EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 26, 2012

Media Advisory: To contact Monika L. Metzger, M.D., call Summer Freeman at 901-595-3061 or email summer.freeman@stjude.org. To contact editorial co-author Frederick D. Goldman, M.D., call Clinton Colmenares at 205-934-3887 or email ccolmena@uab.edu.

CHICAGO – Among children with favorable-risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited radiotherapy was associated with a high rate of 2-year event-free survival, according to a study in the June 27 issue of JAMA.

“Currently more than 90 percent of children with favorable-risk Hodgkin lymphoma will achieve long-term survival. However, studies demonstrate excess mortality among patients followed up beyond 10 years from their Hodgkin lymphoma diagnosis as a result of late toxic effects of therapy, including the development of second malignant neoplasms and nonneoplastic treatment complications. Risk-adapted combined-modality therapy (combined chemotherapy and radiotherapy according to predetermined risk stratification) has therefore been tailored to minimize therapy while maintaining excellent outcome. Response-adapted therapies (tailored according to early initial response) aim to identify patients for whom it would be safe to reduce radiation therapy dose, volume, or both,” according to background information in the article.

Monika L. Metzger, M.D., of St. Jude Children’s Research Hospital, Memphis, Tenn., and colleagues conducted a study to evaluate the efficacy of 4 cycles of vinblastine, Adriamycin (doxorubicin) methotrexate, and prednisone (VAMP) in patients with favorable-risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy. The multi-institutional, phase 2 clinical trial was conducted to assess the need for radiotherapy based on early response to chemotherapy. The study included 88 eligible patients with Hodgkin lymphoma stage I and II enrolled between March 2000 and December 2008. Follow-up data were available through March 12, 2012. The 47 patients who achieved a complete response after 2 cycles received no radiotherapy, and the 41 with less than a complete response were given 25.5 Gy-involved-field radiotherapy. The primary outcome measure for the study was two-year event-free survival. A 2-year event-free survival of greater than 90 percent was desired, and 80 percent was considered to be unacceptably low.

The researchers found that the estimated 2-year event-free survival was 90.8 percent. The 2-year event-free survival for patients who achieved early complete response and did not receive involved field radiotherapy was 89.4 percent compared with 92.5 percent for those who did not achieve complete response and did require radiotherapy. Patients who did not undergo irradiation also had an estimated 5-year event-free survival of 89.4 percent, which is similar to patients who did (5-year event-free survival, 87.5 percent).

“Therapy was well tolerated without major complications. Delay or dose modifications due to adverse toxic effects were rare. The most common adverse effects were neuropathic pain (2 percent of patients) and nausea and vomiting (3 percent of patients), all of which are readily managed with supportive care. Neutropenia [lower-than-normal number of neutrophils (a type of white blood cell) in the blood] was observed in 60 percent of patients (32 percent of cycles), and febrile neutropenia in 2 percent of patients (0.9 percent of cycles),” the authors write. Nine patients (10 percent) were hospitalized 11 times (3 percent of cycles) for febrile neutropenia or nonneutropenic infection.

Long-term adverse effects after radiotherapy included asymptomatic compensated hypothyroidism in 9 patients (10 percent), subclinical pulmonary dysfunction in 12 patients (14 percent), and asymptomatic left ventricular dysfunction in 4 patients (5 percent). No second malignant neoplasms were observed.

“To our knowledge, this is the first trial in which a select group of children with favorable-risk Hodgkin lymphoma experienced a high rate of 2- and 5-year event-free survival without exposure to radiotherapy, alkylating agent, epipodophyllotoxin, or bleomycin chemotherapy and a relatively low cumulative dose of anthracyclines. The desire to avoid late treatment complications—particularly those resulting from high doses of irradiation—has motivated most treatment modifications for pediatric Hodgkin lymphoma,” the authors write.

The researchers add that it would be important to confirm these results in a larger cohort.

(JAMA. 2012;307[24]:2609-2616. Available pre-embargo to the media at http://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: Toward a Safer Cure for Low-Risk Hodgkin Lymphoma in Children

In an accompanying editorial, Kimberly F. Whelan, M.D., M.S.P.H., and Frederick D. Goldman, M.D., of the University of Alabama at Birmingham, write that “these findings highlight the continued commitment to reduce complications in the treatment of childhood malignancies and add to the growing body of evidence detailing the utility of early response-adapted therapy.”

“Response-based regimens have been used for patients enrolled in studies of high-risk and low-risk Hodgkin lymphoma. With the advent of minimal residual disease testing, these regimens similarly play a large role in childhood leukemia treatment. The emphasis on minimizing therapy when possible is especially important in the treatment of childhood malignancies, for which the consequences of late complications is well documented. However, any attempt to decrease therapy to minimize late effects must be balanced with the risk of relapse because the primary cause of death the first 10 years after diagnosis remains recurrent disease.”

(JAMA. 2012;307[24]:2639-2640. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 26, 2012

Media Advisory: To contact John M. Jakicic, Ph.D., call Patricia Lomando White at 412-624-9101 or email laer@pitt.edu. To contact editorial author George A. Bray, M.D., call Angela deGravelles at 225-202-5073 or email robin.post@pbrc.edu.

CHICAGO – Although a standard behavioral weight loss intervention among overweight and obese adults resulted in greater average weight loss over 18 months, a stepped care intervention resulted in clinically meaningful weight loss that cost less to implement, according to a study in the June 27 issue of JAMA.

“Most weight loss programs are intensive during the initial weeks of treatment, become less intensive over time, and maintain a fixed contact schedule for participants irrespective of treatment success or failure. Intensive weight loss programs are costly and require substantial time commitments from the participants, making them impractical in many circumstances. An alternative is a stepped-care approach. It involves an initially low-intensity intervention that is increased if weight loss milestones are not achieved at fixed time points. Stepped care has been effective for treatment of other health conditions. In theory, stepped care could result in better weight loss than conventional therapy because treatment intensity is escalated if weight loss goals are not met during the treatment period,” according to background information in the article. “If shown to be an effective and a lower cost alternative to traditional in-person programs, a stepped-care approach could prove to be a cost-effective means for obesity treatment.”

John M. Jakicic, Ph.D., of the University of Pittsburgh, and colleagues examined whether a stepped-care weight loss intervention (STEP) would result in greater weight loss compared with a standard behavioral weight loss intervention (SBWI). The clinical trial included 363 overweight and obese adults (body mass index: 25-<40; age: 18-55 years, 33 percent nonwhite, and 83 percent female) who were randomized to SBWI (n = 165) or STEP (n=198). Participants were enrolled between May 2008 and February 2010 and data collection was completed by September 2011. All participants were placed on a low-calorie diet, prescribed increases in physical activity, and attended group counseling sessions ranging from weekly to monthly during an 18-month period. The SBWI group was assigned to a fixed program. Counseling frequency, type, and weight loss strategies could be modified every 3 months for the STEP group in response to observed weight loss as it related to weight loss goals.

Of the 363 study participants, 260 (71.6 percent) provided a measure of weight at the 18-month assessment. The researchers found that weight loss at 18 months was -7.6 kg (16.8 lbs.) in the SBWI group compared with -6.2 kg (13.7 lbs.) in the STEP group. The percentage change in weight from baseline to 18 months was -8.1 percent in the SBWI group compared with -6.9 percent in the STEP group.

Both groups had significant and comparable improvements in resting heart rate, blood pressure level, and fitness.

“From the payer perspective, the mean cost per participant was $358 for the STEP group and $494 for the SBWI group. Costs from the participant perspective also were lower in the STEP group ($427) per participant compared with the SBWI group ($863). From the societal perspective (i.e., the sum of payer and participant), the average cost for STEP was $785. This was significantly less expensive than the average cost for SBWI, which was estimated to be $1,357,” the authors write.

The researchers add that using the base-case cost estimates, they found that from the societal perspective, relative to status quo, the incremental cost-effectiveness ratio for STEP was $127 per 1 kg (2.2 lbs.) of weight lost. “The incremental cost-effectiveness ratio for SBWI, relative to the less expensive STEP, was $409 per 1 kg of weight lost. From the payer perspective, the incremental cost-effectiveness ratios were reduced to $58 per 1 kg of weight lost for STEP and $97 per 1 kg of weight lost for SBWI.”

“Among overweight and obese adults, the use of SBWI resulted in a greater mean weight loss than STEP over 18 months. STEP resulted in clinically meaningful weight loss that cost less to implement than SBWI. Whether this weight loss results in improved health-related outcomes warrants further investigation,” the authors conclude.

(JAMA. 2012;307[24]:2617-2626. Available pre-embargo to the media at http://media.jamanetwork.com)

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

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, June 26 at this link.

Editorial: Diet and Exercise for Weight Loss

“Obesity is one of the most important and most frustrating health problems that physicians treat, and the studies in this issue of JAMA provide valuable information for clinicians who treat obese patients,” writes George A. Bray, M.D., of the Pennington Biomedical Research Center, Baton Rouge, La., in an accompanying editorial.

“It may be possible to have a more individualized approach to weight loss, rather than a one-size-fits-all approach. The most efficient treatment approach incorporates periodic reassessments and adjustment of the weight loss regimen based on a patient’s success at any given time.”

“This trial thus shows that the novel approach of spending more time and effort on patients who need it most may be more economical than implementing a standard protocol for all participants re­gardless of their response. Despite the successes of the ap­proaches used in the study by Jakicic et al, the findings do not answer the question of how to achieve weight loss in a manner that will be appealing enough to the participants to result in long-term, sustained weight loss.”

(JAMA. 2012;307[24]:2641-2642. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Bray reported that he has been a consultant to Abbott Laboratories and Takeda Global Research Institute; is an advisor to Medifast, Herbalife, and Global Direction in Medicine; and has received royalties for the Handbook of Obesity.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 26, 2012

Media Advisory: To contact corresponding author David S. Ludwig, M.D., Ph.D., call Keri Stedman at 617-919-3114 or email keri.stedman@childrens.harvard.edu.

CHICAGO – In an examination of the effect on energy expenditure and components of the metabolic syndrome of 3 types of commonly consumed diets following weight loss, decreases in resting energy expenditure and total energy expenditure were greatest with a low-fat diet, intermediate with a low-glycemic index diet, and least with a very low-carbohydrate diet, suggesting that a low-fat diet may increase the risk for weight regain compared to the other diets, according to preliminary research published in the June 27 issue of JAMA.

“Many people can lose weight for a few months, but most have difficulty maintaining clinically significant weight loss over the long term. According to data from the National Health and Nutrition Examination Survey (1999-2006), only 1 in 6 overweight and obese adults report ever having maintained weight loss of at least 10 percent for 1 year,” according to background information in the article. One explanation for the poor long-term outcome is that weight loss elicits biological adaptations—specifically a decline in energy expenditure and an increase in hunger—that promote weight. According to the authors, the effect of dietary composition on energy expenditure during weight-loss maintenance has not been studied.

Cara B. Ebbeling, Ph.D., of Children’s Hospital Boston, and colleagues conducted a study to evaluate the effects of 3 weight-loss maintenance diets on energy expenditure, hormones, and components of the metabolic syndrome. The study, conducted between June 2006 and June 2010, included 21 overweight and obese young adults. After achieving 10 percent to 15 percent weight loss while consuming a run-in diet, participants consumed an isocaloric low-fat diet (60 percent of energy from carbohydrate, 20 percent from fat, 20 percent from protein; high glycemic load), low-glycemic index diet (40 percent from carbohydrate, 40 percent from fat, and 20 percent from protein; moderate glycemic load), and very low-carbohydrate diet (10 percent from carbohydrate, 60 percent from fat, and 30 percent from protein; low glycemic load) in random order, each for 4 weeks. The primary outcome measured was resting energy expenditure (REE), with secondary outcomes of total energy expenditure (TEE), hormone levels, and metabolic syndrome components.

The researchers found that energy expenditure during weight-loss maintenance differed significantly among the 3 diets. The decrease in REE from pre-weight-loss levels, measured by indirect calorimetry in the fasting state, was greatest for the low-fat diet (average relative to baseline, -205 kcal/d), intermediate with the low-glycemic index diet (-166 kcal/d), and least for the very low-carbohydrate diet (-138 kcal/d). The decrease in TEE also differed significantly by diet (average -423 kcal/d for low fat; -297 kcal/d for low glycemic index; and -97 kcal/d for very low carbohydrate).

“Hormone levels and metabolic syndrome components also varied during weight maintenance by diet (leptin; 24-hour urinary cortisol; indexes of peripheral and hepatic insulin sensitivity; high-density lipoprotein [HDL] cholesterol; non-HDL cholesterol; triglycerides; plasminogen activator inhibitor 1; and C-reactive protein), but no consistent favorable pattern emerged,” the authors write.

“The results of our study challenge the notion that a calorie is a calorie from a metabolic perspective,” the researchers write. “TEE differed by approximately 300 kcal/d between these 2 diets [very low-carbohydrate vs. low-fat], an effect corresponding with the amount of energy typically expended in 1 hour of moderate-intensity physical activity.”

“These findings suggest that a strategy to reduce glycemic load rather than dietary fat may be advantageous for weight-loss maintenance and cardiovascular disease prevention. Ultimately, successful weight-loss maintenance will require behavioral and environmental interventions to facilitate long-term dietary adherence. But such interventions will be most effective if they promote a dietary pattern that ameliorates the adverse biological changes accompanying weight loss,” the researchers conclude.

(JAMA. 2012;307[24]:2627-2634. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 7 A.M. (CT) TUESDAY, JUNE 26, 2012

Media Advisory: To contact Amal N. Trivedi, M.D., M.P.H., call David Orenstein at 401-863-1862 or email david_orenstein@brown.edu.

CHICAGO – An analysis that included 1.2 million veterans enrolled in the Veterans Affairs health care system and Medicare Advantage plan finds that the federal government spends a substantial and increasing amount of potentially duplicative funds in these separate managed care programs for the care of same individuals, according to a study appearing in JAMA. This study is being published early online to coincide with its presentation at the Annual Research Meeting of AcademyHealth.

“In the United States, some adults may be eligible to enroll simultaneously in 2 federally funded managed care systems: the Medicare Advantage (MA) program administered by the Centers for Medicare & Medicaid Services (CMS) and the Veterans Healthcare System (VA) administered by the Veterans Health Administration in the U.S. Department of Veterans Affairs,” according to background information in the article. “Dual enrollment in the VA and MA presents a vexing policy problem. The federal government’s payments to private MA plans assume that these plans are responsible for providing comprehensive care for their enrollees and are solely responsible for paying the costs of Medicare-covered services. If enrollees in MA plans simultaneously receive Medicare-covered services from another federally-funded hospital or other health care facility, and this facility cannot be reimbursed, then the government has made 2 payments for the same service.”

Amal N. Trivedi, M.D., M.P.H., of the Providence VA Medical Center and Brown University, Providence, R.I., and colleagues examined the prevalence of dual enrollment, the use of outpatient and acute inpatient care in the VA and MA, and the costs of Medicare-covered services incurred by the VA to care for MA enrollees. The study included a retrospective analysis of 1,245,657 veterans simultaneously enrolled in the VA and an MA plan between 2004-2009.

The number of dual enrollees increased from 485,651 in 2004 to 924,792 in 2009. The number of dual enrollees using VA services increased from 316,281 in 2004 to 557,208 in 2009. In 2009, 8.3 percent of the MA population was enrolled in the VA and 5 percent of MA beneficiaries were VA users.

The researchers found that the total estimated cost of VA care (in 2009 dollars) for MA enrollees was $13.0 billion over 6 years, increasing from $1.3 billion to $3.2 billion per year. “The largest component of this spending was outpatient care, followed by acute and postacute inpatient care, then prescription drugs. The annual costs of VA-financed fee-basis care increased by a factor of 5 during the study period (from $52 million in 2004 to $249 million in 2009), and represented approximately 8 percent of VA total spending for this population in 2009,” the authors write.

Among dual enrollees, 50 percent used both the VA and MA. Within each of the 419 MA plans participating in Medicare in 2009, the average proportion of the plan’s enrollees with use of VA services was 7 percent. The VA financed 44 percent of outpatient visits, 15 percent of acute medical and surgical admissions, and 18 percent of acute medical and surgical hospital days for the dually enrolled population.

“In 2009, the VA submitted collection requests to private insurers totaling $52.3 million on behalf of care provided to MA enrollees (amounting to 2 percent of the total cost of care for these enrollees in 2009),” the researchers write. “Of these requests, the VA collected $9.4 million for care (18 percent of the billed amount; 0.3 percent of the total cost of care).”

The authors suggest that policymakers could consider 2 broad approaches to reducing duplicative expenditures. “First, the VA could be authorized to collect reimbursements from MA plans for covered services, just as the VA currently collects payments from private health insurers for non-Medicare patients. … A second approach may involve adjusting payments to MA plans on behalf of veterans who receive most or all of their care in the VA.”

“In light of the severe financial pressure facing the Medicare program, policymakers should consider measures to identify and eliminate these potentially redundant expenditures.”

(JAMA. 2012;308[1]: 67-72. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 3:30 P.M. (CT) SUNDAY, JUNE 24, 2012

Media Advisory: To contact Robert S. Nocon, M.H.S., call Rob Mitchum at 773-484-9890 or email Robert.Mitchum@uchospitals.edu. To contact editorial co-author Robert J. Reid, M.D., Ph.D., call Joan DeClaire at 206-947-4560 or email declaire.j@ghc.org.

CHICAGO – Federally funded community health centers with higher patient-centered medical home ratings on measures such as quality improvement had higher operating costs, according to a study appearing in JAMA. This study is being published early online to coincide with its presentation at the Annual Research Meeting of AcademyHealth.

“The patient-centered medical home (PCMH) is a model of care characterized by comprehensive primary care, quality improvement, care management, and enhanced access in a patient-centered environment. The PCMH is intuitively appealing and has improved clinical and organizational performance in several early studies, leading a broad range of stakeholders to call for its adoption. It is critical to understand the cost of the PCMH from the perspective of individual clinics. Such cost data are essential for practices to make informed decisions to adopt the PCMH and for policy makers and administrators to design financially sustainable medical home models,” according to background information in the article. “Little is known about the cost associated with a health center’s rating as a PCMH.”

Robert S. Nocon, M.H.S., of the University of Chicago, and colleagues examined the association between PCMH rating and operating cost in primary care practices, specifically among federally funded health centers. The analysis consisted of a cross-sectional study of PCMH rating and operating cost in 2009. PCMH rating was assessed through surveys of health center administrators of all 1,009 Health Resources and Services Administration-funded community health centers. The survey provided scores from 0 (worst) to 100 (best) for total PCMH score and 6 subscales: access/communication, care management, external coordination, patient tracking, test/referral tracking, and quality improvement. Costs were obtained from the Uniform Data System reports submitted to the Health Resources and Services Administration. The primary measured outcomes were operating cost per physician full-time equivalent, operating cost per patient per month, and medical cost per visit. Six hundred sixty-nine health centers (66 percent) were included in the study sample, with 340 excluded because of nonresponse or incomplete data. The final sample of health centers represents 5,966 full-time equivalent physicians, who cared for more than 12.5 million patients nationally in 2009.

The average total PCMH score for the study sample was 60, with a low score of 21 and a high of 90. “In multivariate models that used total PCMH score as the medical home measure, higher total PCMH score was associated with higher operating cost per patient per month. For the average health center in our study sample, a 10-point higher total PCMH score (i.e., a score of 70 instead of 60 on the 100-point scale) was associated with a $2.26 (4.6 percent) higher operating cost per patient per month, assuming all other variables remain constant,” the authors write.

The researchers also found that in multivariate analyses that used PCMH subscale scores, a 10-point higher score was associated with higher operating cost per physician full-time equivalent for patient tracking ($27,300) and quality improvement ($32,731) and higher operating cost per patient per month for patient tracking ($1.06) and quality improvement ($1.86). “A 10-point higher PCMH sub-scale score was associated with lower operating cost per physician full-time equivalent for access/communication ($39,809).”

The authors write that the magnitude of health center cost effect in this study is significant. “The $2.26 (4.6 percent) higher operating cost per patient per month associated with a 10-point higher total PCMH score would translate into an annual cost of $508,207 for the average health center ($2.26 per patient per month for 18,753 patients during 12 months). The cost associated with higher PCMH function is large for a health center, but that cost is relatively small compared with the potential cost savings from averted hospitalization and emergency department use observed in some preliminary PCMH studies.”

“We believe payment for the medical home should be evidence based and grounded in observations of costs that accrue to each stakeholder in the health care system. Without such data, aggressive pressure to reduce health care cost is more likely to erode PCMH payment over time. Strong quantitative documentation of the actual practice cost of higher PCMH rating could provide the basis for evidence-based financial incentive structures that would be useful as the health care system moves toward more integrated care models such as the accountable care organization. It will only be through effective design and implementation of such financial mechanisms that the PCMH can be sustained.”

(JAMA. 2012;308[1]:doi:10.1001/JAMA.2012.7048. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This research was funded by the Commonwealth Fund, the NIDDK, and the Agency for Healthcare Research and Quality. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Financial Implications of the Patient-Centered Medical Home

In an accompanying editorial, Robert J. Reid, M.D., Ph.D., and Eric B. Larson, M.D., M.P.H., of the Group Health Research Institute, Seattle, comment on the findings of this study.

“The report by Nocon et al provides an in-depth analysis of health center finances. In a few years, more information will become available about whether PCMHs improve care and reduce costs, key elements of their architecture, ways to redesign them to meet the needs of diverse populations, and how to efficiently integrate them into larger health systems. Patient-centered medical homes have great potential for remodeling the lagging U.S. primary care system, which will, if strengthened, be able to provide comprehensive health care services to all patients.”

(doi:10.1001/JAMA.2012.7661. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 19, 2012

Viewpoints in This Week’s JAMA

Designing Health Care for the Most Common Chronic Condition—Multimorbidity

Mary E. Tinetti, M.D., of the Yale University School of Medicine,New Haven,Conn., and colleagues write that multimorbidity, the coexistence of multiple chronic diseases or conditions, is the most common chronic condition experienced by adults. “Almost 3 in 4 individuals aged 65 years and older have multiple chronic conditions, as do 1 in 4 adults younger than 65 years who receive health care.”

The authors suggest that to more effectively care for adults with multiple chronic conditions, changes are needed in quality measurement, health care delivery, and clinical decision making.

(JAMA. 2012;307[23]:2493-2494. Available pre-embargo to the media at http://media.jamanetwork.com)

Clopidogrel Efficacy and Cigarette Smoking Status

Paul A. Gurbel, M.D., of the Sinai Hospital of Baltimore, and colleagues write that large-scale clinical trials have led to the dominant use of clopidogrel in the treatment of high-risk patients with cardiovascular disease.

“However, evidence from these same studies consistently supports less or no clinical efficacy from clopidogrel therapy among patients who do not smoke. These observations raise concerns about the costs and potential risks incurred by treating nonsmokers with clopidogrel. The clopidogrel-smoking interaction deserves further scrutiny and may be related to the influence of cigarette smoking on CYP [cytochrome P450] activity.”

(JAMA. 2012;307[23]:2495-2496. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 19, 2012

Media Advisory: To contact Emanuele Di Angelantonio, M.D., email erfc@phpc.cam.ac.uk. To contact editorial author Scott M. Grundy, M.D., Ph.D., call Remekca Owens at 214-648-3404 or email Remekca.Owens@utsouthwestern.edu.

CHICAGO– Among individuals without known cardiovascular disease (CVD), the addition of certain apolipoproteins and lipoproteins to risk scores containing total cholesterol and high-density lipoprotein cholesterol (HDL-C) was associated with slight improvement in CVD prediction, according to a study in the June 20 issue of JAMA.

“Routinely used risk prediction scores for CVD contain information on total cholesterol and HDL-C and several other conventional risk factors. There is considerable interest in whether CVD prediction can be improved by assessment of various additional lipid-related markers either to replace, or supplement, traditional cholesterol measurements in these scores,” according to background information in the article.

Emanuele Di Angelantonio, M.D., of the University of Cambridge, England, and colleagues with the Emerging Risk Factors Collaboration writing group conducted a study to determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein (a), or lipoprotein-associated phospholipase A₂ to total cholesterol and HDL-C improves CVD risk prediction. For this study, individual records were available for 165,544 participants without CVD at the beginning of the study (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 coronary heart disease [CHD] and 4,994 stroke outcomes) during a median (midpoint) follow-up of 10.4 years.

The researchers found that replacement of information on total cholesterol and HDL-C with various lipid parameters did not improve CVD prediction. “For example, none of the following measures were superior to total cholesterol and HDL-C when they replaced traditional cholesterol measurements in risk prediction scores: the total cholesterol:HDL-C ratio; non-HDL-C; the linear combination of apolipoprotein B and A-I; or the apolipoprotein B:A-I ratio. Furthermore, replacement of total cholesterol and HDL-C with apolipoprotein B and A-I actually significantly worsened risk discrimination.”

The authors did find that the addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model’s discrimination. “We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1 percent; lipoprotein (a), 4.1 percent; and lipoprotein-associated phospholipase A₂ mass, 2.7 percent of people to a 20 percent or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.”

However, the authors note that “The clinical benefits of using any of these biomarkers remains to be established.”

(JAMA. 2012;307[23]:2499-2506. Available pre-embargo to the media at http://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: Use of Emerging Lipoprotein Risk Factors in Assessment of Cardiovascular Risk

Scott M. Grundy, M.D., Ph.D., of the University of Texas Southwestern Medical Center, Dallas, writes in an accompanying editorial that the need for reevaluation of statin treatment recommendations for primary prevention is made clear by a recent report from the Cholesterol Treatment Trialists’ Collaborators.

“This report argues that a sizable portion of patients previously identified as low-risk by multiple-risk-factor algorithms could now be considered candidates for cost-effective statin therapy. These algorithms probably are of less value in selection of patients for drug therapy than in the past. More promising approaches for the future risk assessment may be either testing for early, subclinical atherosclerosis by imaging methods or by simple, qualitative risk projection based on age, sex, low-density lipoprotein levels, and perhaps another major risk factor.”

(JAMA. 2012;307[23]:2540-2541. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 19, 2012

Media Advisory: To contact Brenda R. Hemmelgarn, M.D., Ph.D., call Marta Cyperling at 403-210-3835 or email marta.cyperling@ucalgary.ca. To contact editorial co-author Manjula Kurella Tamura, M.D., M.P.H., call Michelle Brandt at 650-723-0272 or email mbrandt@stanford.edu.

CHICAGO– In a study that included nearly 2 millions adults in Canada, the rate of progression to untreated kidney failure was considerably higher among older adults, compared to younger individuals, according to a study in the June 20 issue of JAMA.

“Studies of the association among age, kidney function, and clinical outcomes have reported that elderly patients are less likely to develop end-stage renal disease (ESRD) compared with younger patients and are more likely to die than to progress to kidney failure even at the lowest levels of estimated glomerular filtration rate [eGFR; flow rate of filtered fluid through a kidney],” according to background information in the article. Previous studies have defined kidney failure by receipt of long-term dialysis, which reflects both disease progression and a treatment decision. “Because it is plausible that the likelihood of initiating long-term dialysis among individuals with kidney failure varies by age, earlier studies may provide an incomplete picture of the burden of advanced kidney disease in older adults, based on the incidence of long-term dialysis alone.”

Brenda R. Hemmelgarn, M.D., Ph.D., of the University of Calgary, Alberta, Canada, and colleagues conducted a study to determine whether age is associated with the likelihood of treated kidney failure (renal replacement therapy: receipt of long-term dialysis or kidney transplantation), untreated kidney failure, and all-cause mortality. The study included 1,816,824 adults in Alberta, Canada, who had outpatient eGFR measured between May 2002 and March 2008, with a baseline eGFR of 15 mL/min/1.73 m² or higher and who did not require renal replacement therapy at the beginning of the study. The primary outcome measures for the study were adjusted rates of treated kidney failure, untreated kidney failure (progression to eGFR <15 mL/min/1.73 m² without renal replacement therapy), and death.

During a median (midpoint) follow-up of 4.4 years, 97,451 (5.4 percent) of study participants died, 3,295 (0.18 percent) developed treated kidney failure, and 3,116 (0.17 percent) developed untreated kidney failure. The researchers found that within each eGFR stratum, adjusted rates of death increased with increasing age. Also, within each eGFR stratum, rates of treated kidney failure were consistently higher among the youngest age group. “For example, in the lowest eGFR stratum (15-29 mL/min/1.73 m²), adjusted rates of treated kidney failure were more than 10-fold higher among the youngest (18-44 years) compared with the oldest (85 years or older) groups,” the authors write.

The opposite results were evident for untreated kidney failure. The risk of untreated kidney failure increased with lower vs. higher eGFR categories, and this association was stronger with increasing age. “For the lowest eGFR stratum (15-29 mL/min/1.73 m²), adjusted rates of untreated kidney failure were more than 5-fold higher among the oldest age stratum (85 years or older) compared with the youngest age stratum (18-44 years).”

Rates of kidney failure overall (treated and untreated combined) demonstrated less variation across age groups.

The researchers write that their results suggest that the incidence of advanced kidney disease in the elderly may be substantially underestimated by rates of treated kidney failure alone.

“These findings have important implications for clinical practice and decision making; coupled with the finding that many older adults with advanced chronic kidney disease [CKD] are not adequately prepared for dialysis, these results suggest a need to prioritize the assessment and recognition of CKD progression among older adults. Our findings also imply that clinicians should offer dialysis to older adults who are likely to benefit from it—and should offer a positive alternative to dialysis in the form of conservative management (including end-of-life care when appropriate) for patients who are unlikely to benefit from (or prefer not to receive) long-term dialysis. Given the large number of older adults with severe CKD, these results also highlight the need for more proactive identification of older adults with CKD, assessment of their symptom burden, and development of appropriate management strategies. Finally, our study demonstrates the need to better understand the clinical significance of untreated kidney failure, the factors that influence dialysis initiation decisions in older adults, and the importance of a shared decision making process for older adults with advanced CKD.”

(JAMA. 2012;307[23]:2507-2515. Available pre-embargo to the media at http://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: Treated and Untreated Kidney Failure in Older Adults – What’s the Right Balance?

In an accompanying editorial, Manjula Kurella Tamura, M.D., M.P.H., and Wolfgang C. Winkelmayer, M.D., M.P.H., Sc.D., of the Stanford University School of Medicine, Palo Alto, Calif., (Dr. Winkelmayer is also Contributing Editor, JAMA), comment on the findings of this study.

“…the work by Hemmelgarn and colleagues highlights a potentially sizeable unmeasured burden of untreated kidney failure among older adults. It is of paramount importance to refine the current understanding of what constitutes appropriate treatment for kidney failure, which factors influence the decision-making process, and which methods are optimal for aligning treatment plans with patient goals and prognosis. Finding the right balance between overtreatment and undertreatment is challenging but necessary. This important scientific and ethical debate can no longer be avoided, for both individual and societal good.”

(JAMA. 2012;307[23]:2545-2546. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 11 A.M. (CT) MONDAY, JUNE 18, 2012

Media Advisory: To contact Wendy C. King, Ph.D., call or email Allison Hydzik (HydzikAM@upmc.edu) or Cyndy McGrath (McGrathC3@upmc.edu) at 412-647-9975.

CHICAGO – Among patients who underwent bariatric surgery, there was a higher prevalence of alcohol use disorders in the second year after surgery, and specifically after Roux-en-Y gastric bypass, compared with the years immediately before and following surgery, according to a study in the June 20 issue of JAMA. This study is being published early online to coincide with its presentation at the annual meeting of the American Society for Metabolic and Bariatric Surgery.

“As the prevalence of severe obesity increases in the United States, it is becoming increasingly common for health care providers and their patients to consider bariatric surgery, which is the most effective and durable treatment for severe obesity. Although bariatric surgery may reduce long-term mortality, and it carries a low risk of short-term serious adverse outcomes, safety concerns remain. Anecdotal reports suggest that bariatric surgery may increase the risk for alcohol use disorders (AUD; i.e., alcohol abuse and dependence),” according to background information in the article.

The authors add that there is evidence that some bariatric surgical procedures (i.e., Roux-en-Y gastric bypass [RYGB] and sleeve gastrectomy) alter the pharmacokinetics of alcohol. “Given a standardized quantity of alcohol, patients reach a higher peak alcohol level after surgery compared with case-controls or their preoperative levels.”

Wendy C. King, Ph.D., of theUniversityofPittsburgh, and colleagues conducted a study to determine whether the prevalence of AUD changed following bariatric surgery, comparing reported AUD in the year prior to surgery with the first and second years after surgery. The prospective study included 2,458 adults who underwent bariatric surgery at 10U.S.hospitals. Of these participants, 1,945 (78.8 percent female; 87 percent white; median [midpoint] age, 47 years; median body mass index, 45.8) completed preoperative and postoperative (at 1 year and/or 2 years) assessments between 2006 and 2011. The primary outcome measure for the study was past year AUD symptoms determined with the Alcohol Use Disorders Identification Test (AUDIT) (indication of alcohol-related harm, alcohol dependence symptoms, or score 8 or greater).

The researchers found that the prevalence of AUD symptoms did not significantly differ from 1 year before to 1 year after bariatric surgery (7.6 percent vs. 7.3 percent), but was significantly higher in the second postoperative year (9.6 percent). Frequency of alcohol consumption and AUD significantly increased in the second postoperative year compared with the year prior to surgery or the first postoperative year.

“More than half (66/106; 62.3 percent) of those reporting AUD at the preoperative assessment continued to have or had recurrent AUD within the first 2 postoperative years,” the authors write. “In contrast, 7.9 percent (101/1,283) of participants not reporting AUD at the preoperative assessment had postoperative AUD. Nonetheless, more than half (101/167; 60.5 percent) of postoperative AUD was reported by those not reporting AUD at the preoperative assessment”

The researchers also found that male sex, younger age, smoking, regular alcohol consumption, AUD, recreational drug use, lower score on a measure of a sense of belonging at the preoperative assessment and undergoing a RYGB were independently related to an increased likelihood of AUD after surgery. RYGB accounted for 70 percent of surgeries and doubled the likelihood of postoperative AUD compared with laparoscopic adjustable gastric banding.

The authors note that although the 2 percent increase (7.6 percent to 9.6 percent) in prevalence of AUD from prior to surgery to the 2-year postoperative assessment may seem small, the increase potentially represents more than 2,000 additional people with AUD in the United States each year, with accompanying personal, financial, and societal costs.

“This study has important implications for the care of patients who undergo bariatric surgery. Regardless of alcohol history, patients should be educated about the potential effects of bariatric surgery, in particular RYGB, to increase the risk of AUD. In addition, alcohol screening and, if indicated, referral should be offered as part of routine preoperative and postoperative clinical care. Further research should examine the long-term effect of bariatric surgery on AUD, and the relationship of AUD to postoperative weight control.”

(JAMA. 2012;307[23]:2516-2525. Available pre-embargo to the media at http://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: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 11 a.m. CT Monday, June 18 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 12, 2012

Newborn Screening May Miss Infants With Adrenal Gland Disorder

“The purpose of newborn screening (NBS) for congenital adrenal hyperplasia (CAH; a genetic disorder present at birth characterized by a deficiency of the hormones aldosterone and cortisol and an overproduction of male sex hormones [androgens]) due to 21α-hydroxylase deficiency is the early identification of newborns with the classic salt-wasting [an inappropriately large renal excretion of salt despite the body’s apparent need to retain it] and simple-virilizing forms to avoid a potentially life-threatening adrenal or salt-wasting crisis. Cases of classic CAH missed by NBS (false-negatives) are not well documented,” writes Kyriakie Sarafoglou, M.D., of the University of Minnesota Amplatz Children’s Hospital, Minneapolis and colleagues.

As reported in a Research Letter, the authors conducted a population-based study of all newborns screened in Minnesota (n = 838,241) from January 1999 through December 2010. Through a partnership between the Minnesota Department of Health and the 3 largest pediatric endocrinology centers in Minnesota, cases of CAH missed by NBS were identified through review of the NBS registry and the medical records of the participating institutions. Of the newborns screened during the study period, 52 patients with classic CAH were identified and 15 cases were missed (false-negative rate, 22.4 percent; 6 males, 9 females).

“Over a 12-year period, 22 percent of diagnosed patients born in Minnesota with classic CAH were not identified by NBS, highlighting that a negative screening result does not definitively rule out classic CAH. We also found that a false-negative result can sometimes delay the diagnosis of CAH even in a newborn female with ambiguous genitalia,” the researchers write. “Screening programs should educate clinicians about false-negative results so that any patient for whom there is clinical concern for CAH can receive immediate diagnostic testing, particularly females with ambiguous genitalia.”

(JAMA. 2012;307[22]:2371-2374. Available pre-embargo to the media at http://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

The Cost of Drug Coupons

David Grande, M.D., M.P.A., of the University of Pennsylvania, Philadelphia, writes that “drug coupons that discount patient co-pays have emerged as a popular tool to decrease the financial burden of prescription drugs. From 2009 to 2011, the number of drug manufacturer coupons increased markedly, to an estimated 340 individual drug coupon programs.”

Dr. Grande suggests that these coupons could carry a cost that physicians and patients are overlooking, including increasing out-of-pocket spending for the coupon user in either the short or long term because co-pays may still be higher compared with therapeutic alternatives (i.e., direct costs); and increasing health care spending for coupon users and non-users by increasing aggregate health spending and thus health insurance premiums (i.e., indirect costs).

(JAMA. 2012;307[22]:2375-2376. Available pre-embargo to the media at http://media.jamanetwork.com)

Adaptive Clinical Trials – A Partial Remedy for the Therapeutic Misconception?

William J. Meurer, M.D., M.S., of the University of Michigan, Ann Arbor, and colleagues write that there is a common therapeutic misconception among patients considering participation in clinical trials. “Some trial participants and family members believe that the goal of a clinical trial is to improve their outcomes—a misperception often reinforced by media advertising of clinical research. Clinical trials have primarily scientific aims and rarely attempt to collectively improve the outcomes of their participants. The overarching goal of most clinical trials is to evaluate the effect of a treatment on disease outcomes.”

An adaptive clinical trial design can be used to increase the likelihood that study participants will benefit by being in a clinical trial, the authors suggest. “Broadly speaking, an adaptive clinical trial is one in which key characteristics (e.g., randomization ratio, number of treatment groups, number and frequency of interim analyses, the patient subpopulation being considered) are adjusted while enrollment in the trial is ongoing, using prospectively defined decision rules and in response to information arising from the data accumulating in the trial.”

(JAMA. 2012;307[22]:2377-2378. Available pre-embargo to the media at http://media.jamanetwork.com)

Adaptive Trials in Clinical Research – Scientific and Ethical Issues to Consider

Rieke van der Graaf, Ph.D., of the University Medical Center Utrecht, the Netherlands and colleagues write that certain features of adaptive trials may create some potential scientific and ethical challenges. These issues include that the social and scientific value of adaptive trials may be less than trials with fixed designs; the validity and integrity of adaptive trials may be difficult to maintain; and some trials may raise issues regarding study participant selection, potential burdens to study participants, ethical approvals, and obtaining informed consent.

“Researchers who conduct adaptive trials should be aware of these issues to ensure that the value of adaptive trials is not diminished, that the scientific validity of these trials is maintained, that unfair selection of trial participants does not occur, that burdens to participants do not increase, that trial protocol amendments are kept to the minimum, and that genuine informed consent is obtained. By doing so, the conduct of adaptive trials will be scientifically and ethically comparable to conventional randomized clinical trials.”

(JAMA. 2012;307[22]:2379-2380. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 12, 2012

Media Advisory: To contact Reshma Jagsi, M.D., D.Phil., call Nicole Fawcett at 734-764-2220 or email nfawcett@umich.edu.

CHICAGO – A survey of mid-career academic physician researchers finds that gender differences in salary exist, even after adjustment for differences in specialty, institutional characteristics, academic productivity, academic rank, work hours, and other factors, according to a study in the June 13 issue of JAMA.

“Studies have revealed gender differences in physicians’ pay, but experts continue to debate the magnitude and cause of these differences. Some evidence suggests that disparities in pay are explained by specialization, work hours, and productivity, leading some to believe that they are justifiable outcomes of different choices made by men and women. Debate persists in part because most studies of physicians’ pay have included relatively heterogeneous groups, are now dated, or are limited by lack of information on key factors such as specialty or family characteristics,” according to background information in the article. “It is unclear whether male and female physician researchers who perform similar work are currently paid equally.”

Reshma Jagsi, M.D., D.Phil., of the University of Michigan, Ann Arbor, and colleagues conducted a study to examine whether salaries differ by gender in a relatively homogeneous group of physician researchers and, if so, to determine if these differences are related to differences in specialization, productivity, or other factors. For the study, a U.S. nationwide postal survey was sent in 2009-2010 to recipients of National Institutes of Health (NIH) K08 and K23 career development awards in 2000-2003. The researchers focused on this select population to minimize variability in aptitude or motivation as well as in seniority and content of work activities. Eligibility for the analysis was limited to physicians who continued to practice at U.S. academic institutions and reported their current annual salary. The analysis included 247 female and 553 male physicians; average age was 45 years and 76 percent of respondents were white.

The researchers found that overall, the average salary was $167,669 for women and $200,433 for men in this sample. In the final model, male gender was associated independently and significantly with higher salary (+$13,399), even after adjustment for specialty, academic rank, leadership positions, publications, and research time. Additional analysis suggested that the expected average salary for women, if they retained their other measured characteristics but their gender was male, would be $12,194 higher than observed.

The authors also found that women tended to be in lower-paying specialties, with 34 percent of women and 22 percent of men in the lowest-paying category, and 3 percent of women and 11 percent of men in the highest-paying category. In addition, women were less likely to hold administrative leadership positions (10 percent vs. 16 percent) and had fewer publications (average, 27 vs. 33 publications) and work hours (average, 58 vs. 63 hours).

“Ultimately, this study provides evidence that gender differences in compensation continue to exist in academic medicine, even among a select cohort of physician researchers whose job content is far more similar than in cohorts previously studied, and even after controlling extensively for specialization and productivity. Efforts to investigate the mechanisms by which these gender differences develop and ways to mitigate their effects merit continued attention, as these differences have not been eliminated through the passage of time alone and are difficult to justify.”

(JAMA. 2012;307[22]:2410-2417. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 12, 2012

Media Advisory: To contact Rebecca Smith-Bindman, M.D., call Jason Bardi at 415-502-4608 or email jason.bardi@ucsf.edu. To contact editorial co-author George T. O’Connor, M.D., M.S., call Gina DiGravio at 617-638-8480 or email gina.digravio@bmc.org.

CHICAGO – Among six large integrated health care systems between 1996 and 2010 there was a substantial increase in the use of advanced diagnostic imaging, including approximately a tripling of the use of computed tomography and nearly a quadrupling of the use of magnetic resonance imaging, as well as a substantial increase in estimated radiation exposure, according to a study in the June 13 issue of JAMA.

“The use of diagnostic imaging in the Medicare population has increased significantly over the last 2 decades, particularly using expensive new technologies such as computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine positron emission tomography (PET). The development and improvement in these advanced diagnostic imaging technologies is widely credited with leading to earlier and more accurate diagnoses of disease using noninvasive techniques,” according to background information in the article. The authors note that computed tomography and nuclear medicine examinations deliver much higher doses of ionizing radiation than conventional radiographs, and evidence has linked exposure to radiation levels in this range with the development of radiation-induced cancers.

“Most studies that have evaluated patterns of diagnostic imaging have assessed insurance claims for fee-for-service insured populations where financial incentives encourage imaging. No large, multisite studies have assessed imaging trends in integrated health care delivery systems that are clinically and fiscally accountable for the outcomes and health status of the population served. Understanding imaging utilization and associated radiation exposure in these settings could help us determine how much of the increase in imaging may be independent of direct financial incentives,” the researchers write.

Rebecca Smith-Bindman, M.D., of the University of California, San Francisco, and colleagues conducted a study to estimate trends in imaging utilization and associated radiation exposure among members of integrated health care systems. The study consisted of an analysis of electronic records of members of 6 large integrated health systems from different regions of the United States. Review of medical records allowed estimation of radiation exposure from selected tests. Between 1 million and 2 million member-patients were included each year from 1996 to 2010. Enrollees underwent a total of 30.9 million imaging examinations during the study period, reflecting an average of 1.18 tests per person per year, of which 35 percent involved advanced diagnostic imaging (i.e., CT, MRI, nuclear medicine, and ultrasound).

The researchers found that use of radiography and angiography/fluoroscopy rates were relatively stable over time: radiography increased 1.2 percent per year, and angiography/fluoroscopy decreased 1.3 percent per year. “In contrast, the utilization of advanced diagnostic imaging changed markedly. Computed tomography examinations tripled (52/1000 enrollees in 1996 to 149/1000 in 2010, 7.8 percent annual growth); MRIs quadrupled (17/1000 to 65/1000,10 percent annual growth); ultrasounds approximately doubled over the same period (134/1000 to 230/1000, 3.9 percent annual growth). Nuclear medicine rates decreased (32/1000 to 21/1000, 3 percent annual decline), although after 2004, PET imaging rates increased from 0.24 per 1,000 enrollees to 3.6 per 1,000 enrollees, 57 percent annual growth.”

The authors also found that the increase in the utilization of CT was associated with an increase in estimated exposure to radiation, with the average per capita effective dose increasing from 1.2 mSv in 1996 to 2.3 mSv in 2010. The percent of enrollees who received high (> 20-30 mSv) or very high (> 50 mSv) radiation exposure during a given year also approximately doubled across study years. The researchers also estimated that by 2010, 2.5 percent of enrollees received a high annual dose of greater than 20 to 50 mSv, and 1.4 percent received a very high annual dose of greater than 50 mSv. By 2010, 6.8 percent of patients who underwent imaging received a high dose of more than 20 to 50 mSv and 3.9 percent of patients received a very high dose above 50 mSv during this single year.

The researchers write that the “increase in imaging use over this period was likely driven by many factors, including improvements in the technology that have led to expansion of clinical applications, patient- and physician-generated demand, defensive medical practices, and medical uncertainly—all factors that would be expected to influence utilization across all systems of medical care.”

“The increase in use of advanced diagnostic imaging has almost certainly contributed to both improved patient care processes and outcomes, but there are remarkably few data to quantify the benefits of imaging. Given the high costs of imaging—estimated at $100 billion annually—and the potential risks of cancer and other harms, these benefits should be quantified and evidence-based guidelines for using imaging should be developed that clearly balance benefits against financial costs and health risk.”

(JAMA. 2012;307[22]:2400-2409. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This study was supported by the National Cancer Institute-funded Cancer Research Network Across Health Care Systems and grants from the National Institutes of Health. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, June 12 at this link.

Editorial: Lung Cancer Screening, Radiation, Risks, Benefits, and Uncertainty

George T. O’Connor, M.D., M.S., of the Boston University School of Medicine, and Contributing Editor, JAMA, and Hiroto Hatabu, M.D., Ph.D., of Brigham and Women’s Hospital and Harvard Medical School, Boston, write in an accompanying editorial that while the data from this study and another recent report indicate that a nontrivial number of patients in the United States receive a high or very high annual exposure to ionizing radiation from imaging studies in a given year, “these data are not linked to clinical outcomes and do not reveal whether the radiation risks from these imaging studies are outweighed by the health benefits provided by the diagnostic information obtained.”

“The data also cannot address how much of this testing is driven by defensive practice styles due to concerns about malpractice. They do, however, suggest that clinicians need to consider—and discuss with their patients—radiation risks when ordering diagnostic tests, possibly taking into account the cumulative radiation exposure a patient has received in recent months or years. Furthermore, the radiation risks and financial costs of advanced diagnostic imaging clearly warrant more research, including studies using informatics infrastructures such as that used by Smith-Bindman et al, to enhance decision support to guide the use of these technologies.”

(JAMA. 2012;307[22]:2434-2435. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note:  All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. O’Connor reported no conflicts. Dr. Hatabu reported receiving research grant support from Toshiba Medical, Canon and AZE.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 5, 2012

Media Advisory: To contact corresponding author Antonio Nicolucci, M.D., email nicolucci@negrisud.it. To contact editorial author Jolanta M. Siller-Matula, M.D., Ph.D., email jolanta.siller-matula@meduniwien.ac.at.

CHICAGO – Among nearly 200,000 individuals, daily use of low-dose aspirin was associated with an increased risk of major gastrointestinal or cerebral bleeding, according to a study in the June 6 issue of JAMA. The authors also found that patients with diabetes had a high rate of major bleeding, irrespective of aspirin use.

“Therapy with low-dose aspirin is used for the treatment of cardiovascular disease. It is recommended as a secondary prevention measure for individuals with moderate to high risk of cardiovascular events (i.e., for patients with multiple risk factors such as hypertension, dyslipidemia, obesity, diabetes, and family history of ischemic heart disease),” according to background information in the article. “Any benefit of low-dose aspirin might be offset by the risk of major bleeding. It is known that aspirin is associated with gastrointestinal and intracranial hemorrhagic complications. However, randomized controlled trials have shown that these risks are relatively small.” The authors add that randomized controlled trials evaluate selected patient groups and do not necessarily generalize to an entire population.

In addition, low-dose aspirin use is recommended for certain patients with diabetes. Findings from a meta-analysis suggested that diabetes may increase the risk of extracranial hemorrhage. “These estimates were derived from a limited number of events within randomized trials. Hence, the risk-to-benefit ratio for the use of low-dose aspirin in the presence of diabetes mellitus remains to be clarified,” the researchers write.

Giorgia De Berardis, M.Sc., of Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy, and colleagues conducted a study to determine the incidence of major gastrointestinal and intracranial bleeding episodes in individuals with and without diabetes taking aspirin. For the study, the researchers used administrative data from 4.1 million citizens in 12 local health authorities in Puglia, Italy. Individuals with new prescriptions for low-dose aspirin (300 mg or less) were identified during the index period from January 2003 to December 2008, and were matched with individuals who did not take aspirin during this period.

For the study, the researchers included 186,425 individuals being treated with low-dose aspirin and 186,425 matched controls without aspirin use. During 6 years, 6,907 first episodes of major bleeding requiring hospitalization were registered, of which there were 4,487 episodes of gastrointestinal bleeding and 2,464 episodes of intracranial hemorrhage. Analysis indicated that the use of aspirin was associated with a 55 percent increased relative risk of gastrointestinal bleeding and 54 percent increased relative risk of intracranial bleeding. The authors note that in comparison with other estimates of rates of major bleeding, their findings indicate a 5-times higher incidence of major bleeding leading to hospitalization among both aspirin users and those without aspirin use.

Regarding the use of aspirin being associated with a 55 percent relative risk increase in major bleeding, “this translates to 2 excess cases for 1,000 patients treated per year. In other words, the excess number of major bleeding events associated with the use of aspirin is of the same magnitude of the number of major cardiovascular events avoided in the primary prevention setting for individuals with a 10-year risk of between 10 percent and 20 percent,” they write.

The researchers also found that the use of aspirin was associated with a greater risk of major bleeding in most of the subgroups evaluated, but not in individuals with diabetes. Diabetes was independently associated with a 36 percent increased relative risk of major bleeding episodes, irrespective of aspirin use. Among individuals not taking aspirin, those with diabetes had an increased relative risks of 59 percent for gastrointestinal bleeding and 64 percent for intracranial bleeding.

“Our study shows, for the first time, to our knowledge, that aspirin therapy only marginally increases the risk of bleeding in individuals with diabetes,” the authors write. “These results can represent indirect evidence that the efficacy of aspirin in suppressing platelet function is reduced in this population.”

“In conclusion, weighing the benefits of aspirin therapy against the potential harms is of particular relevance in the primary prevention setting, in which benefits seem to be lower than expected based on results in high-risk populations. In this population-based cohort, aspirin use was significantly associated with an increased risk of major bleeding, but this association was not observed for patients with diabetes. In this respect, diabetes might represent a different population in terms of both expected benefits and risks associated with antiplatelet therapy.”

(JAMA. 2012;307[21]:2286-2294. Available pre-embargo to the media at http://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: Hemorrhagic Complications Associated With Aspirin – An Underestimated Hazard in Clinical Practice?

In an accompanying editorial, Jolanta M. Siller-Matula, M.D., Ph.D., of the Medical University of Vienna, Austria, comments on the findings of this study, and writes that “a decision-making process based on balancing an individual patient’s risk of bleeding and ischemic events is difficult.”

“The study by De Berardis et al underscores that the potential risk of bleeding should be carefully considered in decision making. Assessment of bleeding risk and of net clinical benefit will merit further emphasis as issues inherent to aspirin use also apply to more potent platelet inhibitors and anticoagulants; there is only a thin line between efficacy and safety, and the reduction in ischemic events comes at the cost of increased major bleedings. Therefore, future studies investigating the risks and benefits for individual patients appear to be mandatory to help physicians appropriately make recommendations about aspirin use for primary prevention.”

(JAMA. 2012;307[21]:2318-2320. Available pre-embargo to the media at http://media.jamanetwork.com)

 Editor’s Note: The author completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Siller-Matula reported receiving speaker fees from Eli Lilly and AstraZeneca.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 5, 2012

Life Expectancy Gap Between Blacks, Whites Decreases

“Understanding the causes of black-white differences in mortality has important consequences for interventions to reduce health inequalities in the United States. A previous report found a nearly 2-year decline in the black-white life expectancy gap among men and a 1-year decline among women between 1993 and 2003,” writes Sam Harper, Ph.D., of McGill University, Montreal, Canada, and colleagues who investigated whether these changes have continued in recent years.

As reported in a Research Letter, the authors abstracted data on deaths and population from the U.S. National Vital Statistics System by age and cause of death for non-Hispanic blacks and whites in 2003 and 2008. The researchers found that between this time period, “life expectancy at birth increased from 75.3 to 76.2 years among non-Hispanic white men and from 68.8 to 70.8 years among non-Hispanic black men, whereas for women the changes were from 80.3 to 81.2 years (non-Hispanic whites) and 75.7 to 77.5 years (non-Hispanic blacks). These changes reduced the racial gap from 6.5 to 5.4 years among men and from 4.6 to 3.7 years among women.”

“These racial inequalities among men and women in 2008 are the lowest ever recorded in the United States,” they write. “The black-white life expectancy gap is still large, and declines since 2003 due to HIV and heart disease are a positive development, but rapid increases in accidental death among whites also have contributed to this change.”

(JAMA. 2012;307[21]:2257-2259. Available pre-embargo to the media at http://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

If Accountable Care Organizations Are the Answer, Who Should Create Them?

Victor R. Fuchs, Ph.D., of Stanford University, Stanford, Calif., and Leonard D. Schaeffer, of the University of Southern California, Los Angeles, examine the issue of accountable care organizations, and write that health plans may be the most able to create and manage this type of organization.

“Some health plans are already partnering with physicians and hospitals in different ways to care for patients in a more effective, efficient, and integrated manner,” they write. “Health plans are also purchasing medical groups, independent physician associations, and clinics in an effort to support accountable care.”

(JAMA. 2012;307[21]:2261-2262. Available pre-embargo to the media at http://media.jamanetwork.com)

Why Accountable Care Organizations Are Not 1990s Managed Care Redux

Ezekiel J. Emanuel, M.D., Ph.D., of the University of Pennsylvania, Philadelphia, writes that “many people are concerned that accountable care organizations (ACOs) and other delivery system reforms in the Affordable Care Act will simply bring back the managed care days of the 1990s. These skeptics suspect that payment reforms to control high and increasing costs will simply lead to gate keeping and service denial rather than the promise of care redesign and coordination that removes unnecessary cost and delivers better outcomes.”

Dr. Emanuel suggests that five significant changes make ACOs different from managed care of the 1990s: more knowledge; more data; more guidelines and quality metrics; more collaboration; and more physician control. “This does not guarantee that ACOs will succeed in controlling costs, but it does suggest that the problems of the 1990s will not be repeated.”

(JAMA. 2012;307[21]:2263-2264. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 5, 2012

Media Advisory: To contact P.J. Devereaux. M.D., Ph.D., call 289-237-3748 or 905-527-4322, ext. 40654; or email philipj@mcmaster.ca.

CHICAGO – Certain levels of the biomarker troponin T (a protein) measured in the first three days following noncardiac surgery are associated with an increased risk of death within 30 days, according to a study in the June 6 issue of JAMA.

“Worldwide more than 200 million adults have major noncardiac surgery annually. Despite benefits associated with surgery, major perioperative complications, including death, occur. More than 1 million adults worldwide will die within 30 days of noncardiac surgery each year. Perioperative risk estimation identifies patients who require more intensive monitoring and management in the postoperative period. Current preoperative risk prediction models for 30-day mortality have limitations,” according to background information in the article. Some research has suggested that monitoring troponin measurements after surgery may improve prediction of short-term mortality, although little is known about optimal troponin threshold(s) for predicting mortality after noncardiac surgery.

P.J. Devereaux. M.D., Ph.D., of McMaster University, Hamilton, Ontario, and colleagues with the VISION Study (Vascular Events in Noncardiac Surgery Patients Cohort Evaluation) assessed the relationship between the peak fourth-generation (a newer version of the laboratory test) troponin T (TnT) measurement after noncardiac surgery and 30-day mortality. The VISION study is evaluating major complications after noncardiac surgery; participating patients have TnT levels measured after surgery. For this analysis, patients were enrolled from August 2007 to January 2011. Eligible patients were aged 45 years and older and had at least an overnight hospital admission after having noncardiac surgery. Patients’ TnT levels were measured 6 to 12 hours after surgery and on days 1, 2, and 3 after surgery.

A total of 15,133 patients were included in this study. Approximately 1 in 4 patients (24.2 percent) were at least 75 years of age and 51.5 percent were women. The most common surgeries were major orthopedic surgery (20.4 percent), major general surgery (20.3 percent), and low-risk surgeries (39.4 percent). The 30-day mortality rate was 1.9 percent (282 deaths), with 26.6 percent of deaths occurring after hospital discharge (median [midpoint] time from discharge to death was 11.0 days). The researchers found that peak TnT values after noncardiac surgery proved the strongest predictors of 30-day mortality.

“Based on the identified peak TnT values, there were marked increases in the absolute risk of 30-day mortality (i.e., 1.0 percent for a TnT value 0.01 ng/mL [or less]; 4.0 percent for a value of 0.02 ng/mL; 9.3 percent for a value of 0.03-0.29 ng/mL; and 16.9 percent for a value 0.30 ng/mL [or greater]); 11.6 percent of patients had a prognostically relevant peak TnT value of at least 0.02 ng/mL. The higher the peak TnT value, the shorter the median time to death. Our net reclassification improvement analysis demonstrated that monitoring TnT values for the first 3 days after surgery substantially improved 30-day mortality risk stratification compared with assessment limited to preoperative risk factors.”

“Although no randomized controlled trial has established an effective treatment for patients with an elevated troponin measurement after noncardiac surgery, the prognosis of these patients may be modifiable,” the authors write.

“Our study demonstrates that prognostically relevant TnT measurements after surgery strongly predict who will die within 30 days of surgery. Although at present, troponin measurements are not commonly measured after noncardiac surgery, the simplicity of this test and its prognostic power suggest it may have substantial clinical utility. There is now a need for large randomized controlled trials to evaluate potential interventions to mitigate the high risk of death in patients who have an elevated troponin measurement after noncardiac surgery.”

(JAMA. 2012;307[21]:2295-2304. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 5, 2012

Media Advisory: To contact David C. Mohr, Ph.D., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu.

CHICAGO – Patients with major depression who received telephone-administered cognitive behavioral therapy (T-CBT) had lower rates of discontinuing treatment compared to patients who received face-to-face CBT, and telephone administered treatment was not inferior to face-to-face treatment in terms of improvement in symptoms by the end of treatment; however, at 6-month follow-up, patients receiving face-to-face CBT were less depressed than those receiving telephone administered CBT, according to a study in the June 6 issue of JAMA.

“Depression is common, with the 1-year prevalence rate of major depressive disorder estimated at between 6.6 percent and 10.3 percent in the general population and roughly 25 percent of all primary care visits involving patients with clinically significant levels of depression. Psychotherapy is effective at treating depression, and most primary care patients prefer psychotherapy to antidepressant medication. When referred for psychotherapy, however, only a small percentage of patients follow through. Attrition from psychotherapy in randomized controlled trials is often 30 percent or greater and can exceed 50 percent in clinical practice,” according to background information in the article. The discrepancy between patients’ preference for psychotherapy and the low rates of initiation and adherence is likely due to access barriers, such as time constraints, lack of available and accessible services, transportation problems, and cost. “The telephone has been investigated as a treatment delivery medium to overcome access barriers, but little is known about its efficacy compared with face-to-face treatment delivery.”

David C. Mohr, Ph.D., of the Northwestern University Feinberg School of Medicine, Chicago, and colleagues compared face-to-face cognitive behavioral therapy vs. a telephone-administered cognitive behavioral therapy for the treatment of depression in primary care. The trial included 325 patients with major depressive disorder, recruited from November 2007 to December 2010. Participants were randomized to 18 sessions of T-CBT or face-to-face CBT. The primary measured outcome for the study was attrition (completion vs. non-completion) at post-treatment (week 18). Secondary outcomes included measures of depression.

The researchers found that significantly fewer participants discontinued T-CBT (n = 34; 20.9 percent) before session 18 compared with face-to-face CBT (n = 53; 32.7 percent). Attrition before week 5 was significantly lower in T-CBT (n = 7; 4.3 percent) than in face-to-face CBT (n = 21; 13.0 percent), but there was no significant difference in attrition between sessions 5 and 18. T-CBT patients attended significantly more sessions than those receiving face-to-face CBT.

“The effect of telephone administration on adherence appears to occur during the initial engagement period. These effects may be due to the capacity of telephone delivery to overcome barriers and patient ambivalence toward treatment. Access barriers likely exert their effects early in treatment, and thus the effect of the telephone on overcoming those barriers is most prominent in the first sessions,” the authors write.

In terms of changes in level of depression, the researchers found that T-CBT was not inferior to face to face CBT in reducing depressive symptoms at posttreatment. However, face-to-face CBT was significantly superior to T-CBT during the 6-month follow-up period. By 6-month follow-up, 19 percent of T-CBT vs. 32 percent of face-to-face CBT participants were fully remitted.

“The findings of this study suggest that telephone-delivered care has both advantages and disadvantages. The acceptability of delivering care over the telephone is growing, increasing the potential for individuals to continue with treatment,” the authors write. “The telephone offers the opportunity to extend care to populations that are difficult to reach, such as rural populations, patients with chronic illnesses and disabilities, and individuals who otherwise have barriers to treatment. … “However, the increased risk of posttreatment deterioration in telephone-delivered treatment relative to face-to-face treatment underscores the importance of continued monitoring of depressive symptoms even after successful treatment.”

(JAMA. 2012;307[21]:2278-2285. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This study was funded by a research grant from the National Institute of Mental Health to Dr. Mohr. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, June 5 at this link.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) MONDAY, MAY 21, 2012

International Panel Updates Definition of Acute Respiratory Distress Syndrome

Gordon D. Rubenfeld, M.D., of the Sunnybrook Health Sciences Center, Toronto, Canada, and colleagues with the ARDS (acute respiratory distress syndrome) Definition Task Force, developed a new definition of ARDS (the Berlin Definition) that focused on feasibility, reliability, validity and objective evaluation of its performance.

ARDS is a life-threatening lung condition that prevents enough oxygen from getting to the lungs and into the blood. Among the changes the panel proposed was a draft definition with 3 mutually exclusive categories of mild, moderate, and severe ARDS based on degree of hypoxemia (insufficient oxygenation of the blood) and four ancillary variables for severe ARDS. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27 percent; 32 percent; and 45 percent, respectively), and increased median duration of mechanical ventilation in survivors. The authors write that compared with the previous definition for ARDS, the final Berlin Definition had better predictive validity for mortality. “This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the [previous] definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions, and to better inform clinical care, research, and health services planning.”

(doi:10.1001/JAMA. 2012.5669. Available pre-embargo to the media at http://media.jamanetwork.com)

To contact Gordon D. Rubenfeld, M.D., call Laura Bristow at 416-480-4040 or email laura.bristow@sunnybrook.ca.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) MONDAY, MAY 21, 2012

Combination Antibiotic Treatment Does Not Result in Less Organ Failure Among Adults With Severe Sepsis

Frank M. Brunkhorst, M.D., of Friedrich-Schiller University, Jena, Germany, and colleagues conducted a study to compare the effect of the antibiotics moxifloxacin and meropenem with the effect of meropenem monotherapy on sepsis-related organ dysfunction. Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The authors hypothesized that maximizing the potential benefit and appropriateness of initial antibiotics by using 2 antibiotics would improve clinical outcomes compared with monotherapy.

The trial included 298 patients who fulfilled usual criteria for severe sepsis or septic shock who were randomized to receive monotherapy, and 302 to receive combination therapy. The trial was performed in 44 intensive care units in Germany from October 2007 to March 2010, and the number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. The intervention was recommended for 7 days and up to maximum of 14 days after randomization or until discharge from the intensive care units or death, whichever occurred first.

Among 551 evaluable patients, there was no statistically significant difference in average Sequential Organ Failure Assessment (SOFA; degree of organ failure) score between the meropenem and moxifloxacin group and the meropenem alone group. “The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9 percent) in the combination therapy group compared with 59 deaths (21.9 percent) in the monotherapy group. By day 90, there were 96 deaths (35.3 percent) in the combination therapy group compared with 84 deaths (32.1  percent) in the monotherapy group,” the authors write.

“In conclusion, in this randomized multicenter trial of adult patients with severe sepsis or septic shock, empirical treatment with the combination of meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure.”

(doi:10.1001/JAMA. 2012.5833. Available pre-embargo to the media at http://media.jamanetwork.com)

To contact corresponding author Tobias Welte, M.D., email welte.tobias@mh-hannover.de.

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

EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) SUNDAY, MAY 20, 2012

Study Evaluates Use of Inhaled Saline for Young Children With Cystic Fibrosis

Margaret Rosenfeld, M.D., M.P.H., of Seattle Children’s Hospital, and colleagues conducted a study to examine if hypertonic saline would reduce the rate of pulmonary exacerbations in children younger than 6 years of age with cystic fibrosis (CF). Inhaled hypertonic saline is recommended as therapy for patients 6 years or older with CF, but its efficacy has not been evaluated in patients younger than 6 years.

In the randomized trial, the active treatment group (n = 158) received 7 percent hypertonic saline and the control group (n = 163) received 0.9 percent isotonic saline, nebulized (dispensed in a fine mist) twice daily for 48 weeks. The researchers found that the average pulmonary exacerbation rate was similar between both groups. “Hypertonic saline did not reduce the rate of pulmonary exacerbations in these young children. In addition, hypertonic saline did not demonstrate any significant effects on secondary end points including weight, height, respiratory rate, oxygen saturation, antibiotic use, or parent report of respiratory signs and symptoms.”

(doi:10.1001/JAMA. 2012.5214. Available pre-embargo to the media at http://media.jamanetwork.com)

To contact Margaret Rosenfeld, M.D., M.P.H., call Mary Guiden at 206-987-7334 or email mary.guiden@seattlechildrens.org.

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 EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) SUNDAY, MAY 20, 2012

Low-Dose CT Screening May Benefit Individuals at Increased Risk for Lung Cancer, But Uncertainty Exists About Potential Harms of Screening

Peter B. Bach, M.D., of the Memorial Sloan-Kettering Cancer Center, New York, and colleagues conducted a systematic review to examine the evidence regarding the benefits and harms of low-dose computerized tomography (LDCT) screening for lung cancer, which is the leading cause of cancer death. “Most patients are diagnosed with advanced disease, resulting in a very low 5-year survival rate,” the authors write. “Renewed enthusiasm for lung screening arose with the advent of LDCT imaging, which is able to identify smaller nodules than can chest radiographs.”

For the review, the researchers identified 8 randomized controlled trials and 13 cohort studies of LDCT screening that met criteria for inclusion. Three randomized studies provided evidence on the effect of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53,454 participants enrolled, screening resulted in significantly fewer lung cancer deaths (20 percent lower relative risk). The other 2 smaller studies showed no such benefit. “In terms of potential harms of LDCT screening, across all trials and cohorts, approximately 20 percent of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1 percent had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and percentage of surgical procedures performed in patients with benign lesions.” The authors write that “Low-dose computed tomography screening may benefit individuals at an increased risk for lung cancer, but uncertainty exists about the potential harms of screening and the generalizability of results.”

This report, a multisociety collaborative initiative, forms the basis of the American College of Chest Physicians and the American Society of Clinical Oncology clinical practice guideline, which, in summary is:

Recommendation 1: For smokers and former smokers ages 55 to 74 years who have smoked for 30 pack-years (number of packs of cigarettes smoked per day by the number of years the person has smoked) or more and either continue to smoke or have quit within the past 15 years, it is suggested that annual screening with LDCT should be offered over both annual screening with chest radiograph or no screening, but only in settings that can deliver the comprehensive care provided to National Lung Screening Trial participants. (Grade of evidence 2B, indicating a “weak recommendation based on moderate quality research data”)

Recommendation 2: For individuals who have accumulated fewer than 30 pack-years of smoking or are either younger than 55 years or older than 74 years, or individuals who quit smoking more than 15 years ago, and for individuals with severe comorbidities that would preclude potentially curative treatment, limit life expectancy, or both, it is suggested that CT screening should not be performed. (Grade of evidence 2C, indicating a “weak recommendation based on low quality research data”)

(doi:10.1001/JAMA. 2012.5521. Available pre-embargo to the media at http://media.jamanetwork.com)

To contact Peter B. Bach, M.D., call Jeanne D’Agostino at 212-639-3573 or email dagostij@mskcc.org.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) SUNDAY, MAY 20, 2012

Study Finds No Significant Difference Between Treatments For Relieving Breathing Difficulties Among Patients With Lung Effusions  

Helen E. Davies, M.D., of the University Hospital of Wales, Cardiff, and colleagues compared the effectiveness of treatments to relieve breathing difficulties among patients with malignant pleural effusion (presence of fluid in the pleural cavity [space between the outside of the lungs and the inside wall of the chest cavity], as a complication of malignant disease). The treatments compared were chest tube drainage and talc slurry for pleurodesis (a procedure in which the pleural space is obliterated) vs. indwelling pleural catheters (IPCs).

Malignant pleural effusion causes disabling dyspnea (breathing difficulties) in more than 1 million people worldwide annually; patients have an average life expectancy of 4 months. “There are no robust clinical data to address which of these treatments is more effective at palliating symptoms and improving quality of life,” the authors write. “Indwelling pleural catheters are increasingly used as an alternative treatment to talc pleurodesis.”

The randomized controlled trial compared IPC (n = 52) and talc slurry for pleurodesis (n = 54) for patients with malignant pleural effusion who were treated at 7 U.K. hospitals. Patients were screened from April 2007-February 2011 and were followed up for a year. The researchers found that there was no significant difference between groups in dyspnea in the first 42 days after intervention. Indwelling pleural catheters reduced time in the hospital but were associated with an excess of adverse events. “As such, IPCs cannot be advocated as a superior treatment to talc pleurodesis for palliation of symptoms,” the authors write.

(doi:10.1001/JAMA. 2012.5535. Available pre-embargo to the media at http://media.jamanetwork.com)

To contact corresponding author Najib M. Rahman, D.Phil., email najib.rahman@ndm.ox.ac.uk.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 22, 2012

Surface of Drug-Eluting Stents May Become Damaged During Balloon Expansion

Drug-eluting stents (DES) have advanced percutaneous treatment (such as balloon angioplasty) of coronary artery disease by reducing restenosis (re-narrowing of a coronary artery after angioplasty). However, DES are associated with complications, including thrombosis (formation of blood clots), restenosis, and microvascular dysfunction. Scott J. Denardo, M.D., of the Duke University Medical Center, Durham, N.C., and colleagues hypothesized that the polymer surface of DES may be damaged during delivery balloon expansion and that microparticles may detach, which could contribute to these limitations.

As reported in a Research Letter, the authors used optical microscopy to systematically image the polymer surface of the 4 U.S. Food and Drug Administration-approved DES following expansion using the accompanying delivery balloon. Following balloon expansion, the abluminal and adluminal polymer surfaces of all DES were damaged, affecting 4.6 percent to 100 percent of the surface area imaged. Surface damage ranged from deformation (ridging, cracking, peeling, or webbing) to complete delamination with visually confirmed separation of polymer. “Polymer damage and detached microparticles could theoretically contribute to DES-associated complications, including thrombosis, restenosis, and microvascular and endothelial dysfunction. Confirmation of our results would be useful, and further studies should determine physiological and clinical consequences of polymer damage and microparticle detachment.”
(JAMA. 2012;307[20]:2148-2150. Available pre-embargo to the media at http://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Retail Clinics and Drugstore Medicine

Christine K. Cassel, M.D., of the American Board of Internal Medicine, Philadelphia, writes that easy access to medical clinics in retail settings is gaining momentum in the United States. “Although questions remain about their future, evidence suggests that retail clinics may have an important role in U.S. health care.”

Dr. Cassel discusses the issue of retail clinics, including what they are currently doing and what the future may hold for them.
(JAMA. 2012;307[20]:2151-2152. Available pre-embargo to the media at http://media.jamanetwork.com)

Assessing Value in Health Care Programs

Kevin G. Volpp, M.D., Ph.D., of the University of Pennsylvania, Philadelphia, and colleagues write that many health care services provided in the United States are of low value, meaning that the cost of providing those services is high relative to the health care benefit they confer. “Given estimates that 30 percent of the $2.5 trillion the United States spends on health care services each year may provide little benefit, there is a widespread eagerness to enhance the ratio of benefits to costs.”

The authors examine the question of return on investment for health care costs and other issues related to this topic.
(JAMA. 2012;307[20]:2153-2154. Available pre-embargo to the media at http://media.jamanetwork.com)

Deciphering Harm Measurement

Gareth Parry, Ph.D., of the Institute for Healthcare Improvement, Cambridge, Mass., and colleagues write that there is an urgent need to reach consensus on robust, pragmatic measures for assessing and tracking the rate that patients are harmed in hospitals.

“… hospitals will need to address multiple types of harm before substantial improvement in all-cause harm rates will be observed. Delay in measuring the effect of best practices on harm rates will postpone the day when the nation can celebrate significant improvement in patient safety.”
(JAMA. 2012;307[20]:2155-2156. Available pre-embargo to the media at http://media.jamanetwork.com)

The Journey Across the Health Care (Dis)Continuum for Vulnerable Patients – Policies, Pitfalls, and Possibilities

Grace Jenq, M.D., and Mary E. Tinetti, M.D., of the Yale University School of Medicine, New Haven, Conn., write that there are gaps that need to be filled to ensure better care and outcomes facing vulnerable patients (such as those with multiple chronic conditions, serious injuries or illnesses) as they move through the health care system.

“Current policies and initiatives may benefit or disadvantage millions of vulnerable patients. It remains to be seen whether the most promising ones, assuming they survive the Supreme Court, prove to be a confusing array of piecemeal fixes that create other fissures and unintended consequences or are integrated into a seamless care continuum in which vulnerable patients receive appropriate care in the appropriate setting.”
(JAMA. 2012;307[20]:2157-2158. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 22, 2012
Media Advisory: To contact Sascha Kopke, Ph.D., email sascha.koepke@uksh.de.

CHICAGO – Nursing homes that used a multicomponent intervention that included staff training and supportive materials for staff, residents and relatives had a lower rate of use of physical restraints such as bilateral bed rails and belts, according to a study in the May 23/30 issue of JAMA.

Despite unambiguous legal regulation and evidence for lack of effectiveness and safety, physical restraints are still frequently administered in nursing homes, with a recent survey reporting physical restraint rates of more than 20 percent for U.S. nursing homes, according to background information in the article. “Nursing home care does not necessitate the administration of physical restraints, as demonstrated by our own epidemiological research. We found pronounced center variation, with best-practice centers applying very few physical restraints. Reasons for differences between centers are unclear, but the ‘culture of care,’ as reflected in the attitudes and beliefs of nursing staff, may determine observed variation. Accordingly, a ‘culture change’ has been demanded for nursing homes because avoidance of physical restraints is mandatory from a professional point of view,” the authors write.

Sascha Kopke, Ph.D., of the University of Hamburg, Germany, and colleagues tested the effectiveness of a guideline- and theory-based multicomponent intervention to reduce the prevalence of physical restraints used in nursing homes. The randomized controlled trial of 6 months’ duration was conducted in 2 German cities between February 2009 and April 2010. Nursing homes were eligible if they had 20 percent or more residents with physical restraints. Eighteen nursing home clusters were included in the intervention group (2,283 residents) and 18 in the control group (2,166 residents). All nursing homes completed the study and all residents were included in the analysis.

The intervention was based on a specifically developed evidence-based guideline and applied the theory of planned behavior. Components were group sessions for all nursing staff; additional training for nominated key nurses; and supportive material for nurses, residents, relatives, and legal guardians. Control group clusters received standard information. The primary measured outcome was the percentage of residents with physical restraints (bilateral bed rails, belts, fixed tables, and other measures limiting free body movement) at 6 months, as assessed through direct unannounced observation by investigators on 3 occasions during 1 day.

At the beginning of the study, the prevalence of physical restraint use was comparable between groups: 31.5 percent in the intervention group vs. 30.6 percent in the control group. After 6 months, physical restraint prevalence was significantly lower in the intervention group, 22.6 percent, vs. 29.1 percent in the control group. All physical restraints were used less frequently in the intervention group compared with the control group. At 3 months, results were similar: intervention group: 23.9 percent, vs. 30.5 percent in the control group.

The researchers also found that results for falls, fall-related fractures, and prescriptions of psychotropic medication showed no statistically significant differences between groups.

“… considering the consistent effects after 3 and 6 months, we are confident that a ‘culture change’ has been achieved, resulting in a continuing avoidance of physical restraints. As it seems infeasible to further optimize the intervention with justifiable effort, more pronounced reduction or even complete prevention of physical restraint use may require more stringent implementation of legal regulations with clear penalties. The results of this study are likely generalizable to countries with comparable legal and professional conditions.”

The authors note that the guideline in their study was merely the basis for the intervention, not its central component. “As opposed to other guideline-based interventions, the central recommendation is not to perform a certain action, i.e., not to apply physical restraints. Therefore, the main message of the guideline and the related intervention is that it is possible to refrain from using restraints.”
(JAMA. 2012;307[20]:2177-2184. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The study was funded by a grant from the German Federal Ministry of Education and Research within the Nursing Research Network Northern Germany. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 22, 2012
Media Advisory: To contact Ferran Barbé, M.D., email fbarbe@arnau.scs.es. To contact José M. Marin, M.D., email jmmarint@unizar.es. To contact editorial co-author Edward M. Weaver, M.D., M.P.H., call Clare LaFond at 206-685-1323 or email clareh@uw.edu.

CHICAGO – Two studies that included adults with obstructive sleep apnea examined the effectiveness of reducing the risk of cardiovascular outcomes, including high blood pressure, by treatment with continuous positive airway pressure (CPAP), according to the articles in the May 23/30 issue of JAMA.

Obstructive sleep apnea (OSA) affects 3 percent to 7 percent of the general population and is caused by the collapse of the upper airway during sleep, which leads to transient asphyxia, according to background information in the first study. Studies have shown an association between OSA and hypertension and cardiovascular diseases. First-line treatment for patients with symptomatic OSA is CPAP, which acts as a pneumatic splint to keep the upper airway open during sleep and corrects the obstruction.

Ferran Barbé, M.D., of the Institut de Recerca Biomedica, Lleida, Spain, and colleagues conducted a study to evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in 723 patients with OSA without daytime sleepiness. The randomized controlled trial was conducted in 14 teaching hospitals in Spain between May 2004 and May 2006, with follow-up through May 2009. Patients were allocated to receive CPAP treatment or no active intervention. All participants received dietary counseling and sleep hygiene advice. The primary outcomes measured for the study were the incidence of either systemic hypertension (taking antihypertensive medication or blood pressure greater than 140/90 mm Hg) or cardiovascular event.

The patients in the study underwent followup for a median (midpoint) of 4 years; 357 in the CPAP group and 366 in the control group were included in the analysis. A total of 147 patients with new hypertension and 59 cardiovascular events were identified. In the CPAP group, there were 68 patients with new hypertension and 28 cardiovascular events (17 hospitalizations for unstable angina or arrhythmia, 3 nonfatal stroke, 3 heart failure, 2 nonfatal heart attack, 2 transient ischemic attack, 1 cardiovascular death). In the control group, there were 79 patients with new hypertension and 31 cardiovascular events (11 hospitalizations for unstable angina or arrhythmia, 8 nonfatal heart attack, 5 transient ischemic attack, 5 heart failure, 2 nonfatal stroke). Analysis of the data indicated that treatment with CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events.

However, the authors note that their study may have limited power to detect a significant difference, and that a larger study or longer follow-up might have been able to identify a significant association between treatment and outcome. “A post hoc analysis suggested that CPAP treatment may reduce the incidence of hypertension or cardiovascular events in patients with CPAP adherence of 4 hours/night or longer.”
(JAMA. 2012;307[20]:2161-2168. Available pre-embargo to the media at http://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: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, May 22 at this link.

Treatment of Obstructed Sleep Apnea With CPAP Therapy Associated With A Lower Risk Of Hypertension

In the second study, José M. Marin, M.D., of the Hospital Universitario Miguel Servet, Zaragoza, Spain, and colleagues examined whether CPAP therapy is associated with a lower rate of new-onset hypertension in patients with OSA. “Although treatment of OSA with CPAP therapy is associated with decreased overall cardiovascular risk, its efficacy in preventing new-onset hypertension is unknown,” the authors write. “Short-term studies indicate that CPAP therapy reduces blood pressure in patients with hypertension and OSA.”

The study included 1,889 participants without hypertension who were referred to a sleep center for nocturnal polysomnography between January 1994 and December 2000. Incident hypertension was documented at annual follow-up visits up to January 2011. Multivariable models adjusted for confounding (factors that can influence outcomes) factors, including changes in body mass index during the study, were used to calculate hazard ratios of new hypertension in participants without OSA (controls), with untreated OSA, and in those treated with CPAP therapy according to national guidelines.

The average follow-up of the study was 11.3 years (median 12.2 years). During follow-up, 705 patients (37.3 percent) developed incident hypertension. After including change in body mass index as a covariate in the fully adjusted model, the hazard ratios (risk) for incident hypertension remained 33 percent greater among patients with OSA who were ineligible for CPAP therapy; the risk was nearly twice as great among patients with OSA who declined CPAP therapy; and about 80 percent greater among patients with OSA who were nonadherent to CPAP therapy, compared with controls without OSA. In patients with OSA who were treated with CPAP therapy, the risk of new-onset hypertension was 29 percent lower than in controls.

“Although CPAP therapy was not allocated randomly to our patients, the associated lower excess risk of hypertension strongly suggests that OSA may be an independent modifiable risk factor for development of new-onset hypertension. The observed correlation between severity of OSA and the magnitude of risk for hypertension further supports OSA as a major contributor to cardiovascular risk. In conclusion, compared with participants without OSA, untreated OSA was associated with an increased risk of new-onset hypertension, whereas treatment with CPAP therapy was associated with a lower risk of new-onset hypertension,” the authors write.

“Our observational findings suggest that OSA appears to be a modifiable risk factor for new-onset hypertension. Such findings are clinically relevant considering that OSA, despite a high prevalence in Western populations, remains overwhelmingly unrecognized and untreated.”
(JAMA. 2012;307[20]:2161-2168. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This work was supported by grants from the Instituto Carlos III, Ministry of Health, Madrid, from the Spanish Society of Respiratory Medicine. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Filling in the Pieces of the Sleep Apnea-Hypertension Puzzle

In an accompanying editorial, Vishesh K. Kapur, M.D., M.P.H., and Edward M. Weaver, M.D., M.P.H., of the University of Washington, Seattle, write that “although these studies significantly advance the understanding of the positive relationship between OSA and incident hypertension and the benefit of CPAP therapy, many questions remain regarding OSA, hypertension, and treatment.

“What are the susceptible and responsive subgroups (e.g. OSA severity subgroups, sleepy vs. nonsleepy, and demographic subgroups)? How much CPAP use is necessary for an important treatment effect? What are the effects of other OSA treatments? These questions will require randomized controlled trials when feasible, subgroup analyses within these trials, and well-controlled observational studies. Novel approaches are needed, such as treatment withdrawal protocols.”
(JAMA. 2012;307[20]:2197-2198. Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This work was supported by resources from the Veterans Affairs Puget Sound Health Care System, Seattle, and by a grant from the National Institutes of Health. Dr. Kapur reported having owned stock within the last 3 years in Merck, Johnson & Johnson, and Bristol-Myers Squibb. Dr. Weaver reported no disclosures.
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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 15, 2012
Media Advisory: To contact corresponding author Junfeng (Jim) Zhang, Ph.D., call Alison Trinidad at 323-442-3941 or email alison.trinidad@usc.edu; to contact corresponding author Tong Zhu, Ph.D., email tzhu@pku.edu.cn. To contact editorial co-author Francesca Dominici, Ph.D., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu.

CHICAGO – During the 2008 Beijing Olympics, changes in air pollution were associated with changes in biomarkers of systemic inflammation and thrombosis (formation of blood clot) as well as measures of cardiovascular physiology in healthy young persons, according to a study in the May 16 issue of JAMA, a theme issue on Global Health.

“Air pollution is a risk factor for cardiovascular diseases (CVD), but the mechanisms by which air pollution leads to CVD is not well understood. Hypothesized mechanisms with associated biomarkers include systemic inflammation and thrombosis or endothelial [thin layer of cells that line the heart and certain vessels and cavities within the body] dysfunction,” according to background information in the article. “As a condition for hosting the 2008 Olympic Games, the Chinese government agreed to temporarily and substantially improve air quality in Beijing for the Olympics and subsequent Paralympics. This provided a unique opportunity to use a quasi-experimental design in which exposures and biomarkers were measured at baseline (pre-Olympics), following a change in pollution (during-Olympics), and then repeated after an expected return to baseline (post-Olympics).”

David Q. Rich, Sc.D., of the University of Rochester, New York, and colleagues conducted a study to determine whether markers related to CVD pathophysiological pathways (biomarkers for systemic inflammation and thrombosis, heart rate, and blood pressure) are sensitive to changes in air pollution. The researchers measured environmental air pollutants daily and also measured various biomarkers and other measures (heart rate, blood pressure) in 125 healthy young adults before, during, and after the 2008 Olympics (June 2-October 30). The biomarkers measured included those associated with systemic inflammation (fibrinogen, C-reactive protein [CRP], white blood cell [WBC] count) and thrombosis or endothelial dysfunction (platelet activation markers P-selectin [sCD62P] and soluble CD40 ligand [sCD40L] as well as the adhesive endothelial glycoprotein von Willebrand factor).

Concentrations of particulate and gaseous pollutants decreased substantially (-13 percent to -60 percent) from the pre-Olympic period to the during-Olympic period. There were reductions in the average concentration of sulfur dioxide (-60 percent), carbon monoxide (-48 percent), nitrogen dioxide (-43 percent), elemental carbon (-36 percent), PM2.5 (-27 percent), organic carbon (-22 percent), and sulfate (-13 percent) from the pre-Olympic to the during-Olympic period. “In contrast, ozone concentrations increased (24 percent). Pollutant concentrations generally increased substantially from the during- to post-Olympic period for all the pollutants (21 percent to 197 percent) except ozone (-61 percent) and sulfate (-47 percent),” the authors write.

The researchers observed statistically significant improvements in SCD62P levels (by -34.0 percent), and von Willebrand factor (by -13.1 percent). Changes in the other outcomes were not statistically significant after adjustments for multiple comparisons. In the post-Olympic period when pollutant concentrations increased, most outcomes approximated pre-Olympic levels, but only sCD62P and systolic blood pressure were significantly worsened from the during-Olympic period. “The fraction of above-detection-limit values for CRP was reduced from 55 percent in the pre-Olympic period to 46 percent in the during-Olympic period and reduced further to 36 percent in the post-Olympic period. Interquartile range increases in pollutant concentrations were consistently associated with statistically significant increases in fibrinogen, von Willebrand factor, heart rate, sCD62P, and SCD40L concentrations.”

“Although these findings are of uncertain clinical significance, this study provides quasi-experimental, mechanistic data to support the argument that air pollution may be a global risk factor for CVD.”
(JAMA. 2012;307[19]:2068-2078. Available pre-embargo to the media at www.jamamedia.org)

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

Editorial: China’s Air Quality Dilemma – Reconciling Economic Growth With Environmental Protection

Francesca Dominici, Ph.D., and Murray A. Mittleman, M.D., Dr.P.H., of the Harvard School of Public Health, Boston, write in an accompanying editorial that “China’s dilemma, like many countries with emerging industries, is how to reconcile rapid economic growth with environmental protection.”

“In recent decades, China has achieved industrialization and urbanization. However, China has been much less successful in maintaining the quality of urban air. Several factors challenge the implementation of air pollution controls in China: heavy reliance on coal as a main heating system, especially in subsidized housing; lack of political incentives for trading slower growth for less pollution; economic factors: most Chinese factories and power plants run on extremely thin margins and fines for polluting are generally lower than the cost of controlling emissions; and economic transformation of the landscape, from ubiquitous construction sites to the rapid expansion of the nation’s vehicle fleet. If air pollution in China and other Asian nations cannot be controlled, it could spread to other continents. A recent study by Lin et al provides compelling evidence that Asian emissions may account for as much as 20 percent of ground-level pollution in the United States. Clean air is a shared global resource. It is in the common interest to maintain air quality for the promotion of global health.”
(JAMA. 2012;307[19]:2100-2102. Available pre-embargo to the media at www.jamamedia.org)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 15, 2012

Media Advisory: To contact Eran Bendavid, M.D., M.S., call Ruthann Richter at 650-725-8047 or email richter1@stanford.edu. To contact editorial author Ezekiel J. Emanuel, M.D., Ph.D., call Holly Auer at 215-349-5659 or email holly.auer@uphs.upenn.edu.

CHICAGO – Between 2004 and 2008, all-cause adult mortality declined more in African countries in which the AIDS relief program PEPFAR operated more intensively, according to a study in the May 16 issue of JAMA, a theme issue on Global Health.

“The effect of global health initiatives on population health is uncertain. Between 2003 and 2008, the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), the largest initiative ever devoted to a single disease, operated intensively in 12 African focus countries,” according to background information in the article. PEPFAR has targeted the rapidly expanding human immunodeficiency virus (HIV) epidemic with a coordinated effort to increase HIV treatment, prevention, and care. PEPFAR scaled up the delivery of expanded antiretroviral therapy (ART) and supported large-scale prevention efforts. The initiative’s effect on all-cause adult mortality has not been known.

Eran Bendavid, M.D., M.S., of Stanford University, Stanford, Calif., and colleagues examined the relationship between PEPFAR’s implementation and trends in adult mortality. Using person-level data from the Demographic and Health Surveys (DHS), the researchers conducted cross-country and within-country analyses of adult mortality (annual probability of death per 1,000 adults between 15 and 59 years old) and PEPFAR activities. Across countries, adult mortality was compared in 9 African focus countries (Ethiopia, Kenya, Mozambique, Namibia, Nigeria, Rwanda, Tanzania, Uganda, and Zambia) with adult mortality in 18 African nonfocus countries from 1998 to 2008.

The study included data on 1,538,612 African adults collected from 41 surveys conducted in 27 countries between 1998 and 2008. During this time period, 60,303 deaths were captured in the DHS used in this study. Analysis of the data indicated relatively greater mortality declines among adults living in focus countries between 2004 and 2008, with mortality in the focus countries declining from 8.30 per 1,000 adults in 2003 to 4.10 per 1,000 in 2008. The mortality trends in nonfocus countries did not show a similar decline during the study period (from 8.5 in 2003 to 6.9 in 2008). After adjustments for country-level and personal characteristics, the odds of all-cause death was lower in the focus countries.

The authors also examined district-level data for Tanzania and Rwanda.  High and low PEPFAR activity districts had similar populations, but program intensity was significantly different between the groups. Adults in Tanzania living in the regions with above-median (midpoint) PEPFAR intensity had a lower odds of mortality compared with adults living in regions with below-median intensity; in Rwanda, the similar comparison also revealed a lower odds of mortality for adults living in the regions with above-median PEPFAR intensity.

The researchers also found that, using the results for each focus country and generalizing to the size of each country’s adult population, an estimated total of 740,914 all-cause adult deaths were averted between 2004 and 2008 in association with PEPFAR. In comparison, PEPFAR was associated with an estimated 631,338 HIV-specific deaths averted during the same period.

“In conclusion, we provide new evidence suggesting that reductions in all- cause adult mortality were greater in PEPFAR’s focus countries relative to the nonfocus countries over the time period from 2004 through 2008. Our analysis suggests an association of PEPFAR with these improvements in population health,” the authors write.

(JAMA. 2012;307[19]:2060-2067. Available pre-embargo to the media at www.jamamedia.org)

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: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, May 15 at this link.

Editorial: PEPFAR and Maximizing the Effects of Global Health Assistance

In an accompanying editorial, Ezekiel J. Emanuel, M.D., Ph.D., of the University of Pennsylvania, Philadelphia, writes that the “article by Bendavid et al is welcome news in helping to document the even greater benefits of PEPFAR not only on HIV/AIDS but on overall mortality in countries.”

“However, the further question that must be asked by ethically responsible people and policy makers becomes: Is PEPFAR worth it? Many other global health programs are improving the health of poor people worldwide but are not funded anywhere near the level of PEPFAR. The fundamental ethical, economic, and policy question is not whether PEPFAR is doing good, but rather whether other programs would do even more good in terms of saving life and improving health. Clearly, besides treatment for HIV/AIDS, there are other highly effective and lower-cost interventions for the world’s poor.”

(JAMA. 2012;307[19]:2097-2099. Available pre-embargo to the media at www.jamamedia.org)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Emanuel reported receiving payment for speaking engagements unrelated to this work.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 15, 2012

Media Advisory: To contact Lars Ake Persson, M.D., Ph.D., email lars-ake.persson@kbh.uu.se. To contact editorial co-author Robert E. Black, M.D., M.P.H., call Tim Parsons at 410-955-7619 or email tmparson@jhsph.edu.

 CHICAGO – Pregnant women in poor communities in Bangladesh who received multiple micronutrients, including iron and folic acid combined with early food supplementation, had substantially improved survival of their newborns, compared to women in a standard program that included usual food supplementation, according to a study in the May 16 issue of JAMA, a theme issue on Global Health.

“Maternal and child undernutrition is estimated to be the underlying cause of 3.5 million annual deaths and 35 percent of the total disease burden in children younger than 5 years. The potential long-term consequences of nutritional imbalance or insult in fetal or early life also include cognitive impairment and chronic diseases in adulthood. Effective child nutrition interventions are available to reduce stunting, prevent consequences of micronutrient deficiencies, and improve survival. The knowledge base is weaker regarding prenatal nutrition interventions of benefit for mother and offspring,” according to background information in the article. “The proportion of malnourished mothers and children remains high in many areas of the world, especially in South Asia, where more than one-quarter of newborns have a low weight.”

Lars Ake Persson, M.D., Ph.D., of Uppsala University, Uppsala, Sweden, and colleagues conducted a study (the MINIMat trial) to examine whether a prenatal multiple micronutrient supplementation (MMS), as well as an early invitation to a daily food supplementation, would increase maternal hemoglobin level at 30 weeks’ gestation, birth weight, and infant survival, and that a combination of these interventions (early invitation with MMS) would further improve these outcomes. The randomized trial, conducted in Matlab, Bangladesh, included 4,436 pregnant women who were recruited between November 2001 and October 2003, with follow-up until June 2009. One-third of the women were illiterate and one-fifth experienced occasional or constant deficit in their perceived income-expenditure status.

Participants were randomized into 6 groups; a double-masked supplementation with capsules of 30 mg of iron and 400 μg of folic acid, 60 mg of iron and 400 μg of folic acid, or MMS containing a daily allowance of 15 micronutrients, including 30 mg of iron and 400 μg of folic acid, was combined with food supplementation randomized to either early invitation (9 weeks’ gestation) or usual invitation (20 weeks’ gestation).

There were 3,625 live births out of 4,436 pregnancies. The average birth weight among 3,267 single-birth infants was 2,694 grams (5.9 lbs.). Overall, 31 percent of newborns weighed less than 2,500 g (5.5 lbs.). There was no significant difference in birth weight among treatment groups, and no main-effect differences between food groups or among micronutrient groups. The researchers found that infants in the early invitation with MMS group had a lower risk of death, with a mortality rate of 16.8 per 1,000 live births vs. 44.1 per 1,000 live births for usual invitation with 60 mg of iron and 400 μg of folic acid. The early invitation with MMS group had an under 5-year mortality rate of 18 per 1,000 live births (54 per 1,000 live births for usual invitation with 60 mg of iron and 400 μg of folic acid). Usual care invitation with MMS had the highest infant mortality rate (47.1 per 1,000 live births).

Adjusted maternal hemoglobin level at 30 weeks’ gestation was 115.0 g/L, with no significant differences among micronutrient groups. Women in the early invitation group had a small (0.9 g/L) but statistically significant lower hemoglobin level concentration than those in the usual invitation group.

“Scientists and policymakers have recommended replacing the current iron-folic acid supplements with MMS in the package of health and nutrition interventions delivered to pregnant women to improve size at birth and child growth and development. Other studies have questioned this view based on the limited size of the effect on birth weight and the absence of positive effect on fetal and neonatal survival. The MINIMat trial provides evidence that mortality of the offspring was reduced if multiple micronutrients were combined with a balanced protein-energy supplementation that began early in pregnancy,” the researchers conclude.

(JAMA. 2012;307[19]:2050-2059. Available pre-embargo to the media at www.jamamedia.org)

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

Editorial: Food, Micronutrients, and Birth Outcomes

In an accompanying editorial, Parul Christian, Dr.P.H., M.Sc., and Robert E. Black, M.D., M.P.H., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, write that results from one country, such as in this study, “may not be applicable in other settings for a number of reasons, including variable maternal prepregnancy status, levels of macronutrient and micronutrient deficiencies, and antenatal [before birth] and delivery care availability.”

“Several nutrition programs in Asia and Africa have long targeted pregnant and lactating women in large-scale food supplementation programs, such as the one ongoing in Bangladesh when this trial was conducted. Coverage rates in these programs are known to be generally low and women are normally identified late in pregnancy. Further research on the timing of nutritional interventions including prior to and early and late in pregnancy is needed to examine their efficacy and safety both for survival and other long-term developmental consequences.”

(JAMA. 2012;307[19]:2094-2096. Available pre-embargo to the media at www.jamamedia.org)

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

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Prevalence of Girl Child Marriage Decreases in South Asia

Girl child marriage (i.e., < 18 years of age) affects more than 10 million girls globally each year and is linked to maternal and infant morbidities (e.g., delivery complications, low birth weight) and an increased risk of death. Half (46 percent) of child marriages occur in South Asia. Anita Raj, Ph.D., M.S., of the

University of California, San Diego, and colleagues conducted a study to assess whether the prevalence of girl child marriage has changed over the past 2 decades in 4 South Asian nations (Bangladesh, India, Nepal, and Pakistan) with a girl child marriage prevalence of 20 percent or greater.

As reported in a Research Letter, the authors found that the prevalence of girl child marriage decreased in all countries from 1991-1994 to 2005-2007. Significant relative reductions occurred in marriage of girls prior to age 14 years across all 4 nations.  Little or no change over time was seen in marriage of 16- to 17-year-old adolescent girls for any nation except Bangladesh, where such marriages increased by 35.7 percent. “Reductions in girl child marriage in South Asia have occurred but are largely attributable to success delaying marriage among younger but not older adolescent girls. Improvements in education of girls and increasing rural to urban migration may have supported these reductions, but many schools graduate students at the 10th standard (about 15-16 years), maintaining vulnerability to early marriage for 16- to 17-year-old girls.”

(JAMA. 2012;307[19]:2027-2029. Available pre-embargo to the media at www.jamamedia.org)

A Framework Convention on Global Health – Health for All, Justice for All

In a Special Communication, Lawrence O. Gostin, J.D., of the Georgetown University Law Center, Washington, D.C., writes that “health inequalities represent perhaps the most consequential global health challenge and yet they persist despite increased funding and innovative programs.”

A global coalition of civil society and academics—the Joint Action and Learning Initiative on National and Global Responsibilities for Health (JALI)— has formed an international campaign to advocate for a Framework Convention on Global Health (FCGH). Recently endorsed by the UN Secretary-General, the FCGH would re-imagine global governance for health. Mr. Gostin examines the key modalities of an FCGH to illustrate how it would improve health and reduce inequalities. “The modalities would include defining national responsibilities for the population’s health; defining international responsibilities for reliable, sustainable funding; setting global health priorities; coordinating fragmented activities; reshaping global governance for health; and providing strong global health leadership through the World Health Organization.”

(JAMA. 2012;307[19]:2087-2092. Available pre-embargo to the media at www.jamamedia.org)

Viewpoints in This Week’s JAMA

Primary Health Care in Low-Income Countries – Building on Recent Achievements

Jeffrey D. Sachs, Ph.D., of Columbia University, New York, discusses the advances and challenges of providing health care in low-income countries.

“The dozen years since the adoption of the Millennium Development Goals have been a period of great achievement and advances in public health in the poorest countries. The cynics and naysayers were proven wrong. Ancient scourges such as malaria and newer ones such as AIDS can be controlled, even in the poorest places. Now is the time to redouble efforts to ensure that the gains of the past decade are pushed forward to become lasting triumphs.”

(JAMA. 2012;307[19]:2031-2032. Available pre-embargo to the media at www.jamamedia.org)

Policy Making With Health Equity at Its Heart

Michael G. Marmot, F.R.C.P., of University College London, examines the importance of putting health equity – defined as the systematic inequalities in health between social groups that are deemed to be avoidable by reasonable means – at the heart of all policy making, nationally and globally.

“When governments cut social expenditures, the effect is greatest on those at the lower end of the social hierarchy, those who are most dependent on cash and in-kind government expenditures. It should be of the highest priority to ensure that government policies do not unfairly increase avoidable health inequalities. What applies to policies of governments should also apply to global decision making whether on trade, overseas development assistance, or financial flows—put health equity at the heart of all policy making.”

(JAMA. 2012;307[19]:2033-2034. Available pre-embargo to the media at www.jamamedia.org)

Achieving Equity in Global Health – So Near and Yet So Far

Zulfiqar A. Bhutta, F.R.C.P.C.H., Ph.D., of Aga Khan University, Karachi, Pakistan, and K. Srinath Reddy, M.D., D.M., (Card), of the Public Health Foundation of India, New Delhi, write that “few issues have generated as much passion and imagination over the last few decades as the challenge of global health. From major studies on the global burden of disease to the recognition of the global epidemic of human immunodeficiency virus, AIDS, and tuberculosis, health has been center stage of the global development debate.”

The authors discuss the needs of several major global health issues and cite initiatives that have experienced positive outcomes in certain areas of public health.

(JAMA. 2012;307[19]:2035-2036. Available pre-embargo to the media at www.jamamedia.org)

Noncommunicable Diseases – A Global Health Crisis in a New World Order

Shannon L. Marrero, B.A., of Brown University, Providence, R.I., and colleagues write that in September 2011, the United Nations General Assembly (UNGA) held a High-Level Meeting on the Prevention and Control of Non-communicable Diseases. It is only the second time in history that the UNGA convened a high-level meeting in response to a global health crisis. The authors discuss the outcomes and aftermath of the high-level meeting and affirm that the previously unrecognized non-communicable diseases (NCDs) epidemic has at last acquired a voice.

“The NCDs—cardiovascular disease, chronic respiratory disease, diabetes, and cancers—are the dominant public health challenge of the 21st century. Left unattended, NCDs compromise the Millennium Development Goals, thwart the eradication of poverty, and undercut economic growth.”

(JAMA. 2012;307[19]:2037-2038. Available pre-embargo to the media at www.jamamedia.org)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 15, 2012
Media Advisory: To contact R. Matthew Chico, M.P.H., email Katie Steels at katie.steels@lshtm.ac.uk or call +44 (0)20-7927-2802.

CHICAGO – A review of studies reporting estimates of the prevalence of sexually transmitted infections/reproductive tract infections (STIs/RTIs) and malaria over the past 20 years suggests that a considerable burden of malaria and STIs/RTIs exists among pregnant women attending antenatal (before birth) facilities in sub-Saharan Africa, according to a review and meta-analysis of previous studies published in the May 16 issue of JAMA, a theme issue on Global Health.

“There are 880,000 stillbirths and 1.2 million neonatal deaths each year in sub-Saharan Africa. Low birth weight (< 2.5 kg [5.5 lbs.]), attributable to intrauterine growth retardation, preterm delivery, or both, is the leading risk factor for neonatal mortality. Intrauterine infection is implicated in stillbirth and is associated with 25 percent to 40 percent of preterm births. Sexually transmitted infections and reproductive tract infections and malaria are associated with adverse birth outcomes, but both may be mitigated with preventive or presumptive treatment or by repeated screening and treatment throughout the antenatal period. The extent to which either approach may be beneficial depends on the underlying prevalence of STIs/RTIs and malaria in pregnancy,” according to background information in the article.

R. Matthew Chico, M.P.H., of the London School of Hygiene and Tropical Medicine, London, and colleagues conducted a systematic review and meta-analysis to provide estimates for the dual prevalence of STIs/RTIs and malaria in pregnancy among women in sub-Saharan Africa. The researchers conducted a search for studies reporting malaria, syphilis, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, or bacterial vaginosis among pregnant women attending antenatal care facilities in sub-Saharan Africa. A total of 171 studies, which were conducted from 1990-2011, were identified that met inclusion criteria.

The studies included 340,904 women. The researchers found that the pooled prevalence estimates among studies in East and Southern Africa were: syphilis, 4.5 percent (n = 8,346 positive diagnoses), N gonorrhoeae, 3.7 percent (n = 626), C trachomatis, 6.9 percent (n = 350), T vaginalis, 29.1 percent (n = 5,502), bacterial vaginosis, 50.8 percent (n = 4,280), peripheral malaria, 32.0 percent (n = 11,688), and placental malaria, 25.8 percent (n = 1,388).

“West and Central Africa prevalence estimates were as follows: syphilis, 3.5 percent (n = 851), N gonorrhoeae, 2.7 percent (n = 73), C trachomatis, 6.1 percent (n = 357), T vaginalis, 17.8 percent (n = 822), bacterial vaginosis, 37.6 percent (n = 1,208), peripheral malaria, 38.2 percent (n = 12,242), and placental malaria, 39.9 percent (n = 4,658),” the authors write.

“The dual prevalence of malaria and STIs/RTIs is evident among pregnant women who attend antenatal facilities in sub-Saharan Africa. As malaria control and elimination efforts are brought to scale, the relative contribution of STIs/RTIs to adverse birth outcomes most likely will increase proportionately. Coinfection prevalence estimates for malaria and STIs/RTIs need to be established and routinely reported. Rigorous studies using molecular diagnostic methods are needed to characterize more accurately the prevalence of these infections and their clinical consequences. Clinical trials are needed to compare birth outcomes, operational feasibility/acceptability, and cost-effectiveness of intermittent preventive treatment during pregnancy (IPTp) with azithromycin-based combination therapy against an approach of integrated screening and treatment for malaria and STIs/RTIs,” the researchers conclude.
(JAMA. 2012;307[19]:2079-2086. Available pre-embargo to the media at www.jamamedia.org)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Mr. Chico reports having previously received funding as part of 2 studies co-financed by Pfizer and the Medicines for Malaria Venture that are investigating the use of azithromycin plus chloroquine in IPTp. No other disclosures were reported.

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