conditions.”

“The poorer performance on the USMLE Step examinations, and the longer time needed to graduate from medical school for individuals who have received extra testing time on the MCAT, also suggest that medical schools should examine their learning environments and support systems for individuals with disabilities. Medical school educators and administrators need a better understanding of potential barriers to medical education for students with disabilities in order to develop evidence-based policies, procedures, and resources,” the authors write.

(doi:10.1001/jama.2015.5511; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 9, 2015

Media Advisory: To contact Eyal Leshem, M.D., email the CDC’s media relations department at Media@cdc.gov.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5571

Gastroenteritis Hospitalization Rates for Children Drop Following Implementation of Rotavirus Vaccine

Following implementation of rotavirus vaccination in 2006, all-cause acute gastroenteritis hospitalization rates among U.S. children younger than 5 years of age declined by 31 percent – 55 percent in each of the post-vaccine years from 2008 through 2012, according to a study in the June 9 issue of JAMA.

Eyal Leshem, M.D., of the U.S. Centers for Disease Control and Prevention, Atlanta, and colleagues examined both all-cause gastroenteritis and rotavirus-related hospitalizations among children younger than 5 years from 2000 through 2012. The researchers analyzed State Inpatient Databases of the Healthcare Cost and Utilization Project, which capture hospitalizations in community and academic hospitals. The analyses were restricted to 26 states that consistently reported hospital discharge data each year during 2000 through 2012. Approximately 74 percent of U.S. children younger than 5 years resided in these 26 states.

The analyses included 1,201,458 all-cause acute gastroenteritis hospitalizations among children younger than 5 years of age during 2000 through 2012, of which 199,812 (17 percent) were assigned a rotavirus-specific code. The researchers found that compared with the pre-vaccine average annual acute gastroenteritis hospitalization rate of 76 per 10,000 among children younger than 5 years, post-vaccine introduction rates declined by 31 percent in 2008, 33 percent in 2009, 48 percent in 2010, 47 percent in 2011, and 55 percent in 2012. Similar rate declines were noted in both males and females, all race/ethnicity groups, and all age groups, with the greatest reductions among children age 6 months to 23 months.

Compared with the pre-vaccine average annual rotavirus­coded hospitalization rate of 16 per 10,000 among children younger than 5 years, rates of rotavirus­coded hospitalizations post-vaccine introduction declined by 70 percent in 2008, 63 percent in 2009, 90 percent in 2010, 79 percent in 2011, and 94 percent in 2012.

By 2012, children 48-59 months of age (the oldest age group studied) were age eligible for the vaccine and during this year the estimated rotavirus vaccination coverage among children 19-35 months of age reached 69 percent compared with 44 percent – 67 percent during 2009 through 2011. “With an increase in vaccine coverage, herd protection may have contributed to larger declines in rotavirus hospitalizations. In 2012, when vaccine coverage was highest, the greatest reductions were observed for all-cause acute gastroenteritis (55 percent) and rotavirus-coded (94 percent) hospitalizations,” the authors write.

“The most recent reported coverage of 73 percent for a full rotavirus vaccine series is lower than that of other established childhood vaccines so our findings support continued efforts to increase rotavirus vaccine coverage.”

(doi:10.1001/jama.2015.5571; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 9, 2015

Author Audio Interview – The ADA and the Supreme Court

An author audio interview is available for the JAMA Viewpoint, “The ADA and the Supreme Court.”

The podcast will also be posted on the JAMA website when the embargo lifts.

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 2, 2015

Media Advisory: To contact Krista F. Huybrechts, M.S., Ph.D., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5605

Antidepressant Use in Late Pregnancy May Be Associated With Small, Increased Risk of Respiratory Disorder in Newborns

An analysis of approximately 3.8 million pregnancies finds that use of antidepressants late in pregnancy may be associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN), according to a study in the June 2 issue of JAMA. However, the absolute risk was small and the risk increase appears more modest than suggested in previous studies. PPHN is a rare but life-threatening condition that occurs when a newborn’s circulation system doesn’t adapt to breathing outside the womb.

Persistent pulmonary hypertension of the newborn is associated with substantial illness and death: 10 percent to 20 percent of affected infants will not survive, and infants who survive face serious long-term consequences, including chronic lung disease, seizures, and neurodevelopmental problems. An association between selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and risk of PPHN has been controversial since the U.S. Food and Drug Administration issued a public health advisory in 2006. Studies that found no increased risk tended to be small, raising the possibility that they had insufficient power to detect an increased risk, according to background information in the article.

Krista F. Huybrechts, M.S., Ph.D., of Brigham and Women’s Hospital, Boston, and colleagues examined the risk of PPHN associated with both SSRI and non-SSRI antidepressants among 3,789,330 pregnant women enrolled in Medicaid (from 46 U.S. states and Washington, D.C.; data from 2000-2010).

Of the study population, 128,950 women (3.4 percent) used an antidepressant during the 90 days before delivery: 102,179 (2.7 percent) were exposed to an SSRI and 26,771 (0.7 percent) to a non-SSRI antidepressant. Overall, 20.8 per 10,000 infants not exposed to antidepressants during the last 90 days of pregnancy had PPHN compared with 31.0 per 10,000 infants exposed to antidepressants. This higher risk among exposed infants was observed for both SSRI (31.5 per 10,000 infants) and non-SSRI (29.1 per 10,000 infants) antidepressants.

Associations between antidepressant use and PPHN were decreased with adjustment for confounders (factors that can influence outcomes that may improperly skew the results).

“Evidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However the absolute risk was small, and the risk increase appears more modest than suggested in previous studies,” the authors write.

“The findings in the largest cohort studied to date, using advanced epidemiologic methods to mitigate confounding by the underlying psychiatric illness and its associated conditions and behaviors, suggest that the risk of PPHN associated with late pregnancy exposure to SSRI antidepressants—if present—is smaller than previous studies have reported. Clinicians and patients need to balance the potential small increase in the risk of PPHN, along with other risks that have been attributed to SSRI use during pregnancy, with the benefits attributable to these drugs in improving maternal health and well-being.”

(doi:10.1001/jama.2015.5605; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 2, 2015

Media Advisory: To contact Loreen A. Herwaldt, M.D., call Jennifer Brown at 319-356-7124 or email jennifer-l-brown@uiowa.edu. To contact editorial author Preeti N. Malani, M.D., M.S.J., call Shantell Kirkendoll at 734-764-2220 or email smkirk@umich.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5387. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6018

Multifaceted Intervention Associated With Modest Decrease in Surgical Site Infections

Implementation of a pre-surgical intervention that included screening for the bacteria Staphylococcus aureus, treating patients who were positive for this bacteria, and the administration of antibiotics based on these culture results was associated with a modest reduction in S aureus surgical site infections, according to a study in the June 2 issue of JAMA.

S aureus carriage increases the risk of S aureus surgical site infections (SSIs). The risk for these infections may be decreased by screening patients for nasal carriage of S aureus and decolonizing carriers during the preoperative period. In addition, perioperative prevention with agents such as the antibiotic vancomycin may reduce rates of methicillin-resistant S aureus (MRSA) SSIs. Previous studies suggested that a bundled intervention was associated with lower rates of S aureus SSIs among patients having cardiac or orthopedic operations, according to background information in the article.

Loreen A. Herwaldt, M.D., of the University of Iowa Carver College of Medicine, Iowa City, and colleagues evaluated whether the implementation of an evidence-based bundle is associated with a lower risk of S aureus SSIs in patients undergoing cardiac operations or hip or knee replacement or reconstruction. Twenty hospitals in 9 U.S. states participated in this study; rates of SSIs were collected for a median of 39 months during the pre-intervention period and a median of 21 months during the intervention period.

Patients whose preoperative nasal screens were positive for MRSA or methicillin-susceptible S aureus (MSSA) were asked to apply the antibiotic mupirocin intranasally twice daily for up to 5 days and to bathe daily with chlorhexidine-gluconate (CHG; an antimicrobial agent) for up to 5 days before their operations. MRSA carriers received the antibiotics vancomycin and cefazolin or cefuroxime for perioperative prophylaxis; all others received cefazolin or cefuroxime. Patients who were MRSA-negative and MSSA-negative bathed with CHG the night before and morning of their operations. Patients were treated as MRSA-positive if screening results were unknown.

After a 3-month phase-in period, bundle adherence remained constant at 83 percent (full adherence, 39 percent; partial adherence, 44 percent). The complex (deep incisional or organ space) S aureus SSI rates decreased significantly among patients in the fully adherent group compared with the pre-intervention period, but rates did not decrease significantly in the partially adherent or nonadherent group.

Overall, 101 complex S aureus SSIs occurred after 28,218 operations during the pre-intervention period and 29 occurred after 14,316 operations during the intervention period (average rate per 10,000 operations, 36 for pre-intervention period vs 21 for intervention period). The rates of complex S aureus SSIs decreased for hip or knee arthroplasties (difference per 10,000 operations, -17) and for cardiac operations (difference per 10,000 operations, -6).

“Even though the baseline rate of complex S aureus SSI was low (0.36 per 10,000 operations), the full adherence rate was only 39 percent, and hospitals had implemented some bundle elements before the study began, rates of complex S aureus SSIs decreased significantly,” the researchers write. “Given that approximately 400,000 cardiac operations and 1 million total joint arthroplasties are performed in the United States each year, numerous S aureus SSIs, which can have catastrophic consequences, may be preventable. Moreover, 1 SSI adds from $13,000 to $100,000 to the cost of health care. Thus, implementation of this bundle might reduce patient morbidity and the costs of care substantially.”

(doi:10.1001/jama.2015.5387; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was funded by the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. It also received support from VA Health Services Research and Development.  Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Bundled Approaches for Surgical Site Infection Prevention

In an accompanying editorial, Preeti N. Malani, M.D., M.S.J., of the University of Michigan Health System, Ann Arbor, and Associate Editor, JAMA, writes that although this study is a noteworthy addition to a growing body of high-quality infection prevention trials, many questions remain.

“Although S aureus remains the principal pathogen in terms of prevalence and associated morbidity, many other organisms also cause SSIs. As such, decolonization of MSSA and MRSA can be only one aspect of SSI prevention. Although the current findings demonstrate a decrease in S aureus SSIs, the authors did not find a decrease in gram-negative SSIs or complex SSIs caused by any pathogen. This finding might reflect the overall low rate of infection, but also is a poignant reminder that additional strategies are still needed.”

“Public reporting and nonpayment for preventable complications (including some SSIs) have intensified efforts to eliminate infections—‘to get to zero.’ The low-hanging fruit for SSI prevention has been picked and incremental decreases are unlikely to come from simple interventions. Although getting to zero is unlikely to be achievable, efforts that move closer to this elusive goal hold tremendous value for clinicians, hospitals, payers, and, most importantly, patients.”

(doi:10.1001/jama.2015.6018; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 2, 2015

Media Advisory: To contact Peter S. Hussey, Ph.D., email Kirsten Holguin at kholguin@rand.org.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5089

Study Questions Effectiveness of Computerized Clinical Decision Support Systems

An analysis of the use of computerized clinical decision support systems regarding orders for advanced diagnostic imaging found that the systems failed to identify relevant appropriateness criteria for the majority of orders, according to a study in the June 2 issue of JAMA.

Computerized clinical decision support (CDS) systems that match patient characteristics against appropriateness criteria to produce algorithmic treatment recommendations are a potential means of improving care. The Protecting Access to Medicare Act of 2014 mandates use of CDS systems for the ordering of advanced diagnostic imaging in the Medicare program starting in 2017, according to background information in the article.

Peter S. Hussey, Ph.D., of RAND, Boston, and colleagues used data from the Medicare Imaging Demonstration to evaluate the relationship of CDS system use with the appropriateness of ordered images. Between October 2011 and November 2013, clinicians used computerized radiology order entry systems and CDS systems for selected magnetic resonance imaging, computed tomography, and nuclear medicine procedures. During a 6-month baseline period, the CDS systems tracked whether orders were linked with appropriateness criteria but did not provide clinicians with feedback on appropriateness of orders.

During the 18-month intervention period, the CDS systems provided feedback indicating whether the order was linked to appropriateness criteria and, if so, the appropriateness rating, any recommendations for alternative orders, and a link to documentation supporting each rating. National medical specialty societies developed the appropriateness criteria using expert panels that reviewed evidence and completed a structured rating process.

The 3,340 participating clinicians placed 117,348 orders for advanced diagnostic imaging procedures. The CDS systems did not identify relevant appropriateness criteria for 63.3 percent of orders during the baseline period and for 66.5 percent during the intervention period. During the baseline period, 11.1 percent of final rated orders were inappropriate vs 6.4 percent during the intervention period. During the baseline period, 73.7 percent of final rated orders were appropriate vs 81.0 percent during the intervention period. Of orders initially rated as inappropriate, 4.8 percent were changed and 1.9 percent were canceled.

“Most orders were unable to be matched by the CDS systems to appropriateness criteria. Of those matched, there was a small increase in the percentage of orders rated appropriate between the baseline and intervention periods, although few inappropriate orders were changed or canceled immediately following feedback from the CDS systems. Therefore, improvements in appropriate imaging ordering do not appear related to immediate feedback and instead may be related to physician learning or secular changes,” the authors write.

“Implementing CDS systems in real-world settings has many challenges that must be addressed to meaningfully affect patient care.”

(doi:10.1001/jama.2015.5089; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Funding for this project was provided by the Centers for Medicare & Medicaid Services. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

# # #

EMBARGOED FOR RELEASE: 8 A.M. (ET) FRIDAY, MAY 29, 2015

Media Advisory: To contact Alexander Zarbock, M.D., email zarbock@uni-muenster.de. To contact editorial co-author David Sheikh-Hamad, M.D., call Julia Parsons at 713-798-4710 or email Julia.Parsons@bcm.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4189. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5085

Intervention Reduces Rate of Kidney Injury Among High-Risk Patients Undergoing Cardiac Surgery

Use of a procedure known as remote ischemic preconditioning reduced the rate of kidney injury and the need for renal replacement therapy (dialysis) after cardiac surgery in high-risk patients, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the 52nd European Renal Association/European Dialysis and Transplant Association Congress.

Remote ischemic preconditioning is performed to help protect organs against a type of tissue damage that can occur when normal blood flow is returned to a tissue that had been temporarily deprived of oxygen, such as during cardiac surgery. The procedure is performed just before surgery and involves placing a blood pressure cuff on a limb and alternately inflating and deflating it to restrict and restore blood flow. Evidence has suggested that remote ischemic preconditioning from brief episodes of ischemia (inadequate blood supply) and reperfusion (the restoration of blood flow) in distant tissue may provide protection from subsequent injury.

Up to 30 percent of patients develop acute kidney injury after cardiac surgery, and to date no interventions have yet been identified to reduce this risk. Three small single-center randomized trials investigating the effect of remote ischemic preconditioning on acute kidney injury after cardiac surgery have shown conflicting results, according to background information in the article.

Alexander Zarbock, M.D., of the University Hospital Munster, Germany, and colleagues randomly assigned 240 cardiac surgery patients at high risk for acute kidney injury to receive either remote ischemic preconditioning (n = 120; 3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anesthesia) or sham remote ischemic preconditioning (control; n = 120), both via blood pressure cuff inflation. The study was conducted at 4 hospitals in Germany.

The researchers found that significantly fewer patients in the remote ischemic preconditioning group developed acute kidney injury within 72 hours after surgery compared with the control group (37.5 percent vs 52.5 percent; absolute risk reduction, 15.0 percent). Remote ischemic preconditioning significantly reduced the number of moderate and severe acute kidney injury cases compared with that of the control group (12.5 percent vs 25.8 percent). Use of renal replacement therapy (5.8 percent vs 15.8 percent; absolute risk reduction, 10 percent) and length of intensive care unit stay (3 days vs 4 days) were significantly reduced with remote ischemic preconditioning.

There was no significant effect of remote ischemic preconditioning on heart attack, stroke, or death. No adverse events were reported with remote ischemic preconditioning.

“The observed reduction in the rate of acute kidney injury and the need for renal replacement warrant further investigation,” the authors write.

(doi:10.1001/jama.2015.4189; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Remote Ischemic Preconditioning for Kidney Protection

“Therapeutic strategies to protect against ischemic kidney injury and improve patient outcomes are lacking,” write Jenny Szu-Chin Pan, M.D., and David Sheikh-Hamad, M.D., of the Baylor College of Medicine, Houston, in an accompanying editorial.

“Remote ischemic preconditioning [RIPC], as demonstrated in the study by Zarbock and colleagues, may offer a novel inexpensive and noninvasive clinical intervention to reduce the occurrence and severity of acute kidney injury [AKI]. Further studies are needed to determine whether a longer duration of limb ischemia or earlier induction of RIPC confers better renoprotection; 37.5 percent of the patients in the RIPC group still developed AKI.”

The authors add that before RIPC is adopted for clinical use, the potential risks and adverse effects must be considered carefully. “While remote kidney/cardiac preconditioning after limb muscle ischemia may differ from the changes observed in the heart after kidney ischemia, effects of repeated limb ischemia with RIPC are not known and clinicians should be mindful of potential harms before adopting this approach widely.”

(doi:10.1001/jama.2015.5085; 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.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 26, 2015

Media Advisory: To contact Nicolas Rodondi, M.D., M.A.S., email Nicolas.Rodondi@insel.ch.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5161

Subclinical Hyperthyroidism Associated With an Increased Risk of Hip and Other Fractures

In an analysis that included more than 70,000 participants from 13 studies, subclinical hyperthyroidism was associated with an increased risk for hip and other fractures including spine, according to a study in the May 26 issue of JAMA. Subclinical hyperthyroidism is a low serum thyroid-stimulating hormone concentration in a person without clinical symptoms and normal thyroid hormone concentrations on blood tests.

Overt hyperthyroidism is an established risk factor for osteoporosis and fractures. Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking, according to background information in the article.

Nicolas Rodondi, M.D., M.A.S., of the Bern University Hospital, Bern, Switzerland, and colleagues assessed the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. The authors searched databases for studies with thyroid function data and subsequent fractures. Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (normal functioning) (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥ 4.50-19.99 mIU/L) with normal thyroxine (a hormone that is made by the thyroid gland) concentrations.

Among 70,298 participants, 4,092 (5.8 percent) had subclinical hypothyroidism and 2,219 (3.2 percent) had subclinical hyperthyroidism. In an analysis of the occurrence of fractures among study participants, the researchers found that subclinical hyperthyroidism was associated with an increased risk for hip, spine and nonspine fracture and any fracture. The highest risks were in individuals with suppressed TSH (<0.10 mIU/L) and in those with endogenous (from within ones own body [vs. exogenous – taking too much thyroid replacement]) subclinical hyperthyroidism. No association was found between subclinical hypothyroidism and fractures.

“Our pooled data analysis demonstrates that subclinical hyperthyroidism was associated with increased fracture risk and provides insight on defined subgroups,” the authors write.

“Current guidelines recommend that treatment of subclinical hyperthyroidism should be strongly considered if TSH is persistently lower than 0.1 mIU/L in all individuals aged 65 years or older and that treatment should also be considered if TSH is low but at least 0.1 mIU/L in individuals who are at least 65 years old. Our results from pooling data of all available prospective cohorts, showing increased fracture risk in subclinical hyperthyroidism with even higher risk for participants with TSH levels of less than 0.10 mIU/L, are consistent with these recommendations.”

The researchers note that further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

(doi:10.1001/jama.2015.5161; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 26, 2015

Media Advisory: To contact Lewis J. Smith, M.D., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5024

Soy Isoflavone Supplement Does Not Improve Symptoms, Lung Function for Patients with Poorly Controlled Asthma

Although some data have suggested that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control, a randomized trial that included nearly 400 children and adults found that use of the supplement did not result in improved lung function or clinical outcomes, including asthma symptoms and episodes of poor asthma control, according to a study in the May 26 issue of JAMA. Soy isoflavones are plant (soybean) derived chemicals that have anti-oxidant effects.

Increases in asthma prevalence and severity over the last several decades are likely due at least in part to environmental factors. Diet is one environmental factor that is associated with asthma prevalence and severity. Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited.  Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poorly controlled asthma.  The soy isoflavone genistein inhibits a key pathway that may contribute to asthma severity. With the increasing cost of prescription drugs for asthma, it is important to identify effective, safe, and less expensive therapies than those currently available, according to background information in the article.

Lewis J. Smith, M.D., of Northwestern University, Chicago, and colleagues randomly assigned 386 adults and children age 12 years or older with symptomatic asthma while taking a “controller” medicine (either inhaled corticosteroids and/or a leukotriene modifier) and low dietary soy intake to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. The trial was conducted at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network.

The researchers found that average changes in pre-bronchodilator forced expiratory volume in the first second (FEV₁; a measure of lung function) over 24 weeks were not significantly different between the soy isoflavone group and the placebo group. The supplement also did not improve other aspects of asthma control, including additional measures of lung function, symptoms, quality of life, and airway and systemic inflammation.

“These findings suggest that this supplement should not be used for patients with poorly controlled asthma,” the authors conclude.

(doi:10.1001/jama.2015.5024; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by grants from the National Institutes of Health and the American Lung Association. Archer Daniels Midland (Decatur, Il.) provided the soy isoflavone supplement and the matching placebo. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 26, 2015

Media Advisory: To contact Alexandre Reymond, Ph.D., email alexandre.reymond@unil.ch. To contact editorial author James R. Lupski, M.D., Ph.D., D.Sc., call Glenna Vickers at 713-798-7973 or email

picton@bcm.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4845 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4846

Study Examines Association of Genetic Variants with Cognitive Impairment

Individually rare but collectively common intermediate-size copy number variations may be negatively associated with educational attainment, according to a study in the May 26 issue of JAMA. Copy number variations (CNVs) are regions of the genome that differ in the number of segments of DNA.

The Database of Genomic Variants catalogs approximately 2.4 million DNA CNVs. Some of them have been previously implicated as causal of a wide variety of traits and conditions. According to background information in the article large (defined as larger than 500 kb), recurrent CNVs have been particularly associated with developmental delay and intellectual disability (characterized by limited intellectual functioning and impaired adaptive behavior in everyday life) in symptomatic individuals ascertained in clinical settings.

Alexandre Reymond, Ph.D., and Katrin Männik, Ph.D., of the University of Lausanne, Switzerland, and colleagues used the population biobank of Estonia, which contains samples from 52,000 participants to explore the consequences of CNVs in a presumptively healthy population. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. For example, information was available regarding attained level of education for participants.   Copy number variant analysis was conducted on a random sample of 7,877 individuals and genotype-phenotype associations with education and disease traits were evaluated.  Phenotype is a characteristic of an individual that is the result of the interaction of the person’s genetic makeup (genotype) and his or her environment.

Of the 7,877 in the Estonian cohort, the researchers identified 56 carriers of recurrent large CNVs associated with known syndromes. Many of these individuals had phenotypic features similar to symptomatic individuals ascertained in previous clinical studies.

A genome-wide evaluation of rare intermediate size CNVs (frequency ≤ 0.05 percent; ≥ 250 kb) identified 831 carriers (10.5 percent) in the tested population sample. This group of carriers had increased prevalence of intellectual disability and decreased education attainment. Eleven of 216 (5.1 percent) of carriers of a deletion of at least 250 kb and 5.9 percent of carriers of a duplication of at least l Mb had an intellectual disability compared with 1.7 percent in the Estonian cohort without detected CNVs.

Of the deletion carriers, 33.5 percent did not graduate from high school while 39.1 percent of duplication carriers did not graduate high school compared to 25.3 percent in the Estonian population at large. These evidences for an association between rare intermediate size CNVs and lower educational attainment were further supported by analyses of cohorts including an intellectually high-functioning group of Estonians and 3 geographically distinct populations in the United Kingdom, the United States and Italy.

“Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.”
(doi:10.1001/jama.2015.4845; 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: Cognitive Phenotypes and Genomic Copy Number Variations

“The results reported by Mannik et al indicate that individually rare but collectively common intermediate-size CNVs contribute to the variance in educational attainment,” writes James R. Lupski, M.D., Ph.D., D.Sc., of the Baylor College of Medicine, Houston, in an accompanying editorial.

“This phenotype is an objectively quantifiable trait that could trigger ordering of a genomic study capable of detecting CNV used in clinical care. With the recognition of a potentially causal mutation in an individual, tailored behavioral and educational interventions could be initiated with patients and family that could improve educational outcomes. Although changing a person’s genome is not possible, identifying those with CNVs related to cognitive phenotypes could provide an opportunity to help them reach their fullest potential.”

(doi:10.1001/jama.2015.4846; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 26, 2015

Media Advisory: To contact Catterina Ferreccio, M.D., M.P.H., email catferre@gmail.com.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4559

Study Finds Association Between Exposure to Aflatoxin and Gallbladder Cancer

In a small study in Chile that included patients with gallbladder cancer, exposure to aflatoxin (a toxin produced by mold) was associated with an increased risk of gallbladder cancer, according to a study in the May 26 issue of JAMA.

In Chile, gallbladder cancer is a leading cause of cancer death in women. Exposure to aflatoxin, a liver carcinogen, is associated with gallbladder cancer in primates. Aflatoxin contamination has been identified in Chile, including in aji rojo (red chili peppers). Aji rojo is associated with gallbladder cancer; however, the association of aflatoxin with gallbladder cancer in humans has not been directly evaluated, according to background information in the article.

Catterina Ferreccio, M.D., M.P.H., of the Pontificia Universidad Catolica de Chile, Santiago, Chile, and colleagues evaluated plasma aflatoxin-albumin adducts (a compound) and gallbladder cancer in a pilot study conducted from April 2012 through August 2013. Aflatoxin forms adducts with albumin in peripheral blood that accumulate up to 30-fold higher with chronic vs single exposure. The researchers assessed aflatoxin B₁-lysine adduct (AFB₁ adduct) in participants. Aji rojo consumption was determined via questionnaire.

The final analysis included 36 patients (cases) with gallbladder cancer, 29 controls with gallstones, and 47 community controls. Cases and controls had similar characteristics except for aji rojo consumption (greater percentage of case patients had weekly consumption). AFB₁-adducts were detected in 23 cases (64 percent), 7 controls with gallstones (18 percent), and 9 community controls (23 percent). AFB₁-adduct levels were highest in cases.

“Despite the small number of participants, the associations between aflatoxin exposure and gallbladder cancer were statistically significant. Recall bias may affect self-reported variables, but not exposure measurement. We cannot rule out reverse causation (i.e., cancer may affect AFB₁-adduct detection) using cross-sectional data. Larger and longitudinal efforts are needed to substantiate these preliminary findings, obtain more precise effect estimates, and identify sources of aflatoxin. These findings, if confirmed, may have implications for cancer prevention,” the authors write.

(doi:10.1001/jama.2015.4559; 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.

# # #