EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) TUESDAY, SEPTEMBER 18, 2012

Media Advisory: To contact Thomas A. Farley, M.D., M.P.H., call Jean Weinberg at 347-396-4177 or email jweinberg@health.nyc.gov.

NEW YORK – Addressing the obesity epidemic by preventing excess calorie consumption with government regulation of portion sizes is justifiable and could be an effective measure to help prevent obesity-related health problems and deaths, according to a Viewpoint in the September 19 issue of JAMA, and theme issue on obesity.

Thomas A. Farley, M.D., M.P.H., Commissioner of the New York City Department of Health and Mental Hygiene, presented the article at a JAMA media briefing.

“Americans consume many more calories than needed, and the excess is leading to diabetes, cardiovascular disease, and premature mortality. Since the 1970s, caloric intake has increased by some 200 to 600 calories per person per day. Although it is unclear how important changes in physical activity are to the surge in obesity prevalence, it is quite clear that this increase in calorie consumption is the major cause of the obesity epidemic—an epidemic that each year is responsible for the deaths of more than 100,000 Americans and accounts for nearly $150 billion in health care costs,” writes Dr. Farley.

Many foods contribute to excess calorie intake, Dr. Farley adds, but sugary drinks have drawn particular blame because of the near-tripling of consumption since the 1970s and their association in epidemiologic studies with obesity, weight gain, diabetes, and markers of cardiovascular disease. Also, the size of sugary drinks sold has increased substantially from a standard 6.5- or 8-ounce size in the 1960s to 20, 32, and even 64 ounces today. “The increase in portion sizes of these beverages is important because studies consistently show that when people are offered larger portions they simply consume more without recognizing it and without compensating for the increased consumption by decreasing intake later.”

Dr. Farley writes that the food industry is effective at marketing foods with a high-profit margin. “How should government address the health problems caused by this successful marketing of food? To do nothing is to invite even higher rates of obesity, diabetes, and related mortality.”

He suggests one option is to encourage food companies to voluntarily alter their products or marketing to reduce health risks. “Food companies understand how customers respond to their products and marketing better than anyone and could make many changes that would promote health. Food companies have indeed been responding to the obesity crisis by marketing products that have lower calorie contents by substitution (as with ‘diet’ beverages) and more recently by offering smaller portions. However, as publicly traded companies responsive to the interests of their shareholders, food companies cannot make decisions that will lower profits, and larger portion sizes are more profitable because most costs of delivering food items to consumers are fixed.”

“The balanced and most effective approach is for governments to regulate food products that harm the most people, simultaneously encourage food companies to voluntarily produce and market healthful products, and then provide information to consumers in ways that facilitate their choosing healthful products.”

Dr. Farley cites a number of initiatives taken by New York City to improve public health, including requiring restaurants to eliminate artificial trans fat, working with food companies to voluntarily lower sodium levels in packaged/processed foods, and providing information to consumers by requiring that chain restaurants  post calorie counts on their menus and menu boards. These actions followed similar steps to address smoking, which have led to a 35 percent reduction in smoking rates in the city in the past 10 years.

Dr. Farley describes steps taken by the city to address what many believe is the greatest single contributor to the obesity epidemic—sugary drinks. Among the initiatives, New York City supported a 1-cent-per-ounce excise tax on sugary drinks; the city also supported a change in policy on the Supplemental Nutrition Assistance Program that would have prohibited the use of program benefits to purchase sugary drinks; and the city’s Health Department proposed a cap on the portion size of sugary drinks served at restaurants. “… the portion-size studies strongly suggest that, with a smaller default portion size, most consumers will consume fewer calories. This change will not by itself reverse the obesity epidemic, but it can have a substantial effect on it.”

“Although the idea of government action to prevent obesity by regulating portion size is new, this action is easily justifiable, is manageable by the dynamic food industry, and will be effective in preventing needless deaths,” Dr. Farley concludes.

(JAMA. 2012;308[11]:1093-1094. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) TUESDAY, SEPTEMBER 18, 2012

Media Advisory: To contact James A. de Lemos, M.D., call Lisa Warshaw at 214-648-9349 or email lisa.warshaw@utsouthwestern.edu.

NEW YORK – Obese adults with excess visceral fat (fat located inside the abdominal cavity, around the body’s internal organs) and biomarkers of insulin resistance had an associated increased risk for the development of type 2 diabetes mellitus, while obese individuals with higher amounts of total body fat and subcutaneous fat (underneath the skin) did not have this increased risk, according to a study in the September 19 issue of JAMA, and theme issue on obesity.

James A. de Lemos, M.D., of the University of Texas Southwestern Medical Center, Dallas, presented the findings of the study at a JAMA media briefing.

“A marked increase in the prevalence of overweight and obesity has contributed to a doubling in type 2 diabetes mellitus incidence over the past three decades,” according to background information in the article. “Prediabetes, an intermediate hyperglycemia phenotype and risk factor for diabetes, is also associated with obesity and carries an excess risk for cardiovascular disease (CVD) and death. Although increased body mass index (BMI) is associated with diabetes at the population level, it does not adequately discriminate diabetes risk among obese individuals. Indeed, many obese persons appear resistant to the development of metabolic disease. Because the metabolic disease risks associated with obesity are heterogeneous [dissimilar], there remains an unmet clinical need for tools that differentiate obese persons who will ultimately develop prediabetes and diabetes from those who will remain metabolically healthy.”

Dr. de Lemos and colleagues examined the associations of adipose (body fat) tissue distribution, lipids, and biomarkers of insulin resistance and inflammation with the risk of prediabetes and diabetes in obese adults. The study included 732 obese participants (body mass index 30 or greater) ages 30 to 65 years without diabetes or cardiovascular disease enrolled between 2000 and 2002 in the Dallas Heart Study.

The researchers measured body composition by dual energy x-ray absorptiometry (low dose x-ray to determine amounts and distribution of body fat) and magnetic resonance imaging (MRI); circulating adipokines (proteins secreted by fat tissue) and biomarkers of insulin resistance, dyslipidemia (abnormal cholesterol levels), and inflammation; and subclinical atherosclerosis and cardiac structure and function by computed tomography and MRI.

Over a median (midpoint) follow-up of 7 years, 84 participants (11.5 percent) developed diabetes. In multivariable analysis, higher measures of visceral fat mass at the beginning of the study, fructosamine level (a measurement used to estimate  the average plasma glucose concentration over several weeks), fasting glucose level, family history of diabetes, systolic blood pressure, and weight gain over the follow-up period were independently associated with the development of diabetes.

The composite outcome of prediabetes or diabetes occurred in 39.1 percent of 512 participants with normal baseline glucose values, and was independently associated with baseline measurements of visceral fat mass; levels of fasting glucose, insulin, and fructosamine; older age; non-white race; family history of diabetes; and weight gain over follow-up, but not with measurements of general adiposity.

Diabetes incidence increased significantly among individuals with higher categories of visceral fat mass, but no association was seen for abdominal subcutaneous fat, total body fat or body mass index.

“These findings suggest that clinically measurable markers of adipose tissue distribution and insulin resistance may be useful in prediabetes and diabetes risk discrimination among obese individuals and support the notion of obesity as a heterogeneous disorder with distinct adiposity subphenotypes,” the authors write.

“Further research is needed to determine whether assessment of adipose tissue distribution and function using imaging tools, circulating biomarkers, or both can improve clinical risk prediction in obese individuals.”

(JAMA. 2012;308[11]:1150-1159. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. This JAMA theme issue is being published the same week as the Obesity Society’s Annual Scientific Meeting.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) TUESDAY, SEPTEMBER 18, 2012

Media Advisory: To contact Ted D. Adams, Ph.D., M.P.H., call Jennifer Barrett at 801-408-2182 or email jennifer.barrett@imail.org. To contact editorial author Anita P. Courcoulas, M.D., M.P.H., call Amy Dugas Rose at 412-586-9776 or email dugasak@upmc.edu.

NEW YORK – Severely obese patients who had Roux-en-Y gastric bypass surgery had significant weight loss that was sustained for an average of 6 years after the surgery and also experienced frequent remission and lower incidence of diabetes, hypertension, and abnormal cholesterol levels, compared to participants who did not have the surgery, according to a study in the September 19 issue of JAMA, and theme issue on obesity.

Ted D. Adams, Ph.D., M.P.H., of the University of Utah School of Medicine and Intermountain Healthcare, Salt Lake City, presented the findings of the study at a JAMA media briefing.

“The prevalence of extreme obesity in the United States is increasing at a rate greater than moderate obesity. Unfortunately, lifestyle therapy is generally insufficient as a weight management intervention for patients who are extremely obese. To date, effective long-term weight loss through pharmacological therapy has been marginal, leaving bariatric surgery as the only medical intervention providing substantial, long-term weight loss for most patients who are severely obese. For this high-risk population, however, the number of studies reporting long-term weight loss following bariatric surgery are limited and generally have incomplete follow-up,” according to background information in the article.

Dr. Adams and colleagues conducted a study to examine the association of Roux-en-Y gastric bypass (RYGB) surgery with weight loss, diabetes mellitus, and other health risks 6 years after surgery. The study included 1,156 severely obese (body mass index [BMI] 35 or greater) participants, ages 18 to 72 years (82 percent women; average BMI, 46) who sought and received RYGB surgery (n = 418), sought but did not have surgery (n = 417; control group 1), or who were randomly selected from a population-based sample not seeking weight loss surgery (n = 321; control group 2).

At 6 years, 92.6 percent (387/418) of the surgical group had follow-up data. Average unadjusted weight loss in the surgical group was 27.7 percent from the beginning of the study to year 6. Weight gain from baseline to year 6 was 0.2 percent in control group 1 and 0 percent in control group 2. “At 2 years, 99 percent of surgical patients had maintained more than 10 percent weight loss from baseline and 94 percent had maintained more than 20 percent weight loss. At 6 years, 96 percent of surgical patients had maintained more than 10 percent weight loss from baseline and 76 percent had maintained more than 20 percent weight loss,” the authors write.

The 6-year RYGB surgery group diabetes remission rates were significantly higher than the 2 control groups (62 percent for RYGB surgery group; vs. 8 percent for control group 1; and 6 percent for control group 2). At the same time, diabetes incidence in the RYGB surgery group was significantly lower than in the 2 control groups (2 percent vs. 17 percent and 15 percent; respectively). Remission rates of hypertension and low HDL-C levels at year 6 remained significantly improved in the RYGB surgical group compared with the 2 control groups, with similar improvements observed with remission rates for high LDL-C levels and high triglyceride levels. The numbers of participants with bariatric surgery-related hospitalizations were 33 (7.9 percent), 13 (3.9 percent), and 6 (2.0 percent) for the RYGB surgery group and 2 control groups, respectively.

The authors write that metabolic and cardiovascular risk profiles during the 6 years of follow-up remained significantly improved after RYGB surgery. “In contrast, cardiovascular and metabolic status of severely obese control participants generally worsened during the 6-year period.”

“These findings are important considering the rapid increase in total numbers of bariatric surgical operations performed in the United States and worldwide, and may have significant ramifications for the projected 31 million U.S. individuals meeting criteria for bariatric surgery.”

(JAMA. 2012;308[11]:1122-1131. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by a grant from the National Institutes of Health/The National Institute of Diabetes and Digestive and Kidney Diseases and a Public Health Service research grant from the National Center for Research Resources. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc. This JAMA theme issue is being published the same week as the Obesity Society’s Annual Scientific Meeting.

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 10 a.m. ET Tuesday, September 18 at this link.

Editorial: Progress in Filling the Gaps in Bariatric Surgery

In an accompanying editorial, Anita P. Courcoulas, M.D., M.P.H., of the University of Pittsburgh Medical Center, writes that an “important aspect of these findings is that despite the attenuation [lessening] of weight loss between 2 and 6 years in the RYGB group, the control of comorbid conditions remained very good.”

“These findings are important because they show in a RYGB cohort and control group with nearly complete follow-up at 6 years that weight loss and associated health benefits following RYGB are durable. The mortality rates in this study were too small to assess statistically, but serve as a reminder of an uncommon but important outcome needing objective monitoring.”

(JAMA. 2012;308[11]:1160-1161. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) TUESDAY, SEPTEMBER 18, 2012

Media Advisory: To contact Leonardo Trasande, M.D., M.P.P., call Jessica Guenzel at 212-404-3591 or email Jessica.Guenzel@nyumc.org.

NEW YORK – In a nationally representative sample of nearly 3,000 children and adolescents, those who had higher concentrations of urinary bisphenol A (BPA), a manufactured chemical found in consumer products, had significantly increased odds of being obese, according to a study in the September 19 issue of JAMA, and theme issue on obesity.

Leonardo Trasande, M.D., M.P.P., of the NYU School of Medicine, New York City, presented the findings of the study at a JAMA media briefing.

“In the U.S. population, exposure [to BPA] is nearly ubiquitous, with 92.6 percent of persons 6 years or older identified in the 2003-2004 National Health and Nutrition Examination Survey (NHANES) as having detectable BPA levels in their urine. A comprehensive, cross-sectional study of dust, indoor and outdoor air, and solid and liquid food in preschool-aged children suggested that dietary sources constitute 99 percent of BPA exposure,” according to background information in the article. “In experimental studies, BPA exposure has been shown to disrupt multiple metabolic mechanisms, suggesting that it may increase body mass in environmentally relevant doses and therefore contribute to obesity in humans.” BPA exposure is plausibly linked to childhood obesity, but evidence is lacking.

Dr. Trasande and colleagues conducted a study to examine association between urinary BPA concentrations and body mass in children. The study consisted of a cross-sectional analysis of a nationally representative subsample of 2,838 participants, ages 6 through 19 years, randomly selected for measurement of urinary BPA concentration in the 2003-2008 National Health and Nutrition Examination Surveys. Body mass index (BMI), converted to sex- and age-standardized z scores (indicates how many units [of the standard deviation] a child’s BMI is above or below the average BMI value for their age group and sex) was used to classify participants as overweight (BMI 85th percentile or greater for age/sex) or obese (BMI 95th percentile or greater). The median (midpoint) urinary BPA concentration for participants in the study was 2.8 ng/mL. The prevalence of obesity was 17.8 percent (n = 590), and overweight 34.1 percent (n = 1,047). The BPA concentrations of the participants were divided into quartiles (four groups). Controlling for race/ethnicity, age, caregiver education, poverty to income ratio, sex, serum cotinine level, caloric intake, television watching, and urinary creatinine level, children in the lowest urinary BPA quartile had a lower estimated prevalence of obesity (10.3 percent) than those in quartiles 2 (20.1  percent), 3 (19.0 percent), and 4 (22.3 percent). Compared with the first quartile, participants in the third quartile had approximately twice the odds for obesity. Participants in the fourth quartile had a 2.6 higher odds of obesity.

Further analyses showed this association to be statistically significant in only 1 racial subpopulation, white children and adolescents. The researchers also found that obesity was not associated with exposure to other environmental phenols commonly used in other consumer products, such as sunscreens and soaps.

“To our knowledge, this is the first report of an association of an environmental chemical exposure with childhood obesity in a nationally representative sample,” the authors write.

The researchers note that advocates and policy makers have long been concerned about BPA exposure. “We note the recent FDA ban of BPA in baby bottles and sippy cups, yet our findings raise questions about exposure to BPA in consumer products used by older children. Last year, the FDA declined to ban BPA in aluminum cans and other food packaging, announcing ‘reasonable steps to reduce human exposure to BPA in the human food supply’ and noting that it will continue to consider evidence on the safety of the chemical. Carefully conducted longitudinal studies that assess the associations identified here will yield evidence many years in the future.”

(JAMA. 2012;308[11]:1113-1121. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 11, 2012

Study Analyzes Changes in Pharmaceutical Advertising Following Shift to OTC Status

“The U.S. Food and Drug Administration (FDA) regulates prescription drug advertising, including requirements to provide consumers with a ‘fair balance’ of risks and benefits. When prescription drugs switch to over-the-counter (OTC) status, regulatory oversight of their advertising shifts to the Federal Trade Commission (FTC). Unlike the FDA, the FTC holds drug advertisements to the same standards as any consumer product: it applies a ‘reasonable consumer’ standard of truthfulness and nondeception that does not require any balancing of potential benefits and harms. Such a shift may be associated with changes in content,” writes Jeremy A. Greene, M.D., Ph.D., of Brigham and Women’s Hospital, Boston, and colleagues.

As reported in a Research Letter, the authors analyzed all print and broadcast advertisements from 4 commonly used prescription drugs that were the subject of extensive direct-to-consumer advertising (DTCA) promotion before and after OTC shift: loratidine (OTC in 2002), omeprazole (in 2004), orlistat (in 2007), and cetirizine (in 2008). Television and print materials spanning 24 months before and 6 months following OTC shift for each drug were obtained from an advertising database, and ads were stratified by whether they appeared in print or television, and coded for descriptive characteristics, presentation of health benefits, and potential health harms.

The researchers found that after the OTC switch, 62 of 64 (97 percent) advertisements described benefits of medications compared with 57 of 69 (83 percent) during the prescription only period. “The difference was not statistically significant for individual drugs. Differences existed in the presentation of potential harms during the prescription-only period in 48 of 69 advertisements (70 percent) vs. 7 of 64 (11 percent) after OTC shift. With the exception of print advertisements for orlistat, no post-switch advertisements mentioned contraindications or adverse effects. Print and broadcast advertisements after OTC switch were less likely to mention drugs’ generic names (33 of 64 [52 percent] vs. 65 of 69 [94 percent]).”

(JAMA. 2012;308[10]:973-975. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

The Attending Physician on the Wards – Finding a New Homeostasis

Robert M. Wachter, M.D., of the University of California, San Francisco, and Abraham Verghese, M.D., M.A.C.P., of Stanford University, Stanford, Calif., examine the changes that have taken place in recent years regarding attending physicians, including the reasons for the marked shift in demographics (such as from older to younger attendings), consider its effects on education and clinical care, and suggest interventions that may help improve the experience of trainees as well as attendings.

“Although some challenges will be more easily addressed by junior attendings and others by senior ones, the goals are the same. All attendings will need encouragement and wisdom to take a step back, keeping a measured distance that allows house staff to achieve and demonstrate competency while still ensuring patient safety. It is time that programs, trainees, and attendings take vigorous action to balance all these competing imperatives and establish a ‘new normal.’”

(JAMA. 2012;308[10]:977-978. Available pre-embargo to the media at https://media.jamanetwork.com)

Engaging Physicians and Leveraging Professionalism – A Key to Success for Quality Measurement and Improvement

Patrick H. Conway, M.D., M.Sc., of the Centers for Medicare & Medicaid Services, Baltimore, and Cincinnati Children’s Hospital Medical Center, and Christine K. Cassel, M.D., M.Sc., of the American Board of Internal Medicine, Philadelphia, discuss the topic of quality measurement and improvement, including the implementation of Maintenance of Certification, which includes assessment of physician performance. Also, the authors examine initiatives by the Centers for Medicare & Medicaid Services on this topic.

(JAMA. 2012;308[10]:979-980. Available pre-embargo to the media at https://media.jamanetwork.com)

Surgical vs. Lifestyle Treatment for Type 2 Diabetes

David S. Ludwig, M.D., Ph.D., of Boston Children’s Hospital, and colleagues write that “recent clinical trials have reported that substantially more weight loss and greater likelihood of diabetes remission occur following bariatric surgery compared with medical therapy, leading to calls for earlier consideration of surgery in the treatment of this obesity-related metabolic disease. Although these studies demonstrate the lack of efficacy of conventional practices, they do not prove the inherent superiority of surgery to lifestyle change.”

In this Viewpoint, the authors consider the limitations of published research and highlight the need for clinical trials with improved design.

“Before bariatric surgery becomes a mainstay for obesity-related complications, additional research is needed to compare the efficacy and safety of these procedures with that of truly intensive lifestyle intervention, not just standard practice. Design issues warranting consideration include the need for standardization of treatment, statistical methods (e.g., superiority vs. noninferiority trial), and generalizability. Because drug and device manufacturers would not profit from, and therefore have little incentive to sponsor, lifestyle intervention, the federal government should consider funding this research as a high priority.”

(JAMA. 2012;308[10]:981-982. Available pre-embargo to the media at https://media.jamanetwork.com)

Changing Eating Habits for the Medical Profession

Lenard I. Lesser, M.D., M.S.H.S., of the Palo Alto Medical Foundation Research Institute, Palo Alto, Calif., and colleagues write that health professionals spend a great deal of time at meetings. “Grand rounds, noon seminars, research meetings, and medical conferences are part of the life of a health professional. At many of these activities, food is available. Although some members of the health professional community have called for changes to the food environment in the community in which they live, they have paid less attention to the quality of food served at hospitals, physician offices, and at conferences.”

The authors examine steps that the medical profession can take to improve eating habits.

“The medical profession was influential in reducing smoking in the United States; it has the capacity to encourage food-system change within its own institutions. This would likely reduce caloric consumption of health professionals, promote the health of physicians, and could also cause a ripple effect in local food economies.”

(JAMA. 2012;308[10]:983-984. Available pre-embargo to the media at https://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, SEPTEMBER 11, 2012

Media Advisory: To contact Carrie H. Colla, Ph.D., call Annmarie Christensen at 603-653-0897 or email annmarie.christensen@dartmouth.edu. To contact editorial author Donald M. Berwick, M.D., M.P.P., email donberwick1@gmail.com.

CHICAGO – In an analysis of the cost-savings achieved by an earlier pilot program, the Medicare Physician Group Practice Demonstration (PGPD), researchers found modest estimates of overall savings associated with the PGPD, but larger savings among the dually eligible patients (Medicare and Medicaid), with savings achieved in large part through reductions in hospitalizations, according to a study in the September 12 issue of JAMA.

“To improve care and slow cost growth, payers are increasingly turning to new payment models, including accountable care organizations (ACOs). The Centers for Medicare & Medicaid Services (CMS) has launched 3 ACO programs—Pioneer, the Shared Savings Program, and the Advance Payment Model—which differ slightly in their details but share a common approach: participating organizations can share in savings if they meet quality and cost targets for their assigned beneficiaries. Accountable care organizations were included in the Affordable Care Act in part because simulations suggested that CMS could achieve savings from these models, and an earlier program, the Physician Group Practice Demonstration, appeared to be effective,” according to background information in the article.

In the PGPD program, participating physician groups were eligible for up to 80 percent of any savings they generated if they were also able to demonstrate improvement on 32 quality measures, including the adequacy of preventive care and the effectiveness of chronic disease management. “Although evidence indicates the PGPD improved quality, uncertainty remains about its effect on costs,” the authors write.

Carrie H. Colla, Ph.D., of the Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine at Dartmouth, Lebanon, N.H., and colleagues conducted a study to estimate the cost savings achieved by the PGPD program for all beneficiaries and for both dually and nondually eligible beneficiaries. The analyses compared pre-intervention (2001-2004) and post-intervention (2005-2009) trends in spending of PGPD participants to local control groups. The study included 10 physician groups from across the United States. The intervention group was composed of fee-for-service Medicare beneficiaries (n = 990,177) receiving care primarily from the physicians in the participating medical groups. Controls were Medicare beneficiaries (n = 7,514,453) from the same regions who received care largely from non-PGPD physicians. Overall, 15 percent of beneficiaries were dually eligible for Medicare and Medicaid. The primary outcome measure for the study was annual spending per Medicare fee-for-service beneficiary.

For all enrollees, the reduction in growth of spending for nondually eligible beneficiaries was modest. After adjustment, annual savings estimates per beneficiary were modest ($114), with this result reflecting the average of significant annual savings in the dually eligible beneficiaries ($532) and nonsignificant savings in the nondually eligible beneficiaries ($59, $166 in savings to $47 in additional spending).

The adjusted average spending reductions were concentrated in acute care (overall, $118; dually eligible: $381; nondually eligible: $85). Further analysis revealed that in sites where savings occurred for acute care, hospitalization rates declined during the PGPD.

The PGPD was associated with lower medical 30-day readmissions on average across the 10 sites and lower readmissions for both medical and surgical admissions in the dually eligible beneficiaries. There was significant variation in savings across practice groups, ranging from an overall mean per-capita annual saving of $866 to an increase in expenditures of $749.

“The variation both in levels and changes in risk-adjusted spending across the participating organizations was remarkable. We know little about why some succeeded and others failed to achieve savings. One hypothesis is that organizations beginning with higher spending levels have greater opportunities to achieve savings,” the authors write. “Other factors may have contributed to achieving higher levels of performance in some sites, such as governance models; internal leadership; physician engagement strategies; the degree of coherence of electronic health records and other health information technological tools; and the specific approaches adopted for chronic disease management, care transitions, and quality improvement.”

“Our results suggest that the ACO reforms included in the Affordable Care Act, such as the Pioneer and the Medicare Shared Savings Programs, have at least the potential to slow spending growth, particularly for costly patients. The remarkable degree of heterogeneity across participating sites underscores the importance of timely evaluation of current payment reforms and a better understanding of the institutional factors that lead to either success or failure in effecting changes in health care practices.”

(JAMA. 2012;308[10]:1015-1023. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was funded by a grant from the National Institute on Aging, the Dartmouth Atlas Project (supported by a consortium led by the Robert Wood Johnson Foundation), and the Commonwealth Fund.  All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: ACOs—Promise, Not Panacea

In an accompanying editorial, Donald M. Berwick, M.D., M.P.P., former president and CEO of the Institute for Healthcare Improvement and former Administrator of the Centers for Medicare & Medicaid Services, examines the question of what this new analysis adds to predictions about the promise of ACOs.

“First, the results for dually eligible beneficiaries are important and encouraging. Most of the 9.2 million people in that Medicare subgroup receive poor, uncoordinated care in the status quo, and they account for over $300 billion in annual costs and 40 percent of state Medicaid expenditures. Improvements of cost and quality for them can have big payoffs. Second, the Dartmouth group documented a small overall savings for the entire beneficiary population and, were this to be multiplied over the whole of Medicare, the total would be about $5 billion per year, that is, about 1 percent of the budget. Third, the substantial variation of results among PGPD sites offers hope for continual learning about best practices, and therefore, maybe, better results in more places over time. Fourth, the evidence of what the authors gently call ‘coding biases’ in PGPD sites serves notice once again that surveillance by CMS and objective evaluators is necessary and prudent. Neither patients nor the nation are well served when administrative manipulations masquerade as changes in care. What is needed is better care, not better coding.”

(JAMA. 2012;308[10]:1038-1039. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 11, 2012

Media Advisory: To contact corresponding author Joachim Klode, M.D., email joachim.klode@uk-essen.de.

CHICAGO – Preoperative 3-dimensional visualization of sentinel lymph nodes (SLNs) with a technique known as single-photon emission computed tomography/computed tomography was associated with a higher rate of detection of positive SLNs and a higher rate of disease-free survival among patients with melanoma, according to a study in the September 12 issue of JAMA.

“Melanoma has become an increasing interdisciplinary public health challenge worldwide. According to the World Health Organization, the incidence of melanoma is increasing faster than any other cancer in the world. Melanoma is the third most common cancer in Australia and the fifth most common cancer in the United States. The American Cancer Society estimated that approximately 70,230 new melanomas were diagnosed in the United States during 2011, resulting in approximately 8,790 deaths,” according to background information in the article. “Because melanoma, depending on tumor depth, metastasizes early into regional lymph nodes, sentinel lymph node excision (SLNE) is probably the most important diagnostic and potentially therapeutic procedure for patients with melanoma. The histological status of the sentinel lymph node is the most relevant prognostic factor for overall survival in patients with melanoma, independent of primary tumor thickness.” The authors add that the recently introduced hybrid single-photon emission computed tomography/computed tomography (SPECT/CT) imaging technique could help overcome the high false-negative rate of SLNE by providing additional anatomical information to the surgeon.

Ingo Stoffels, M.D., of the University of Essen-Duisburg, Essen, Germany, and colleagues conducted a study to compare the association between SLNE with vs. without preoperative SPECT/CT imaging and metastatic node detection and disease-free survival in patients with cutaneous melanoma. The study included use of a melanoma patient database to identify a group of 464 patients eligible for SLNE between March 2003 and April 2011. A total of 403 patients with clinically negative lymph nodes, who underwent SLNE with or without preoperative SPECT/CT, qualified for subsequent analysis. Between March 2003 and October 2008, 254 patients with melanoma underwent SLNE without preoperative SPECT/CT. Between November 2008 and April 2011, all sentinel node scintigraphies (type of diagnostic imaging tests) were performed as SPECT/CT in 149 patients. Using SPECT/CT allowed SLNE in the head and neck area more frequently (2.0 percent for standard vs. 23.5 percent for SPECT/CT).

A total of 833 SLNs were removed from 403 patients. The researchers found 2.40 SLNs per patient in the SPECT/CT group and 1.87 SLNs per patient in the standard group; 51 of 358 excised SLNs (14.2 percent) in the SPECT/CT cohort and 54 of 475 SLNs (11.4 percent) in the standard cohort showed metastatic involvement. The authors were able to identify 41 patients (27.5 percent) with positive SLNs in the SPECT/CT cohort and 48 (18.9 percent) with positive SLNs in the standard cohort. The number of positive SLNs per patient was significantly higher in the SPECT/CT cohort than in the standard cohort (0.34 vs. 0.21).

“The local relapse rate in the SPECT/CT cohort was lower than in the standard cohort (6.8 percent vs. 23.8 percent,), which prolonged 4-year disease-free survival (93.9 percent vs. 79.2 percent),” the researchers write.

The authors note that with the SPECT/CT technique, they were able to use smaller incisions in the head and neck area as well as alternative entry points due to the exact anatomical localization of the SLN.

“In conclusion, the preoperative visualization of SLN with SPECT/CT is technically feasible and facilitates the detection of additional positive SLNs. The use of this technique offers the physician the preoperative possibility of determining the exact location and visualization of the SLN …”, the researchers write. “In patients with cutaneous melanoma, the use of SPECT/CT-aided SLNE compared with SLNE alone was associated with higher detection of metastatic involvement and a higher rate of disease-free survival.”

(JAMA. 2012;308[10]:1007-1014. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was not supported by any grant or sponsor. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 11, 2012

Media Advisory: To contact William J. Calhoun, M.D., call Raul Reyes at 409-747-0794 or email rareyes@utmb.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 adults with asthma controlled with low-dose inhaled corticosteroid therapy, the time to treatment failure was not significantly different among patients who received corticosteroid dose adjustment based on physician assessment, a biomarker, or symptom occurrence, according to a study in the September 12 issue of JAMA.

Asthma disease activity varies daily, seasonally, and episodically, presumably related to airway inflammation. “Accordingly, asthma management requires periodic dose adjustments of controller medications, particularly inhaled corticosteroids. Adjustments have been based on (1) physician assessment of symptoms, activity limitation, rescue albuterol use (a bronchodilator used for treating asthma), lung function, and exacerbations at usual office or clinic visits, (2) a biomarker of disease activity (e.g., exhaled nitric oxide), or (3) the occurrence of symptoms on a day-to-day basis,” according to background information in the article. “No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma.”

William J. Calhoun, M.D., of the University of Texas Medical Branch, Galveston, and colleagues hypothesized that adjustment of inhaled corticosteroids based on symptoms or measurement of exhaled nitric oxide would be superior to adjustment based on physician assessment. The researchers conducted a randomized, placebo-controlled trial that included 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]). The Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010. For physician assessment-based adjustment and biomarker-based adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.

The researchers found that the time to treatment failure, the primary study outcome, did not differ significantly among the 3 treatment strategies. The 9-month Kaplan-Meier failure rates were 22 percent (24 events) for physician assessment-based adjustment (PABA), 20 percent (21 events) for biomarker-based adjustment (BBA), and 15 percent (16 events) for symptom-based adjustment (SBA).

Treatment failure rates were not different among groups when multiple episodes of treatment failure were included. There were not significant differences among the treatment groups for asthma exacerbation (including multiple episodes) rates; and the average proportion of treatment failures that progressed to exacerbations. The authors also found that measures of lung function and asthma symptoms were not significantly different among the groups.

“In summary, among adult participants with mild to moderate persistent asthma, neither the SBA nor the BBA strategy for inhaled corticosteroid therapy was superior to the standard PABA strategy for the outcome of treatment failure.”

(JAMA. 2012;308[10]:987-997. Available pre-embargo to the media at https://media.jamanetwork.com)

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

Please Note: 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, September 11 at this link.

Editorial: Inhaled Corticosteroid Dose Adjustment in Mild Persistent Asthma

In an accompanying editorial, George T. O’Connor, M.D., M.S., of the Boston University School of Medicine, (and Contributing Editor, JAMA), and Joan Reibman, M.D., of New York University, New York, comment on the findings of this study.

“This report adds to prior randomized trials that have compared the typical physician-prescribed dosing of inhaled corticosteroids (ICS) with intermittent dosing guided by symptoms for patients with relatively mild asthma. A prior Asthma Clinical Research Network (ACRN) study of adults with mild persistent asthma indicated that a strategy of initiating a course of inhaled or oral corticosteroid only when asthma symptoms became bothersome (according to a written action plan), led to a similar peak expiratory flow rate and asthma exacerbation rate as the everyday physician-prescribed dosing of controller medications (ICS or leukotriene antagonist), although some outcomes such as bronchial reactivity and symptom-free days were improved by regular twice daily use of ICS. Like the BASALT trial, the prior ACRN study was designed to show superiority of one strategy over another, rather than to test equivalence, and the lack of superiority of any strategy over the others must be interpreted accordingly.”

(JAMA. 2012;308[10]:1036-1037. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 11, 2012

Media Advisory: To contact corresponding author Moses S. Elisaf, M.D., Ph.D., F.A.S.A., F.R.S.H., email egepi@cc.uoi.gr.

CHICAGO – In a study that included nearly 70,000 patients, supplementation with omega-3 polyunsaturated fatty acids was not associated with a lower risk of all-cause death, cardiac death, sudden death, heart attack, or stroke, according to an analysis of previous studies published in the September 12 issue of JAMA.

“Treatment with marine-derived omega-3 polyunsaturated fatty acids (PUFAs) for the prevention of major cardiovascular adverse outcomes has been supported by a number of randomized clinical trials (RCTs) and refuted by others. Although their mechanism of action is not clear, their postulated effect on cardiovascular outcomes may be due to their ability to lower triglyceride levels, prevent serious arrhythmias, or even decrease platelet aggregation and lower blood pressure. Current guidelines issued by major societies recommend their use, either as supplements or through dietary counseling, for patients after myocardial infarction [MI; heart attack], whereas the U.S. Food and Drug Administration has approved their administration only as triglyceride-lowering agents in patients with overt hypertriglyceridemia, and some (but not all) European national regulatory agencies have approved the omega-3 administration for cardiovascular risk modification. The controversy stemming from the varying labeling indications causes confusion in everyday clinical practice about whether to use these agents for cardiovascular protection,” according to background information in the article.

Evangelos C. Rizos, M.D., Ph.D., of the University Hospital of Ioannina, Ioannina, Greece, and colleagues performed a large-scale synthesis of the available randomized evidence by conducting a systematic review and meta-analysis to determine the association between omega-3 PUFAs and major cardiovascular outcomes.

Of the 3,635 citations retrieved, 20 studies with 68,680 randomized patients were included, reporting 7,044 deaths, 3,993 cardiac deaths, 1,150 sudden deaths, 1,837 heart attacks, and 1,490 strokes. Analysis indicated no statistically significant association with all-cause mortality, cardiac death, sudden death, heart attack, and stroke when all supplement studies were considered.

“In conclusion, omega-3 PUFAs are not statistically significantly associated with major cardiovascular outcomes across various patient populations. Our findings do not justify the use of omega-3 as a structured intervention in everyday clinical practice or guidelines supporting dietary omega-3 PUFA administration. Randomized evidence will continue to accumulate in the field, yet an individual patient data meta-analysis would be more appropriate to refine possible associations related to, among others, dose, adherence, baseline intake, and cardiovascular disease risk group,” the authors conclude.

(JAMA. 2012;308[10]:1024-1033. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Elisaf reported having given talks, attended conferences, and participated in trials sponsored by industry not associated with those that manufacture or market omega-3 supplements.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 4, 2012

Prone Position During Breast Cancer Radiation Therapy Associated With Reduced Amount of Irradiation to Lung, Heart

Radiation therapy to the breast contributes to improved outcomes in breast cancer patients after breast preservation surgery. “However, whole breast radiotherapy is associated with damage to the heart and lung, increased cardiovascular mortality, and lung cancer development, with risks that remain 15 to 20 years after treatment. These consequences occur when breast cancer patients are treated supine [lying on their back]. Preliminary data on prone positioning [lying face downward] suggest that radiation exposure to the heart and lung can be reduced compared with supine positioning with similar efficacy,” writes Silvia C. Formenti, M.D., of the New York University School of Medicine, New York, and colleagues.

As reported in a Research Letter, the authors conducted a study to test the hypothesis that prone positioning is superior to standard supine positioning, comparing the volume of heart and lung within the radiation field. The prospective study included breast cancer patients who underwent 2 computed tomography (CT) simulation scans, first supine and next prone. Two hundred patients per stratum (left and right breast cancer) were enrolled. The researchers found that prone positioning was associated with a reduction in the amount of irradiated lung in all patients and in the amount of heart volume irradiated in 85 percent of patients with left breast cancer. “The study is limited to a single institution. A multi-institutional prospective trial with outcome measures is warranted to confirm these findings. If prone positioning better protects normal tissue adjacent to the breast, the risks of long-term deleterious effects of radiotherapy may be reduced.”

(JAMA. 2012;308[9]:861-863. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

The Safety Risks of Innovation – The FDA’s Expedited Drug Development Pathway

Thomas J. Moore, A.B., of the Institute for Safe Medication Practices, Alexandria, Va., and Curt D. Furberg, M.D., Ph.D., of the Wake Forest School of Medicine, Winston-Salem, N.C., examine the FDAs program for speeding approval of new drugs, known officially as the “Expedited Drug Development Pathway.” The authors discuss the complex safety issues raised by the expedited approval process, and cite three examples involving drugs for treatment of cancer, multiple sclerosis, and stroke prevention, with these new drugs including some agents with limited clinical trial data and substantial risks.

“It takes years of development, costly clinical trials, and extensive analyses to establish the clinical conditions under which new drugs will do more good than harm. Risks persist, even with standard approvals. Meanwhile, the U.S. Senate, in approving a regular 5-year update to the Food, Drug, and Cosmetic Act, proposed a further expansion of expedited review, with a new category for ‘breakthrough drugs.’ For physicians, the FDA’s emphasis on rapid drug approval underlines the importance of the 6 ‘principles of conservative prescribing’ that include the warning, ‘Exercise caution and skepticism regarding new drugs.’”

(JAMA. 2012;308[9]:869-870. Available pre-embargo to the media at https://media.jamanetwork.com)

Clinical Trial Data as a Public Good

Marc A. Rodwin, J.D., Ph.D., of Harvard University, Cambridge, Mass., and John D. Abramson, M.D., M.S., of Harvard Medical School, Boston, discuss the need to improve public access to clinical trial data, and suggest mandatory disclosure of the standardized Clinical Study Report (CSR) for all clinical trials involving FDA-approved drugs.

The CSR summarizes the trial, clinical end points, methods, key data, and data analysis and includes the most pertinent information about a clinical trial in an easily analyzed format. “Drug manufacturers already produce these reports to meet international and national regulatory requirements. Making CSRs publicly available would not be expensive, yet disclosure would promote research integrity, medical knowledge, and public health. Furthermore, CSRs are more likely to be reliable than other summaries. Drug manufacturers submit CSRs to public authorities when they seek marketing approval and cannot alter or delete data without potentially jeopardizing their relationships with regulatory agencies and risking criminal prosecution,” the authors write.

They add that “to expand public access to clinical trial data, Congress could require the FDA to disclose all CSRs that drug manufacturers submit when seeking marketing approval and also could require drug firms to disclose CSRs for all clinical trials they conduct for drugs that they market in the United States. Those actions would go a long way toward making the knowledge derived from clinical trials truly a public good.”

(JAMA. 2012;308[9]:871-872. Available pre-embargo to the media at https://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, SEPTEMBER 4, 2012

Media Advisory: To contact corresponding author Maria E. Suarez-Almazor, M.D., Ph.D., call Julie Penne at 713-792-0662 or email jpenne@mdanderson.org.

CHICAGO – Although there are concerns regarding the potential development of malignancies in patients with rheumatoid arthritis who are receiving treatment with biologic response modifiers (BRMs), pooled results from more than 60 randomized controlled trials did not find a statistically significant increased risk of any type of cancer with use of BRMs for at least 6 months compared with traditional disease-modifying antirheumatic drugs or with placebo, according to the results of a meta-analysis published in the September 5 issue of JAMA.

“Rheumatoid arthritis (RA) is a systemic inflammatory polyarthritis that can lead to significant morbidity, joint deformity, and impaired quality of life and affects approximately 1 percent of the general population. Treatment with traditional disease-modifying antirheumatic drugs (DMARDs) reduces disease activity, retards joint destruction, and improves patients’ quality of life. However, in many patients with active disease, traditional DMARDs fail or are not tolerated. Biologic response modifiers provide clinically important improvement in patients not responding to traditional DMARDs by targeting specific immune pathways, reducing inflammation, and leading to better control of symptoms and structural damage. In 2010, published data from European and U.S. registries reported that 25 percent to 56 percent of patients with RA used BRMs,” according to background information in the article.

The authors add that because these biologic agents interfere with the immune system, concerns exist regarding their safety, specifically with respect to infections and malignancies. “Since 2005, conflicting data have existed associating tumor necrosis factor (TNF) inhibitors with an increased risk of developing certain types of malignancies.”

Maria A. Lopez-Olivo, M.D., Ph.D., of the University of Texas MD Anderson Cancer Center, Houston, and colleagues conducted a study to evaluate the risk of developing any type of malignancy in patients with RA receiving treatment with BRMs. The authors searched the medical literature to identify randomized controlled trials that included the BRMs abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Studies were selected that compared the safety of any BRMs used in RA patients with placebo and/or any traditional DMARDs with a minimum of 24 weeks of follow-up.

The researchers identified 63 RCTs with 29,423 patients for inclusion in the analysis. No statistically significant increased risk of developing malignancy was observed. Of the 29,423 patients, 211 developed a malignancy during the trial (0.72 percent): 23 of 3,615 patients in the BRM monotherapy group (0.64 percent), 123 of 15,989 patients in the BRM combination therapy group (0.77 percent), and 65 of 9,819 patients in the control group (0.66 percent).

“Of the 211 malignancies, 118 were solid tumors (i.e., adrenal, bladder, breast, cholangiocarcinoma, fibrosarcoma, gastrointestinal, hepatic, leiomyosarcoma, liposarcoma, lung, ovarian, pancreatic, prostate, renal, testicular, thyroid, tongue, uterine), 48 were skin cancers (i.e., basal cell, squamous cell, and 4 melanomas), 14 were lymphomas, 26 were not specified, and 5 were hematologic nonlymphoma (i.e., multiple myeloma, leukemia),” the authors write.

No statistically significant risk was observed for specific cancer sites. Anakinra plus methotrexate showed lower odds compared with methotrexate alone.

“Overall, our findings do not support an increased risk of malignancy for patients with RA receiving BRMs in RCTs of at least 24 weeks’ duration. Additional systematic reviews of observational studies are needed to establish risk in the longer term. Although the findings suggest that BRMs may be generally safe with respect to risk of malignancy in the short term, the risk of recurrence in patients with RA with history of cancer or cancer risk factors remains unknown,” the authors conclude.

(JAMA. 2012;308[9]:898-908. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was not funded or supported by any organization. Dr. Suarez-Almazor has a K24 career award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. 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, SEPTEMBER 4, 2012

Media Advisory: To contact Charlotte Andersson, M.D., Ph.D., email ca@heart.dk. To contact editorial author Deepak L. Bhatt, M.D., M.P.H., call Lori Schroth at 617-534-1604 or email ljschroth@partners.org.

CHICAGO – In a study that included nearly 60,000 patients with a first-time heart attack, patients with diabetes who received conventional platelet-inhibition with clopidogrel had a lower reduction in the risk of all-cause death and cardiovascular death compared with heart attack patients without diabetes who received clopidogrel, according to a study in the September 5 issue of JAMA.

“Patients with diabetes have an increased risk of ischemic adverse events and death compared with patients without diabetes,” according to background information in the article. “Pharmacodynamic studies have shown that persistently high platelet reactivity is common in patients with diabetes in spite of clopidogrel treatment. Clinical trials have not convincingly demonstrated that clopidogrel benefits patients with diabetes as much patients without diabetes.”

Charlotte Andersson, M.D., Ph.D., of Gentofte Hospital, Hellerup, Denmark, and colleagues analyzed the outcomes associated with clopidogrel treatment after heart attack in patients with and without diabetes.  The study included data from the Danish nationwide administrative registries between 2002-2009 of patients who were hospitalized with incident heart attack and who had survived and not undergone coronary artery bypass surgery 30 days after discharge and who were followed up for as long as 1 year. Analysis was conducted to investigate the association between clopidogrel treatment in patients with and without diabetes and the outcomes of all-cause mortality, cardiovascular mortality, and a composite end point of recurrent heart attack and all-cause mortality.

Of the 58,851 patients—7,247 of whom (12 percent) had diabetes—who were included in the analyses, 35,380 (60 percent) received clopidogrel at the beginning of the study. Patients were followed up for a median (midpoint) of 365 days. In total, 1,790 patients (25 percent) with and 7,931 patients (15 percent) without diabetes met the composite end point. Of these, 1,225 (17 percent) with and 5,377 (10 percent) without diabetes died. Of the patients who died, 978 patients (80 percent) with and 4,100 patients (76 percent) without diabetes died of cardiovascular-related events.

Of patients with diabetes, those who took clopidogrel had lower crude incidence rates of all-cause mortality than those who were not taking clopidogrel. Of patients who did not have diabetes, those who took clopidogrel had lower crude incidence rates of all-cause mortality than those who did not take clopidogrel. Adjusted for other variables, patients with diabetes were found to have a smaller relative risk reduction for mortality than patients without diabetes. “When adjusted, this finding applied for the all-cause mortality end point and the cardiovascular mortality end point, but not for the composite end point,” the authors write.

“In the present analysis, clopidogrel treatment was associated with a relative risk reduction of 25 percent for all-cause mortality, 23 percent for cardiovascular mortality, and 9 percent for the combination of recurrent myocardial infarction [MI; heart attack] and all-cause mortality in patients without diabetes, and a relative risk reduction of 11  percent for all-cause mortality but no significant reduction in cardiovascular mortality or the combined end point in patients with diabetes.”

“In summary, data from previous clinical trials and data from the present analyses strongly suggest that patients with diabetes have a significantly diminished relative effectiveness of conventional platelet-inhibition with clopidogrel after MI compared with patients without diabetes. It should however be emphasized that considering the relatively higher absolute risks found for patients with diabetes, use of clopidogrel may still translate into a significant reduction in event rates for patients with diabetes, which data from the subgroup analyses supported. Available data nevertheless raise a possibility that patients with diabetes may benefit from a more potent platelet inhibitor strategy to achieve a relative risk reduction similar to patients without diabetes,” the researchers conclude.

(JAMA. 2012;308[9]:882-889. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was funded by an internal research foundation grant at the Department of Cardiology, Gentofte Hospital. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Antiplatelet Therapy Following Myocardial Infarction in Patients With Diabetes

Deepak L. Bhatt, M.D., M.P.H., of the VA Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston, writes in an accompanying editorial that the “study by Andersson et al highlights the elevated risk of recurrent myocardial infarction and cardiovascular mortality among patients with diabetes following MI.”

“More needs to be done to reduce these risks among such patients. At least a portion of this excess risk appears due to platelet activity and function and to the effects of antiplatelet medications in patients with diabetes. Therefore, in appropriately selected patients, intensification of the antiplatelet regimen may be one method by which their outcomes might be markedly improved.”

(JAMA. 2012;308[9]:921-922. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 4, 2012

Media Advisory: To contact corresponding author Andrew E. Arai, M.D., call Nick Zagorski at 301-496-4236 or email nicholas.zagorski@nih.gov.

CHICAGO – Using cardiac magnetic resonance imaging among older adults in Iceland, researchers estimated the prevalence of unrecognized heart attacks, which was associated with an increased risk of death, according to a study in the September 5 issue of JAMA.

“The prevalence and prognosis of unrecognized myocardial infarction [MI; heart attack] in older people with and without diabetes may be higher than previously suspected in population studies. Advances in MI detection, such as cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE), are more sensitive than prior methods. Ascertaining the prevalence of unrecognized MI (UMI) in these groups is relevant because age and diabetes increase the risks of coronary heart disease. Pathologic studies indicate that subclinical coronary plaque rupture occurs frequently, particularly in diabetic individuals, which may culminate in a high prevalence of UMI,” according to background information in the article.

Erik B. Schelbert, M.D., M.S., of the National Institutes of Health, Bethesda, Md., and colleagues conducted a study to compare the prevalence and prognosis of recognized and unrecognized MI diagnosed with CMR vs. electrocardiography (ECG) in older diabetic and nondiabetic participants. ICELAND MI is a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study (enrollment January 2004-January 2007) using ECG or CMR to detect UMI. From a community-dwelling group of older individuals in Iceland, data for 936 participants ages 67 to 93 years were analyzed, including 670 who were randomly selected and 266 with diabetes. The median (midpoint) age was 76 years, and 52 percent of the participants were women.

A total of 91 of 936 participants (9.7 percent) had recognized myocardial infarction (RMI), and the prevalence of UMI by CMR was 17 percent (157/936). Those with diabetes had a higher prevalence of UMI by CMR than those without diabetes (n=72; 21 percent, vs. n=85; 14 percent). Cardiac magnetic resonance detected 157 UMI, which was more than the 46 UMI detected by ECG (prevalence by CMR, 17 percent; vs. ECG, 5 percent, respectively). “In the randomly sampled cohort (n=670), 61 participants (9 percent) had RMI and 97 (14 percent) had UMI by CMR whereas only 35 (5 percent) had UMI by ECG, significantly less than UMI by CMR,” the authors write. Unrecognized MI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease.

Over a median follow-up of 6.4 years, 30 of 91 participants with RMI died (33 percent), and 44 of 157 with UMI by CMR died (28 percent), which were both significantly higher rates than the 17 percent with no MI who died (119/688). After adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (absolute risk increase, 8 percent), but UMI by ECG was not associated with mortality (absolute risk increase, -2 percent).

The researchers add that they observed more use of aspirin, β-blocker, and statin medications in those with UMI by CMR compared with those without MI. “Yet the use of cardiac medications was significantly less in those with UMI compared with those with RMI. Roughly half of those with UMI were taking aspirin, whereas less than half were taking statins or β-blockers.”

The authors suggest that several factors may contribute to the high prevalence of UMI. “First, subclinical coronary plaque rupture occurs frequently, particularly in diabetic individuals. Cardiac magnetic resonance may detect the myocardial sequelae of coronary plaque rupture or coronary plaque erosion that either spontaneously reperfused or were nonocclusive. Second, symptom variation in acute MI may lead patients or their clinicians to attribute MI symptoms to noncardiac causes. Third, given their propensity to be clinically detected, RMI may be more severe than UMI and impart greater lethality.”

“This investigation also suggests limitations in current prevention strategies. Herein we report a burden of MI in community-dwelling older individuals that is higher than previously appreciated. The burden of UMI was higher than the total burden of recognized MI, and prescription of cardioprotective medications was less than for participants with RMI. The high prevalence of MI specifically in individuals with diabetes confirms their increased vulnerability. Less than one-third of those with UMI by CMR had prior revascularization to establish coronary disease and trigger secondary prevention strategies. Detection of UMI by CMR may provide an opportunity to optimize treatment for these vulnerable individuals, but further study is needed to assess this.”

(JAMA. 2012;308[9]:890-897. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, SEPTEMBER 4, 2012

Media Advisory: To contact corresponding author Gary F. Mitchell, M.D., call 781-255-6930 or email garyfmitchell@gmail.com. To contact editorial author Debabrata Mukherjee, M.D., M.S., call Laura Gallegos at 915-309-5647 or email laura.gallegos@ttuhsc.edu.

CHICAGO – An analysis of the relationship between several vascular function measures and blood pressure levels finds that certain measures including higher aortic stiffness were associated with a higher risk of new hypertension; however, initial blood pressure was not independently associated with risk of progressive aortic stiffening, suggesting that vascular stiffness may be a precursor rather than the result of hypertension, according to a study in the September 5 issue of JAMA.

“Vascular stiffness increases with advancing age and is a major risk factor for age-related morbidity and mortality. A compliant aorta provides an important buffer for each ventricular contraction that maintains pulse pressure at low levels. Stiffening of the aortic wall and improper matching between aortic diameter and flow are associated with unfavorable alterations in pulsatile hemodynamics, including an increase in forward arterial pressure wave amplitude, which increases pulse pressure,” according to background information in the article. “The association between vascular stiffening and blood pressure is particularly interesting because the functional relationship is likely bidirectional. Elevated blood pressure may cause vascular damage and accelerated conduit artery stiffening. Conversely, aortic stiffening increases pressure pulsatility and therefore affects systolic blood pressure. However, temporal relationships between vascular stiffness and blood pressure remain incompletely elucidated. In particular, whether vascular stiffness antedates hypertension or vice versa is unclear.”

Bernhard M. Kaess, M.D., of the National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Mass., and colleagues the examined temporal relationship between vascular stiffening and blood pressure by evaluating vascular stiffness, central hemodynamics, peripheral blood pressure, and incident hypertension. The investigation was based on the 2 latest examination cycles (cycle 7: 1998-2001; cycle 8: 2005-2008 [last visit: January 25, 2008]) of the Framingham Offspring study (recruited: 1971-1975). Temporal relationships among blood pressure and 3 measures of vascular stiffness and pressure pulsatility derived from arterial tonometry (carotid-femoral pulse wave velocity [CFPWV], forward wave amplitude [FWA], and augmentation index) were examined over a 7-year period in 1,759 participants (average age, 60 years). The primary outcome measures were blood pressure and incident hypertension during examination cycle 8. The secondary outcomes were CFPVW, FWA, and augmentation index during examination cycle 8.

The researchers found that aortic stiffness, central FWA, and wave reflection were jointly associated with future systolic blood pressure, pulse pressure, and incident hypertension. Initial blood pressure traits were associated with future FWA and augmentation index but not with aortic stiffness assessed by CFPWV.

Brachial artery measures of microvascular resistance and endothelial function were jointly associated with incident hypertension after considering blood pressure and tonometry variables.

“Our data suggest that aortic stiffness, central pressure pulsatility, peripheral wave reflection, large artery endothelial function, and microvascular function jointly antedate and potentially contribute to the development of clinical hypertension. Arterial stiffness and function may therefore be important potential targets for interventions aimed at preventing incident hypertension,” the authors write.

(JAMA. 2012;308[9]:875-881. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported through contracts with the National Institutes of Health, National Heart, Lung, and Blood Institute, and a grant from the Donald W. Reynolds Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Atherogenic Vascular Stiffness and Hypertension – Cause or Effect?

In an accompanying editorial, Debabrata Mukherjee, M.D., M.S., of the Texas Tech University Health Sciences Center, El Paso, writes that the “implications of the study by Kaess et al for prevention may be substantial.”

“By concentrating on the underlying drivers of chronic diseases like hypertension and atherosclerosis, clinicians may be able to move from today’s sick care system to a true health care system that encourages health and well-being. If prospective studies validate both prevention of hypertension and improved cardiovascular outcomes using lifestyle modifications as well as a combination therapy approach in individuals with vascular stiffness, endothelial dysfunction, or both, before hypertension develops, such a strategy could become a cornerstone of a national preventive strategy.”

(JAMA. 2012;308[9]:919-920. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of interest and reported receiving royalties from Lippincott Williams & Wilkins for editing 1001 Questions: An Interventional Cardiology Board Review and from Informa Healthcare Books for editing Cardiovascular Catheterization and Intervention.

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EMBARGOED FOR EARLY RELEASE: 1 A.M. (CT) MONDAY, AUGUST 27, 2012

Media Advisory: To contact corresponding author Nicolas Danchin, M.D., Ph.D., email nicolas.danchin@egp.aphp.fr.

CHICAGO – The overall rate of death in patients hospitalized with ST-segment elevation myocardial infarction (STEMI; a certain pattern on an electrocardiogram following a heart attack) decreased from 1995 to 2010 in France, with possible factors associated with this decline including an increase in the proportion of STEMI patients who were women younger than age 60, and an increase in the use of reperfusion therapy and recommended therapeutic measures following a heart attack, according to a study being published online by JAMA. The study is being released early to coincide with its presentation at the European Society of Cardiology Congress.

“Several sources, including registries specific to acute myocardial infarction [AMI; heart attack] and large administrative or billing databases, have shown a decrease in mortality in patients with STEMI over the past 10 to 15 years. This decline is usually attributed to increased use and improved delivery of reperfusion therapy, in particular primary percutaneous coronary intervention (PCI; procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries). We hypothesized that, beyond primary PCI, other factors such as temporal changes in patient population characteristics may account for part of the observed reduction in mortality of patients with STEMI,” the authors write.

Etienne Puymirat, M.D., of the Hôpital Européen Georges Pompidou, Paris, and colleagues conducted a study to assess the association between changes in early mortality following STEMI and patient management and risk profile. The researchers analyzed data from four 1-month French nationwide registries, conducted 5 years apart (in 1995, 2000, 2005 and 2010), which included a total of 6,707 STEMI patients admitted to intensive care or coronary care units.

During the study period, the average age of patients with STEMI declined from 66.2 years to 63.3 years, and history of cardiovascular disease, such as heart attack, heart failure, peripheral artery disease, stroke or transient ischemic attack also decreased. The proportion of younger women (60 years or less) with STEMI increased from 11.8 percent to 25.5 percent, consistent with their increased prevalence of smoking (from 37.3 percent to 73.1 percent) and obesity (from 17.6 percent to 27.1 percent). The proportion of younger patients developing STEMI despite not having hypertension, diabetes, or hypercholesterolemia increased markedly, particularly in younger women.

The authors also found that the use of reperfusion therapy increased over time, from 49.4 percent to 74.7 percent, with more frequent use of primary PCI, (11.9 percent to 60.8 percent). The use of evidence-based treatments during the first 48 hours from admission increased gradually over the 15-year period, including the early use of b-blockers, ACE inhibitors or angiotensin-receptor blockers, and statins. Also, there was increasing early use of antiplatelet agents and low-molecular-weight heparins.

Thirty-day mortality decreased from 13.7 percent in 1995 to 4.4 percent in 2010; mortality decreased from 9.8 percent to 2.6 percent in men and from 23.7 percent to 9.8 percent in women. Consistent with the decrease in mortality, major hospital complications of STEMI also decreased over this time period.

In addition, time from symptom onset to hospital admission decreased, with a shorter time from onset to first call, and broader use of mobile intensive care units.

“The progressive decline in early mortality over time observed in the present nationwide surveys is consistent with many other sources in the United States and Europe,” the authors note.

“Within the STEMI population targeted by these sequential registries, the relative proportion of older patients has decreased, while the proportion of younger men and the proportion and numbers of younger women have increased. These observations suggest that future reductions in the incidence and mortality related to AMI will need specific targeting of preventive measures toward younger women and possibly younger men.”

(doi:10.1001/2012.jama.11348. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 1 A.M. (CT) SUNDAY, AUGUST 26, 2012

Media Advisory: To contact James K. Min, M.D., call Sally Stewart at 310-423-4768 or email sally.stewart@cshs.org. To contact editorial author Manesh R. Patel, M.D., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

CHICAGO – Among patients with suspected or known coronary artery disease, use of a method that applies computational fluid dynamics to derive certain data from computed tomographic (CT) angiography demonstrated improved diagnostic accuracy vs. CT angiography alone for the diagnosis of ischemia, according to a study being published online by JAMA. The study is being released early to coincide with its presentation at the European Society of Cardiology Congress.

“Coronary computed tomographic angiography is a noninvasive anatomic test for diagnosis of coronary stenosis [narrowing of a blood vessel] that does not determine whether a stenosis causes ischemia [inadequate blood supply]. In contrast, fractional flow reserve (FFR) is a physiologic measure of coronary stenosis expressing the amount of coronary flow still attainable despite the presence of a stenosis, but it requires an invasive procedure. Noninvasive FFR computed from CT (FFR_CT) is a novel method for determining the physiologic significance of coronary artery disease (CAD), but its ability to identify ischemia has not been adequately examined to date,” according to background information in the article.

James K. Min, M.D., of the Cedars-Sinai Heart Institute, Los Angeles, and colleagues conducted a study to evaluate the performance of noninvasive FFR_CT compared with an invasive FFR reference standard for diagnosis of ischemia. The study included 252 patients with suspected or known CAD from 17 centers in 5 countries who underwent CT, invasive coronary angiography (ICA), FFR, and FFR_CT between October 2010 and October 2011. About 77 percent of patients had experienced angina within the last month. Ischemia was defined by certain criteria. Anatomically obstructive CAD was defined by a stenosis of 50 percent or larger on CT and ICA. Among 615 study vessels, 271 had less than 30 percent stenosis and 101 had at least 90 percent stenosis.

Among study participants, 137 (54.4 percent) had an abnormal FFR as determined by ICA. The researchers found that the diagnostic accuracy for FFR_CT plus CT was 73 percent, which did not meet a prespecified primary end point for accuracy (as pre-specified based on the lower limit of a calculated 95 percent confidence interval). By comparison, diagnostic accuracy of CT alone for detecting coronary lesions with stenosis of 50 percent or greater, was 64 percent. When comparing FFR_CT alone with CT alone for detecting these lesions, FFR_CT demonstrated superior discrimination.

“On a per-patient basis, diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of FFR_CT plus CT were 73 percent, 90 percent, 54 percent, 67 percent, and 84 percent, respectively,” the authors write. They note that the sensitivity and negative predictive value of FFR_CT were high, indicating a low rate of false-negative studies. “These diagnostic features of FFR_CT may encourage a greater sense of diagnostic certainty that patients who undergo CT who have ischemia are not overlooked, such that clinicians may be confident in not proceeding to invasive angiography in patients with stenoses on CT when FFR_CT results are normal.”

“Taken together, these study results suggest the potential of FFR_CT as a promising noninvasive method for identification of individuals with ischemia.”

(doi:10.1001/2012.jama.11274. Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Detecting Obstructive Coronary Disease With CT Angiography and Noninvasive Fractional Flow Reserve

In an accompanying editorial, Manesh R. Patel, M.D., of Duke University Medical Center, Durham, N.C., writes that future studies with the FFR_CT technology “should be aimed at diagnostic strategies involving patients with varying pretest risks, thereby providing information on the incremental benefit from the test.”

“Additionally, important comparison technologies beyond invasive angiography are needed, although improved access techniques and safety of invasive FFR may make it a plausible comparator. In addition to diagnostic performance, other outcomes of interest such as resource utilization and clinical outcomes should be captured. Finally, future studies will need to have local sites rather than core laboratories perform, analyze, and interpret the images to provide a sense of real-world function. It is with these types of continued rigorous studies that noninvasive technologies such as FFR_CT plus CT may move the clinical community closer to the holy grail of a high-quality combined anatomic and functional test for detection of CAD that improves efficiency and patient outcomes.”

(doi:10.1001/2012.jama.11383. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 21, 2012

Preventing Patient Harms Through Systems of Care

Peter J. Pronovost, M.D., Ph.D., of the Johns Hopkins Medical Institutions, Baltimore, and George W. Bo-Linn, M.D., M.H.A., of the Gordon and Betty Moore Foundation, Palo Alto, Calif., discuss the problem of preventable harms to patients, which include adverse drug events, catheter-associated urinary tract infections, central line-associated bloodstream infections, and pressure ulcers. The authors suggest “clinicians can reduce patient harm in the same way that engineers manage dynamic complexity: as a systems problem that requires an interdisciplinary systems solution.”

“It is time for the science of health care delivery to mature and embrace systems engineering. It is time for health care to embrace the compelling goal of reducing preventable patient harm. By systematically addressing all the known harms patients may experience, clinicians may realize this goal and, by doing so, improve health care and reduce costs of care, ultimately improving value for the nation and its citizens.”

(JAMA. 2012;308[8]:769-770. Available pre-embargo to the media at https://media.jamanetwork.com)

Transforming Quality of Care and Improving Outcomes After Acute Ml – Lessons From the National Registry of Myocardial Infarction

William J. French, M.D., of the Harbor-UCLA Medical Center, Torrance, Calif., and colleagues write that the “National Registry of Myocardial Infarction (NRMI) was the leading cardiovascular disease (CVD) patient registry from 1990 to 2006 in both size and duration. Notably, the various analyses and publications that resulted from the NRMI had direct and substantial effects in improving quality care for acute myocardial infarction treatment in the United States.” In this Viewpoint, the authors discuss the history of the NRMI, and building on the NRMI model.

“As health care practice and treatment options evolve, patient registries remain an important tool for evaluating the interface among patients, physicians, and sites of care. The NRMI was a remarkable achievement and unexpectedly successful in transforming CVD care, in part because it set a high standard for observational research and met an emerging need in the U.S. health care system. The legacy of the NRMI is a model to build upon.”

(JAMA. 2012;308[8]:771-772. Available pre-embargo to the media at https://media.jamanetwork.com)

The Value of Statistical Analysis Plans in Observational Research – Defining High-Quality Research From the Start

Laine Thomas, Ph.D., of the Duke University School of Medicine, Durham, N.C., and Eric D. Peterson, M.D., M.P.H., of the Duke Clinical Research Institute, and Contributing Editor, JAMA, suggest that there needs to be improvement in defining standards for reporting observational research, and that “the concepts for improving observational research can be operationalized via use of a formal, prospectively defined statistical analysis plan (SAP).” The authors discuss the development and potential benefits of the use of an SAP.

“The process of writing and submitting an SAP captures many of the attributes of clinical trials, without excessive rigidity that would inhibit exploratory research. It requires extra work on the front end but greater efficiency and clarity in producing and reporting results. Current practice may be augmented by making the SAP publicly available as online ancillary material. This would allow readers to confirm and, if desired, replicate the methods used in the study.”

(JAMA. 2012;308[8]:773-774. Available pre-embargo to the media at https://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, AUGUST 21, 2012

Media Advisory: To contact co-author Michiel L. Bots, M.D., Ph.D., email m.l.bots@umcutrecht.nl.

CHICAGO – In an analysis of data from previously published studies that included more than 45,000 patients, the value of adding to the Framingham Risk Score a measure of the common carotid artery intima-media thickness (CIMT; a measurement of the thickness of the carotid artery wall) in 10-year risk prediction of first-time heart attack or stroke was small and unlikely to be of clinical importance, according to an article in the August 22/29 issue of JAMA.

“Cardiovascular disease is among the leading causes of morbidity and mortality worldwide. Preventive treatment of high-risk asymptomatic individuals depends on accurate prediction of a person’s risk to develop a cardiovascular event. Currently, cardiovascular risk prediction in asymptomatic individuals is based on the level of cardiovascular risk factors incorporated in scoring equations. Several scores are available, with the Framingham Risk Score (FRS) among the most widely used. These risk equations perform reasonably well, yet there remains considerable overlap in estimated risk between those who are affected by a cardiovascular event and those who are not,” according to background information in the article.

Measurement of CIMT has been proposed to be added to cardiovascular risk factors to improve individual risk assessment. “So far, individual studies reported on the added value of CIMT measurements in cardiovascular risk prediction, but the evidence is not consistent across studies,” the authors write.

Hester M. Den Ruijter, Ph.D., of the University Medical Center Utrecht, the Netherlands, and colleagues conducted a meta-analysis to determine whether common CIMT has added value in 10-year risk prediction of first-time heart attacks or strokes, above that of the Framingham Risk Score. The authors searched the medical literature and identified relevant studies for inclusion in the analysis. Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time heart attack or stroke.

This analysis included 14 studies contributing data for 45,828 individuals. During a median (midpoint) follow-up of 11 years, 4,007 first-time heart attacks or strokes occurred. The researchers refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time heart attack or stroke in both models. More than 90 percent of the individuals remained in the same risk category. The numbers of individuals shifting downward or upward without and with events were similar. The net reclassification improvement with the addition of common CIMT was small (0.8 percent were correctly reclassified). In those at intermediate risk, the net reclassification improvement was 3.6 percent in all individuals, with no differences between men and women.

“Our results suggest that common CIMT measurements should not routinely be performed in the general population, as the overall added value may be too limited to result in health benefits,” the authors write. “However, as the interest in risk prediction is currently shifting from a 10-year risk to lifetime risk, the added value of a CIMT measurement and its cost-effectiveness using a horizon of 20 to 30 years may be worthwhile to explore.”

(JAMA. 2012;308[8]:796-803. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project is supported by a grant from the Netherlands Organisation for Health Research and Development. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 21, 2012

Media Advisory: To contact David Preiss, M.D., Ph.D., email david.preiss@glasgow.ac.uk.

CHICAGO – Although some studies have suggested that use of lipid-lowering therapies may increase the risk of pancreatitis, an analysis that involved pooling of data from previous studies and included more than 150,000 participants found that statin therapy was associated with a reduction in the risk of pancreatitis in patients with normal or mildly elevated triglyceride levels, according to an article in the August 22/29 issue of JAMA.

“Pancreatitis has a clinical spectrum ranging from a mild, self-limiting episode to a severe or fatal event. Case reports and pharmacoepidemiology studies have claimed that statins may cause pancreatitis, although few of these studies comprehensively considered confounding factors. Very few large randomized trials of statin therapy have published data on incident pancreatitis,” according to background information in the article. “Although lipid guidelines recommend fibrate therapy to reduce pancreatitis risk in persons with hypertriglyceridemia, fibrates may lead to the development of gallstones, a risk factor for pancreatitis.”

David Preiss, M.D., Ph.D., of the University of Glasgow, United Kingdom, and colleagues examined the associations between use of a statin or a fibrate and the incidence of pancreatitis by conducting collaborative meta-analyses of published and unpublished data from large randomized clinical trials. The authors conducted a search of the medical literature to identify relevant studies for inclusion in the analysis.

In 16 placebo- and standard care-controlled statin trials with 113,800 participants conducted over 4.1 years, 309 participants (0.27 percent) developed pancreatitis (134 assigned to statin, 175 assigned to control; a 23 percent lower risk of pancreatitis for those assigned to statin therapy). In 5 dose-comparison statin trials with 39,614 participants conducted over 4.8 years, 156 participants (0.39 percent) developed pancreatitis (70 assigned to intensive dose, 86 assigned to moderate dose; an 18 percent lower risk for the intensive dose group).

In the combined data set of 21 trials, 465 participants (0.30 percent) developed pancreatitis (of whom 204 were assigned to statin therapy or intensive-dose statin therapy and 261 were assigned to placebo, standard care, or moderate-dose statin therapy, respectively), a 21 percent lower risk.

Seven randomized clinical trials of fibrate therapy (4 with published data and 3 with unpublished data regarding incident pancreatitis) provided data on 40,162 participants over a weighted average follow-up period of 5.3 years. Baseline average triglyceride levels in the trials varied from 145 mg/dL to 184 mg/dL. During this time, 144 participants (0.36 percent) developed pancreatitis (84 assigned to fibrate therapy, 60 assigned to placebo), but the risk difference was not statistically significant.

“Although the present results for both statins and fibrates should be considered hypothesis-generating and the number of pancreatitis cases was small in this trial population at low risk of pancreatitis, the analysis raises questions regarding the choice of lipid-modifying agents in patients with hypertriglyceridemia. In those with slightly elevated triglyceride levels, statins appear better supported by the available data than fibrates for preventing pancreatitis. Lifestyle modifications also remain important to improve lipid profiles in such individuals. In patients with severe hypertriglyceridemia, a trial comparing fibrates and statins for preventing pancreatitis would be clinically valuable,” the authors write.

(JAMA. 2012;308[8]:804-811. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was not supported by external funding. Dr. Welsh is supported by a British Heart Foundation fellowship grant. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 21, 2012

Media Advisory: To contact corresponding author Stephan Windecker, M.D., email stephan.windecker@insel.ch. To contact editorial co-author Adnan Kastrati, M.D., email kastrati@dhm.mhn.de.

CHICAGO – Compared with a bare-metal stent, the use of a stent with a biodegradable polymer that releases the drug biolimus resulted in a lower rate of major adverse cardiac events at 1 year among patients with ST-segment elevation myocardial infarction (STEMI; a certain pattern on an electrocardiogram following a heart attack) undergoing primary percutaneous coronary intervention (PCI; procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries), according to a study in the August 22/29 issue of JAMA.

“The efficacy and safety of drug-eluting [releasing] stents compared with bare-metal stents remains controversial in patients with STEMI undergoing primary PCI,” according to background information in the article. “Early generation drug-eluting stents releasing sirolimus or paclitaxel from durable polymers reduce the need for repeat revascularization compared with bare-metal stents. However, vessel healing is delayed with evidence of chronic inflammation related at least in part to the persistence of durable polymer components in patients with acute STEMI. … Newer-generation drug-eluting stents with biodegradable polymers provide controlled drug release with subsequent degradation of the polymer rendering the stent surface more closely to a bare-metal stent after the period of biodegradation.”

Lorenz Räber, M.D., of Bern University Hospital, Bern, Switzerland, and colleagues compared the efficacy and safety of stents eluting biolimus from a biodegradable polymer with bare-metal stents of otherwise identical design. The randomized controlled trial included 1,161 patients with STEMI at 11 sites in Europe and Israel between September 2009 and January 2011. Clinical follow-up was performed at 1 and 12 months. Patients were randomized to receive the biolimus-eluting stent (n = 575) or the bare-metal stent (n = 582). The primary outcome measured for the study was the rate of major adverse cardiac events, a composite of cardiac death, target vessel-related reinfarction, and ischemia-driven target-lesion revascularization at 1 year. The average age of patients was 61 years and 79 percent were men.

The researchers found that at one year, the primary end point of major adverse cardiac events occurred in 4.3 percent of patients receiving biolimus-eluting stents and 8.7 percent of patients receiving bare-metal stents, which is a significant 4.4 percent absolute reduction and 51 percent relative reduction in the risk of major adverse cardiac events (and the prevention of 42 events per 1,000 patients treated with biolimus-eluting stents compared with bare-metal stents at 1 year). “For cardiac death alone, the percentages were smaller [(2.9 percent vs. 3.5 percent, respectively]. The treatment effect in favor of patients receiving biolimus-eluting stents was attributable to both a lower risk of target vessel-related reinfarction (0.5 percent vs. 2.7 percent) and ischemia-driven target-lesion revascularization (1.6 percent vs. 5.7 percent).”  At 1 year, rates of definite stent thrombosis amounted to 0.9 percent among patients receiving biolimus-eluting stents and 2.1 percent among patients receiving bare-metal stents.

The authors also observed no differences in all-cause and cardiac mortality between the groups at 1 year. “In addition to the device-oriented primary outcome measure, we recorded a lower risk of the comprehensive patient-oriented composite of death, any reinfarction, and any revascularization in favor of biolimus-eluting stents (8.4 percent vs. 12.2 percent).”

“… our results suggest better clinical outcomes in terms of major adverse cardiac events of a stent releasing biolimus from a biodegradable polymer compared with a bare-metal stent for the treatment of patients with STEMI.”

(JAMA. 2012;308[8]:777-787. Available pre-embargo to the media at https://media.jamanetwork.com)

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

Please Note: 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, August 21 at this link.

Editorial: New-Generation Drug-Eluting Stents for Patients With Myocardial Infarction

In an accompanying editorial, Salvatore Cassese, M.D., and Adnan Kastrati, M.D., of the Technische Universitat, Munich, Germany, write that the findings from this study (COMFORTABLE AMI) and from a series of previous trials on drug-eluting stents (DESs) in patients with heart attack provide several important lessons.

“First, the efficacy of DESs vs. bare-metal stents (BMSs) in STEMI is already established and, therefore, further studies comparing these interventions might not be needed. Second, concerns about a possible very late safety issue with DESs are apparently DES-type specific, mostly related to first-generation DESs and less justified with newer DESs. Larger randomized trials with longer follow-up and head-to-head comparisons of the available DES technologies are, however, required to completely eliminate these concerns. These studies should also take broader advantage of intravascular imaging technologies to provide mechanistic insights into the clinical findings. Third, although there is almost no rationale for performing DES vs. BMS studies anymore, it might be conceivable to expect studies that test the hypothesis of noninferiority of new, improved BMSs to available DESs. Until then, recent studies such as the COMFORTABLE AMI trial should make cardiologists feel more comfortable with the use of new-generation DESs in patients with STEMI.”

(JAMA. 2012;308[6]:619-620. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by the European Commission. Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Kastrati holds a patent related to polymer-free sirolimus and probucol coating and reported receiving honoraria from Abbott, Biosensors, Cordis, and Medtronic. Dr. Cassese reports no conflicts.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 21, 2012

Media Advisory: To contact Joseph Yeboah, M.D., M.S., call Marguerite Beck at 336-716-2415 or email marbeck@wakehealth.edu. To contact editorial co-author J. Michael Gaziano, M.D., M.P.H., call Lori Schroth at 617-534-1604 or email ljschroth@partners.org.

CHICAGO – In a comparison of novel cardiovascular risk markers, coronary artery calcium, ankle-brachial index, high-sensitivity C-reactive protein, and family history were independent predictors of coronary heart disease/cardiovascular disease in intermediate-risk individuals beyond traditional risk factors, with coronary artery calcium providing superior discrimination and risk reclassification compared with other risk markers, according to a study in the August 22/29 issue of JAMA.

“Current trends in primary prevention of cardiovascular disease (CVD) emphasize the need to treat individuals based on their global cardiovascular risk. Accordingly, practice guidelines recommend approaches to classify individuals as high, intermediate, or low risk using the Framingham Risk Score (FRS) or other similar CVD risk prediction models. However, there is increasing recognition of the imprecision of these classifications such that the intermediate-risk group actually represents a composite of higher-risk individuals for whom more aggressive (i.e., drug) therapy might be indicated. The intermediate-risk group also contains lower-risk individuals in whom CVD might be managed with lifestyle measures alone. This recognition has motivated researchers to identify markers that could offer greater discrimination of higher- and lower-risk patients within the intermediate-risk group,” according to background information in the article.

“Risk markers including coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial index (ABI), brachial flow-mediated dilation (FMD), high-sensitivity C-reactive protein (CRP), and family history of coronary heart disease (CHD) have been reported to improve on the Framingham Risk Score for prediction of CHD, but there are no direct comparisons of these markers for risk prediction in a single cohort,” the authors write.

Joseph Yeboah, M.D., M.S., of the Wake Forest University School of Medicine, Winston-Salem, N.C., and colleagues assessed the improvements in CHD/CVD prediction accuracy and reclassification to high- and low-risk categories using CIMT, CAC, FMD, ABI, high-sensitivity CRP, and family history of CHD in asymptomatic adults classified as intermediate risk who participated in the Multi-Ethnic Study of Atherosclerosis (MESA). Of 6,814 MESA participants from 6 U.S. field centers, 1,330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002, with follow-up through May 2011. Analysis was conducted to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity. Incident CHD was defined as heart attack, angina followed by revascularization, resuscitated cardiac arrest, or CHD death. Incident CVD additionally included stroke or CVD death.

After a median (midpoint) follow-up of 7.6 years, 94 participants (7.1 percent) experienced a CHD event and 123 (9.2 percent) experienced a CVD event. After analyses, the researchers found that each of the novel risk markers was associated with incident CHD; however, after adjusting for confounders, the associations with CIMT and FMD were no longer significant. Among all of the risk markers, CAC had the strongest association. Similarly, for incident CVD, each of the markers was associated with events except high-sensitivity CRP. However, after adjusting for confounders, the associations between CIMT and FMD were no longer significant. CAC also had the strongest association in the multivariable models for CVD.

“The current study shows that among 6 of the most promising novel risk markers, CAC provides the highest improvement in discrimination over the FRS and Reynolds score (RS) in individuals classified as intermediate risk. The present study provides additional support for the use of CAC as a tool for refining cardiovascular risk prediction in individuals classified as intermediate risk by the FRS or the RS,” the authors write. “Additional research is warranted to explore further both the costs and benefits of CAC screening in intermediate-risk individuals.”

(JAMA. 2012;308[8]:788-795. Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Cardiovascular Risk Assessment in the 21st Century

In an accompanying editorial, J. Michael Gaziano, M.D., M.P.H., of the Boston VA Healthcare System, Brigham and Women’s Hospital, Harvard Medical School, Boston, (and Contributing Editor, JAMA), and Peter W. F. Wilson, M.D., of the Atlanta VA Medical Center and Emory Clinical Cardiovascular Research Institute, comment on the two studies in this issue of JAMA on assessing cardiovascular risk.

“These reports illustrate the means by which the enhancement of a given model such as FRS with additional data is evaluated. Area under the receiver operating characteristic curve has been used for many diagnostic tests. A clinically useful approach describes the proportion of individuals who are reclassified, known as the net reclassification index. However, not all reclassifications are created equally. Refining risk estimation at the low or high end of the risk spectrum is not helpful because it will not likely alter management. On the other hand, reclassification can assist in decision making for patients who are near clinical decision boundaries. For this reason, both studies provided information on the reclassification that occurred among those at 5 percent to 20 percent risk. In this intermediate range, risk estimates inform clinical decisions about certain interventions.”

(JAMA. 2012;308[8]:816-817. Available pre-embargo to the media at https://media.jamanetwork.com)

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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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 14, 2012

Media Advisory: To contact the corresponding author for the first study, Takeshi Tanigawa, M.D., Ph.D., email tt9178tt9178@gmail.com. To contact the corresponding author for the second study, Masaharu Tsubokura, M.D., email tsubokura-tky@umin.ac.jp.

CHICAGO – The results of two studies in the August 15 issue of JAMA report on the psychological status of workers at the Fukushima nuclear power plants in Japan several months after the earthquake and tsunami in March 2011, and the amount of internal radiation exposure among residents of a city north of the power plant that experienced a meltdown.

As reported in a Research Letter, Jun Shigemura, M.D., Ph.D., of the National Defense Medical College, Saitama, Japan, and colleagues examined the psychological status of Fukushima workers 2 to 3 months after the disaster for symptoms of general psychological distress, including posttraumatic stress response (PTSR). The study included all full-time workers from the Daiichi plant (n = 1,053; plant experienced meltdown) and Daini plant (n = 707; plant experienced damage but remained intact) in May and June 2011. Using a self-report questionnaire, the researchers assessed sociodemographic characteristics and disaster-related experiences, including discrimination/slurs because the electric company that managed these plants was criticized for their disaster response and the workers have been targets of discrimination. Measures of general psychological distress included feeling nervous, hopeless, restless/fidgety, depressed, and worthless in the last 30 days.

Of 1,760 eligible workers, 1,495 (85 percent) participated (Daiichi: n = 885 [84 percent]; Daini: n = 610 [86 percent]). The authors found that compared with Daini workers, Daiichi workers were more often exposed to disaster-related stressors. Experiencing discrimination or slurs was not statistically significantly different between groups (14 percent vs. 11 percent). The researchers found that general psychological distress and PTSR were common in nuclear plant workers 2 to 3 months after the disaster. “Daiichi workers had significantly higher rates of psychological distress (47 percent vs. 37 percent) and PTSR (30 percent vs. 19 percent). For both groups, discrimination or slurs were associated with high psychological distress and high PTSR. Other significant associations in both groups included tsunami evacuation and major property loss with psychological distress and pre-existing illness and major prop­erty loss with PTSR.”

(JAMA. 2012;308[7]:667-669. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by Health and Labour Sciences Research Grants from the Ministry of Health Labour and Welfare of Japan. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Study Finds Low Levels of Radiation Exposure to Residents of City North of Meltdown

In another Research Letter, Masaharu Tsubokura, M.D., of the University of Tokyo, and colleagues conducted a study to gauge the level of radiation exposure to residents of the city of Minamisoma, located 14 miles north of the Fukushima Daiichi nuclear plant. “Release of radioactive material into the air, water, and soil raised concern about internal radiation exposure and the long-term risk of cancer in nearby residents,” they write.

Many residents were evacuated after the meltdown, but by August 2011, approximately half had returned. A voluntary screening program for levels of cesium, known to be representative of total internal radiation exposure, was conducted between September 2011 and March 2012 for all residents ages 6 years or older. Total cesium exposure was converted into committed effective dose (sievert, Sv). Common dose-limit recommendations for the public are 1 mSv or less. A total of 9,498 residents enrolled in the study, 24 percent of the registered population on August 15, 2011. The sample consisted of 1,432 children and 8,066 adults. A total of 3,286 individuals (34.6 percent) had detectable levels of cesium, including 235 children (16.4 percent) and 3,051 adults (37.8 percent). Committed effective doses were less than 1 mSv in all but 1 resident (1.07 mSv).

“To our knowledge, this is the first report on internal exposure to cesium radiation after the Fukushima Daiichi nuclear plant incident. In this sample, exposure levels were low in most adults and children tested and much lower than those reported in studies years after the Chernobyl incident. Even the highest levels of contamination observed are below the thresholds for the administration of Prussian blue [an antidote used in the treatment of cesium poisoning],” the authors write.

The researchers note that because this screening program started 6 months after the nuclear power plant disaster, higher exposure levels might have been detected earlier, and that it is not possible to ascertain whether the low levels of exposure were due to low ongoing exposure or decay from high exposure values. “Because data were collected from volunteers, the results may not be representative of the entire population in contaminated areas. No case of acute health problems has been reported so far; however, assessments of the long-term effect of radiation requires ongoing monitoring of exposure and the health conditions of the affected communities.”

(JAMA. 2012;308[7]:669-670. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 14, 2012

Preventing Suicides in U.S. Service Members and Veterans – Concerns After a Decade of War

Charles W. Hoge, M.D., of the Walter Reed Army Institute of Research, Silver Spring, Md., and Carl A. Castro, Ph.D., of the U.S. Army Medical Research and Materiel Command, Fort Detrick, Md., write that “between 2005 and 2009, the incidence of suicide in Army and Marine personnel nearly doubled. From 2009 through the first half of 2012, the incidence of suicide among Army soldiers remained elevated (22 per 100,000 per year), with the number dying of suicide each year exceeding the number killed in action.” In this Viewpoint, the authors discuss issues such as screening and risk assessment, education and public awareness, and treatment.

“The most important challenges in suicide prevention are stigma surrounding mental illness, negative perceptions of treatment, and other barriers (including confidentiality concerns in the military setting) that result in the majority of service members and veterans not accessing care when needed or dropping out prematurely. It is imperative that intervention strategies—and research efforts—prioritize patient engagement and satisfaction, screening for underlying mental disorders in primary care, care coordination, capacity for timely appointments, effective treatment, and reinforcing protective effects of family and peer connections.”

(JAMA. 2012;308[7]:671-672. Available pre-embargo to the media at https://media.jamanetwork.com)

The State of the World’s Refugees – Adapting Health Responses to Urban Environments

Antonio Guterres, M.Eng., United Nations High Commissioner for Refugees, Geneva, Switzerland, and Paul Spiegel, M.D., M.P.H., of the Office of the United Nations High Commissioner for Refugees, write that the “forced displacement of populations, across borders and within their own countries, is one of the most visible and enduring manifestations of persecution and conflict. At the end of 2011, more than 42 million people had been forcibly displaced from their homes by conflict, including 15 million refugees and 26 million internally displaced people.”  They note that a phenomenon of urbanization is affecting refugees and displaced people, with 58 percent of adult refugees living in cities. The authors discuss the challenges and consequences of this urbanization issue, and address health needs and initiatives that have been beneficial.

“Innovations in access to care will have a meaningful effect only if they form part of a comprehensive protection-based approach addressing the needs of refugees and internally displaced people across a range of sectors, including livelihoods, education, nutrition, water and sanitation, and the environment. Only by addressing these in an integrated manner, within a framework that promotes self-reliance and durable solutions, will reductions in morbidity and mortality be achieved, along with a real improvement in the quality of life for the world’s 40 million refugees and displaced persons—until they can return home.”

(JAMA. 2012;308[7]:673-674. Available pre-embargo to the media at https://media.jamanetwork.com)

A Framework for Catastrophic Disaster Response

Dan Hanfling, M.D., of the Inova Health System, Falls Church, Va., and colleagues write that the Japanese tsunami, Haitian earthquake, and Gulf Coast hurricane offered stark reminders of how vulnerable organized societies are to catastrophic events. In this Viewpoint, the authors examine 3 critical components of catastrophic disaster preparedness: the development of crisis standards of care; development of a “systems” approach that ensures integration among key stakeholders; and meaningful engagement with health professionals and the public.

“To reduce morbidity and death, and to ensure democratic accountability, the government and health system at every level will need to plan carefully, adopt ethically rigorous standards, and meaningfully engage professionals. What is most important is that government and stakeholders—from local communities to states and nationally—design and test a rigorous response well in advance of a major disaster.”

(JAMA. 2012;308[7]:675-676. Available pre-embargo to the media at https://media.jamanetwork.com)

Sexual Violence as a Weapon of War

Lindsay Stark, Dr.P.H., and Mike Wessells, Ph.D., of the Mailman School of Public Health, Columbia University, New York, write that there is an increased understanding that rape is used as a strategic and systematic tactic during armed conflict. In this Viewpoint, the authors examine why sexual violence is an effective weapon of war, its health and psychosocial sequelae, and its association with other forms of gender-based violence.

“To aid prevention and support survivors, additional research is needed to address important questions. For example, in different conflict settings, what proportion of sexual violence is perpetrated by soldiers and armed groups as opposed to partners, spouses, and other family members? To what extent do these forms of sexual violence have common or interrelated causes? How can steps toward prevention build on what is known about changing norms of abuse, discrimination, and devaluation of women in nonconflict settings? Which interventions—individual and communal— are most effective in supporting survivors? Particularly needed are assessments of different approaches to reducing the severe stigma and isolation that typically follow wartime sexual violence and for enhancing survivors’ coping skills. Answering these and related questions requires acknowledging sexual violence as a weapon of war and as a critical component of the public health research agenda in conflict-affected settings.”

(JAMA. 2012;308[7]:677-678. Available pre-embargo to the media at https://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, AUGUST 14, 2012

Media Advisory: To contact Katherine L. Mills, Ph.D., email k.mills@unsw.edu.au.

CHICAGO – Study participants who received an integrated treatment for posttraumatic stress disorder (PTSD) and substance dependence plus usual treatment for substance dependence showed significantly greater reductions in PTSD symptom severity compared with participants who only received usual treatment for substance dependence, according to a study in the August 15 issue of JAMA, a theme issue on violence and human rights.

“Prolonged exposure therapy, a cognitive-behavioral therapy involving exposure to memories and reminders of past trauma, has long been regarded as a gold standard treatment for PTSD,” according to background information in the article.  There is a concern, however, that exposure therapy may be inappropriate because of risk of relapse for patients with co-occurring substance dependence. “There is, however, an absence of evidence to support or refute this recommendation, because most trials of PTSD treatment have excluded individuals with substance dependence.”

Katherine L. Mills, Ph.D., of the University of New South Wales, Sydney, Australia, and colleagues conducted what is believed to be the first randomized controlled trial of an integrated treatment for PTSD and substance dependence that incorporates prolonged exposure therapy. The study enrolled 103 participants who met criteria for both PTSD and substance dependence. Participants were recruited from 2007-2009; outcomes were assessed at 9 months, with interim measures collected at 6 weeks and 3 months.  Participants were randomized to receive either an integrated treatment for PTSD and substance dependence called Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE), plus usual treatment for substance dependence (n = 55); or usual treatment alone (control) (n = 48). COPE consists of 13 individual 90-minute sessions (i.e., 19.5 hours) with a clinical psychologist.

The primary outcomes measured were changes in severity of PTSD symptoms and substance dependence.

The researchers found that from the beginning of the study to 9-month follow-up, significant reductions in PTSD symptom severity were found for both the treatment group and the control group; however, the treatment group demonstrated a significantly greater reduction in PTSD symptom severity compared with the control group.

By the 9-month follow-up, rates of substance dependence had decreased to 45.4 percent in the treatment group and 56.2 percent in the control group; however, the difference between groups was not statistically significant. Both the treatment and the control group also demonstrated significant reductions in severity of dependence from baseline to 9-month follow-up; however, the degree of change did not differ significantly between groups. Also, there were not any significant between-group differences in relation to changes in substance use, depression, or anxiety.

The researchers write that it is important to note that most participants randomized to receive COPE plus usual treatment continued to use substances throughout the study. “These findings challenge the widely held view that patients need to be abstinent before any trauma work, let alone prolonged exposure therapy, is commenced. Although we agree that patients need to show some improvement in their substance use and an ability to use alternative coping strategies before prolonged exposure therapy is initiated, findings from the present study demonstrate that abstinence is not required.”

(JAMA. 2012;308[7]:690-699. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by a Australian National Health and Medical Research Council project grant. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 14, 2012

Media Advisory: To contact Joanne Klevens, M.D., Ph.D., call Gail Hayes at 770-488-4902 or email shayes@cdc.gov. To contact editorial co-author C. Nadine Wathen, Ph.D., call Jeff Renaud at 519-661-2111, ext. 85165, or email jrenaud9@uwo.ca.

CHICAGO – In a study that included more than 2,700 women receiving care in primary care clinics, those who were screened for partner violence and received a partner violence resource list did not experience significant differences for several outcomes, including overall quality of life, general health, and recurrence of partner violence, compared to women who just received a partner violence resource list, according to a study in the August 15 issue of JAMA, a theme issue on violence and human rights.

“Recognition of partner violence as a health and public health problem has led numerous professional and health care organizations, as well as the Institute of Medicine, to recommend screening (i.e., testing asymptomatic patients to identify those requiring special intervention) or assessment of women for partner violence in primary care settings. However, the United States Preventive Services Task Force, the Canadian Task Force, and the United Kingdom’s Health Technology Assessment Program have concluded there is insufficient evidence to support this recommendation,” according to background information in the article.

Joanne Klevens, M.D., Ph.D., of the Centers for Disease Control and Prevention, Atlanta, and colleagues from Chicago area hospitals conducted a study to evaluate the effect of computer-based partner violence screening and distribution of local partner violence resource lists to women seeking care in outpatient clinical settings. The study was a 3-group randomized controlled trial at 10 primary health care centers in Cook County, Illinois. Participants were enrolled from May 2009 – April 2010, and included 2,364 women who were re-contacted 1 year after enrollment. The women were predominantly non-Latina African American (55 percent) or Latina (37 percent), had a high school education or less (57 percent), and were uninsured (57 percent).

The participants were randomized into 3 intervention groups: (1) partner violence screen (using the Partner Violence Screen instrument) plus a list of local partner violence resources if screening was positive (n = 909); (2) partner violence resource list only without screen (n = 893); and (3) no-screen, no-partner violence list control group (n = 898). For the Partner Violence Screen instrument, trained research assistants approached potential participants in each clinic’s waiting room to determine their interest and eligibility. Participants completed an audio-computer-assisted self-interview, which consisted of several questions regarding partner violence, in private rooms or kiosks equipped with touch-screen computers and headphones. Women who screened positive (affirmative response to 1 or more questions) were shown a brief video on the computer screen in which a partner violence advocate provided support and information about the hospital-based partner violence advocacy program and encouraged the viewer to seek help. Women who screened negative received the list of general resources only.

The primary outcomes measured for the study were quality of life (QOL, physical and mental health components, measured on the 12-item Short Form [scale range 0-100, average score of 50 for U.S. population]). Days lost from work or household activities, use of health care and partner violence services, and the recurrence of partner violence were secondary outcomes.

The researchers found that at 1-year follow-up, average scores on the QOL components and subscales ranged from 44 to 52 among all women with no statistically significant differences by study group status for any of the components or subscales. There were also no differences between groups in days unable to work or complete housework; number of hospitalizations, emergency department, or ambulatory care visits; or proportion who contacted a partner violence agency.

At follow-up, 9.9 percent of women (235/2,362) reported experiencing partner violence in the year before enrolling in the study and in the previous year (recurrence), with no statistically significant difference between study groups.

“In conclusion, the results of this study suggest providing a partner violence resource list with or without computerized screening of female adult patients in primary care settings does not result in significant benefits in terms of general health outcomes. These findings provide important information for clinicians and others to consider in light of recent professional recommendations calling for routine screening,” the authors write.

(JAMA. 2012;308[7]:681-689. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by the Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Division of Violence Prevention. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Sadowski reports receipt of consultancy fees from the World Health Organization. The other authors report no disclosures.

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, August 14 at this link.

Editorial: Health Care’s Response to Women Exposed to Partner Violence – Moving Beyond Universal Screening

In an accompanying editorial, C. Nadine Wathen, Ph.D., of Western University, London, Ontario, and Harriet L. MacMillan, M.D., M.Sc., F.R.C.P.C., of McMaster University, Hamilton, Ontario, write that this and another large-scale trial have shown that universal screening does not improve women’s health or life quality or reduce re-exposure to partner violence.

“It is time to enact an approach in which individual women are assessed according to their presenting histories, which include symptoms and risks. With exposure to partner violence being understood in the context of its health-relevant consequences, clinical teams may more effectively be able to address these issues. Although there may be emerging evidence regarding specific counseling and advocacy programs in reducing partner violence and improving health outcomes for women, replication in larger and more diverse samples using rigorous methods is required. Another important goal of research and policy, along with evaluation of primary prevention interventions, is to develop coordinated care models that will allow seamless referral and transition of women from the clinic to appropriate community-based services.”

(JAMA. 2012;308[7]:712-713. Available pre-embargo to the media at https://media.jamanetwork.com)

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 14, 2012

Media Advisory: To contact Candice M. Monson, Ph.D., call Suelan Toye at 416-979-5000, ext. 7161 or email stoye@ryerson.ca. To contact editorial author Lisa M. Najavits, Ph.D., call Gina DiGravio at 617-638-8480 or email gina.digravio@bmc.org.

CHICAGO – Among couples in which one partner was diagnosed as having posttraumatic stress disorder (PTSD), participation in disorder-specific couple therapy resulted in decreased PTSD symptom severity and increased patient relationship satisfaction, compared with couples who were placed on a wait list for the therapy, according to a study in the August 15 issue of JAMA, a theme issue on violence and human rights.

“There are well-documented associations between PTSD and intimate relationship problems, including relationship distress and aggression, and studies demonstrate that the presence of PTSD symptoms in one partner is associated with caregiver burden and psychological distress in the other partner. Although currently available individual psychotherapies for PTSD produce overall improvements in psychosocial functioning, these improvements are not specifically found in intimate relationship functioning. Moreover, it has been shown that even when patients receive state-of-the-art individual psychotherapy for the disorder, negative interpersonal relations predict worse treatment outcomes,” according to background information in the article.

Candice M. Monson, Ph.D., of Ryerson University, Toronto, Canada, and colleagues conducted a study to examine the effect of a cognitive-behavioral conjoint therapy (CBCT) for PTSD, designed to treat PTSD and its symptoms and enhance intimate relationships in couples. The randomized controlled trial, conducted from 2008 to 2012, included heterosexual and same-sex couples (n = 40 couples; n = 80 individuals) in which one partner met criteria for PTSD according to the Clinician-Administered PTSD Scale. Symptoms of PTSD, co-existing conditions, and relationship satisfaction were collected by assessors at the beginning of the study, at mid treatment (median [midpoint], 8 weeks after baseline), and at post-treatment (median, 16 weeks after baseline). An uncontrolled 3-month follow-up was also completed. Couples were randomly assigned to take part in the 15-session cognitive-behavioral conjoint therapy for PTSD protocol immediately (n = 20) or were placed on a wait list for the therapy (n = 20). Clinician-rated PTSD symptom severity was the primary outcome; intimate relationship satisfaction, patient- and partner-rated PTSD symptoms, and co-existing symptoms were secondary outcomes.

The researchers found that PTSD symptom severity and patients’ intimate relationship satisfaction were significantly more improved in couple therapy than in the wait-list condition. Also, change ratios (calculated by dividing the change in the CBCT condition from pretreatment to post-treatment by the change in the wait-list condition over this period) indicated that PTSD symptom severity decreased almost 3 times more in CBCT from pretreatment to post-treatment compared with the wait list; and patient-reported relationship satisfaction increased more than 4 times more in CBCT compared with the wait list.

The secondary outcomes of depression, general anxiety, and anger expression symptoms also improved more in CBCT relative to the wait list.

Treatment effects were maintained at 3-month follow-up.

“This randomized controlled trial provides evidence for the efficacy of a couple therapy for the treatment of PTSD and comorbid symptoms, as well as enhancements in intimate relationship satisfaction. These improvements occurred in a sample of couples in which the patients varied with regard to sex, type of trauma experienced, and sexual orientation. The treatment effect size estimates found for PTSD and comorbid symptoms were comparable with or better than effects found for individual psychotherapies for PTSD. In addition, patients reported enhancements in relationship satisfaction consistent with or better than prior trials of couple therapy with distressed couples and stronger than those found for interventions designed to enhance relationship functioning in nondistressed couples,” the authors write.

“Cognitive-behavioral conjoint therapy may be used to efficiently address individual and relational dimensions of traumatization and might be indicated for individuals with PTSD who have stable relationships and partners willing to engage in treatment with them.”

(JAMA. 2012;308[7]:700-709. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a National Institute of Mental Health grant to Dr. Monson. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Expanding the Boundaries of PTSD Treatment

Lisa M. Najavits, Ph.D., of the Veterans Affairs Boston Healthcare System and Boston University School of Medicine, comments in an accompanying editorial on the 2 studies in this issue of JAMA on treating PTSD.

“The results of the trials by Mills at al and Monson et al are important scientific attempts to study new options for treatment of PTSD. Overall, comparative studies of PTSD therapies find that they rarely outperform each other in efficacy. Thus, the cost and appeal of treatments to clinicians and patients, their intensity of intervention, and clinical setting and training issues may ultimately be as or more relevant than comparative efficacy in choosing a course of treatment for PTSD. In the current era, there is a focus on short-term treatments (in part an antidote to the overly long psychotherapies of much of the 20th century). However, it is not clear how long treatment needs to be maintained to produce enduring positive outcomes, especially for patients with PTSD and comorbidities and difficult social circumstances. The field of PTSD therapy is still young, and the pursuit of clinically meaningful treatments for all types of patients, like the process of recovery for patients with PTSD, is an ongoing challenge.”

(JAMA. 2012;308[7]:714-716. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of interest and reported receiving royalties from Guilford Press and New Harbinger Press and that she is director of Treatment Innovations, which provides consultation, training, and materials related to psychotherapy.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 7, 2012

Transcatheter Valve Replacement for Aortic Stenosis – Balancing Benefits, Risks, and Expectations

Chintan S. Desai, M.D., and Robert O. Bonow, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, write that “transcatheter aortic valve replacement (TAVR) represents a transformative technology with potential for the management of complex patients with aortic stenosis, including those who are not considered candidates for surgical aortic valve replacement because of age and medical comorbidities. Currently, more than 50,000 TAVR procedures have been performed worldwide, with mounting enthusiasm for the ‘rational dispersion’ of transcatheter therapies.”

The authors note that “the increasing consumer expectations that this therapy might become available soon for even young, low-risk patients requiring valve replacement must be balanced against safety concerns that have arisen in both clinical trials and registries.”

(JAMA. 2012;308[6]:573-574. Available pre-embargo to the media at https://media.jamanetwork.com)

The Importance of Potential Studies That Have Not Existed and Registration of Observational Data Sets

John P. A. Ioannidis, M.D., D.Sc., of the Stanford University School of Medicine, Stanford, Calif., examines the issue of potential studies that do not exist, studies that could readily have been conducted. “Is it possible to know the unknowable? It is important to consider why studies have not been conducted and what could be done about them. Related to this phenomenon is the continuing problem of unregistered, exploratory observational studies often derived from large data sets.”

“When the number of potential studies that have not existed is large, then the published literature is mostly a reflection of what is considered plausible and reasonable by experts in the field. Thousands of scientists could have data-peeked; their decision to generate and publish a full study with specific results is molded by their expectations and the expectations of peers. Although researchers often come across unexpected, implausible findings, data shaped into publishable studies are mostly those that seem orthodox to peers— plus some extravagant studies in which investigators venture bold claims. When only 1 percent of the potential studies see the light of day, this 1 percent is often a conformity sample, not a random one.”

(JAMA. 2012;308[6]:575-576. Available pre-embargo to the media at https://media.jamanetwork.com)

Payment Reform for Primary Care Within the Accountable Care Organization – A Critical Issue for Health System Reform

Allan H. Goroll, M.D., of Harvard Medical School and Massachusetts General Hospital, Boston, and Stephen C. Schoenbaum, M.D., M.P.H., of the Josiah Macy Jr. Foundation, New York, write that “primary care, the foundation of the accountable care organizations (ACOs), requires payment reform to enable and make durable its transformation into a high-performance model such as the patient-centered medical home.”

The authors examine the major barriers to primary care payment reform and the measures needed to address these impediments.

“Payment reforms must overcome the suspicions and distrust of change that have built up over the last 2 decades within much of the physician community. There must be, and physicians must have confidence in, a commitment by new organizations such as ACOs to provide practices with the supports necessary for them to do their jobs well and to pay commensurately with the value they create. Such payment reform can provide the basis for a new social contract between the profession and society and help achieve the goal needed by the nation of better health care at lower cost.”

(JAMA. 2012;308[6]:577-578. Available pre-embargo to the media at https://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, AUGUST 7, 2012

Media Advisory: To contact Mercedes R. Carnethon, Ph.D., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu. To contact Hermes Florez, M.D., M.P.H., Ph.D., call Lisa Worley at 305-243-5184 or email lworley2@med.miami.edu.

CHICAGO – Participants in a study who were normal weight at the time of a diagnosis of diabetes experienced higher rates of total and noncardiovascular death compared with those who were overweight or obese at diabetes diagnosis, according to a study in the August 8 issue of JAMA.

“Type 2 diabetes in normal-weight adults is an understudied representation of the metabolically obese normal-weight phenotype that has become increasingly common over time. It is not known whether the ‘obesity paradox’ that has been observed in chronic diseases such as heart failure, chronic kidney disease, and hypertension extends to adults who are normal weight at the time of incident diabetes,” according to background information in the article

Mercedes R. Carnethon, Ph.D., of the Feinberg School of Medicine, Northwestern University, Chicago, and colleagues conducted a study to compare mortality between participants who were normal weight and overweight/obese at the time of new adult-onset diabetes. The study consisted of a pooled analysis of 5 longitudinal studies with a total of 2,625 participants with new diabetes. Included were men and women (older than 40 years of age) who developed incident diabetes based on fasting glucose 126 mg/dL or greater or newly initiated diabetes medication and who had concurrent measurements of body mass index (BMI). Participants were classified as normal weight if their BMI was 18.5 to 24.99 or overweight/obese if BMI was 25 or greater. Half (50 percent) of the participants were women, 36 percent were non-white.

The proportion of adults who were normal weight at the time of incident diabetes ranged from 9 percent to 21 percent (overall 12 percent). During follow-up, 449 participants died: 178 (6.8 percent) from cardiovascular causes and 253 (10.4 percent) from noncardiovascular causes; 18 causes of death were unidentified. In the pooled sample, total mortality and cardiovascular and noncardiovascular mortality were higher in normal-weight participants as compared with rates among overweight or obese participants. Following adjustment for certain variables, the researchers found that participants with normal-weight diabetes experienced a significantly elevated total mortality and noncardiovascular mortality. While cardiovascular mortality was elevated, the association was not statistically significant.

“These findings are relevant to segments of the U.S. population, including older adults and nonwhite persons (e.g., Asian, black), who are more likely to experience normal-weight diabetes.”

The researchers write that mechanisms to explain their findings are unknown. “However, previous research suggests that normal-weight persons with diabetes have a different genetic profile than overweight or obese persons with diabetes. If those same genetic variants that predispose to diabetes are associated with other illnesses, these individuals may be ‘genetically loaded’ toward experiencing higher mortality. Future research in normal-weight persons with diabetes should test these genetic hypotheses, along with other plausible mechanisms to account for higher mortality, including inflammation, the distribution and action of adipose tissue, atherosclerosis burden and the composition of fatty plaques, and pancreatic beta-cell function.”

(JAMA. 2012;308[6]:581-590. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research is funded by a National Institute of Diabetes and Digestive and Kidney Disease grant. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Beyond the Obesity Paradox in Diabetes – Fitness, Fatness, and Mortality

In an accompanying editorial, Hermes Florez, M.D., M.P.H., Ph.D., and Sumaya Castillo-Florez, M.D., M.P.H., of the University of Miami Miller School of Medicine, and Miami Veterans Affairs Healthcare System, write that “the article by Carnethon et al addresses an emerging challenge regarding diabetes and weight status.”

“This could be a wake-up call for timely prevention and management to reduce adverse outcomes in all patients with type 2 diabetes, particularly in those metabolically obese normal-weight at diagnosis, who may have a false sense of protection because they are not overweight or obese. Standards of diabetes care recommend weight loss for all overweight or obese individuals who have diabetes. Low carbohydrate, low-fat, calorie-restricted, or Mediterranean diets may be effective weight-loss strategies in these individuals. The additional benefits of increased physical activity and behavior modification strategies may lead to the successful implementation of weight management and healthy living programs for all patients with diabetes. It is important to understand how diabetes duration relates to the benefits of intentional weight loss, as well as the clinical consequence associated with sarcopenic obesity and bone loss in older adults with or at high risk for diabetes.”

(JAMA. 2012;308[6]:619-620. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Support was provided by the Department of Veterans Affairs Geriatrics Research, Education, and Clinical Center program and a grant from the National Institutes of Health and Department of Health and Human Services. Both 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, AUGUST 7, 2012

Media Advisory: To contact Brian K. Kit, M.D., M.P.H., call Karen Hunter at 404-639-3286 or email ksh7@cdc.gov. To contact editorial author Sarah D. de Ferranti, M.D., M.P.H., call Rob Graham at 617-919-3110 or email rob.graham@childrens.harvard.edu.

CHICAGO – In a study involving more than 16,000 U.S. children and adolescents, there has been a decrease in average total cholesterol levels over the past 2 decades, although almost 1 in 10 had elevated total cholesterol in 2007-2010, according to a study in the August 8 issue of JAMA.

“The process of atherosclerosis begins during childhood and is associated with adverse serum lipid concentrations including high concentrations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides, and low concentrations of high-density lipoprotein cholesterol (HDL-C). Serum lipid concentrations in childhood are associated with serum lipid concentrations in adulthood,” according to background information in the article. “For more than 20 years, primary prevention of coronary heart disease has included strategies intended to improve overall serum lipid concentrations among youths.”

Brian K. Kit, M.D., M.P.H., of the Centers for Disease Control and Prevention, Hyattsville, Md., and colleagues conducted a study to examine the trends in serum lipid concentrations among children and adolescents in the U.S. The study included data on 16,116 youths ages 6 to 19 years who participated in the nationally representative National Health and Nutrition Examination Survey (NHANES) during 3 time periods: 1988-1994,1999-2002, and 2007-2010. Among the measures analyzed for all the participants were average serum total cholesterol (TC), non-HDL-C, HDL-C; and among adolescents only (ages 12-19 years), LDL-C and geometric average triglyceride levels. Trends in adverse lipid concentrations were reported for TC levels of 200 mg/dL and greater, non-HDL-C levels of 145 mg/dL and greater, HDL-C levels of less than 40 mg/dL, LDL-C levels of 130 mg/dL and greater, and triglyceride levels of 130 mg/dL and greater.

The researchers found that among youths ages 6 to 19 years between 1988-1994 and 2007-2010, there was a decrease in average serum TC from 165 mg/dL to 160 mg/dL and an increase in average serum HDL-C from 50.5 mg/dL to 52.2 mg/dL. There was also a decrease in the average serum non-HDL-C levels during this time period. “Generally, the sex-, age-, and race/ethnicity-specific trends for TC, HDL-C, and non-HDL-C were similar in direction to the overall trends and consistent with a favorable trend, although for each group, the magnitude was not the same and the trend was not always significant,” the authors write.

Between 1988-1994 and 2007-2010, there was a decrease in prevalence among youths ages 6 to 19 years of elevated TC from 11.3 percent to 8.1 percent and non-HDL-C from 13.6 percent to 10 percent. Prevalence of low HDL-C was 17.3 percent in 1988-1994 and 14.8 percent in 2007-2010, a nonsignificant decrease.  Among adolescents, there was a decrease in prevalence of elevated LDL-C and triglycerides between 1988-1994 and 2007-2010 and a decrease in average serum LDL-C from 95 mg/dL to 90 mg/dL and geometric average serum triglycerides from 82 mg/dL to 73 mg/dL.

In 2007-2010, 22 percent of youths had either a low HDL-C level or high non-HDL-C, which was lower than the 27.2 percent in 1988-1994.

The authors also found that age- and race/ethnicity-adjusted TC was 4.3 mg/dL lower for males and 6.5 mg/dL lower for females in 2007-2010 than in 1988-1994. Males and females who were non-Hispanic black or Mexican American, and also females who were non-Hispanic white had a lower age-adjusted TC in 2007-2010 than in 1988-1994. Age- and race/ethnicity- adjusted HDL-C was higher for males and females in 2007-2010 than in 1988-1994.

“Between 1988-1994 and 2007-2010, a favorable trend in serum lipid concentrations was observed among youths in the United States but adverse lipid profiles continue to be observed among youths,” the researchers write. “For example, in 2007-2010, slightly more than 20 percent of children aged 9 to 11 years had either a low HDL-C or high non-HDL-C concentration, which, according to the most recent cardiovascular health guidelines for children and adolescents, indicates a need for additional clinical evaluation.”

“The recently released Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents provides recommendations for preventing the development of cardiovascular risk factors including optimizing nutrition and physical activity and reducing exposure to tobacco smoke. Specific screening approaches, including universal screening at select ages and management of adverse lipid concentrations, have also been detailed in these recent guidelines for youths. Future research from longitudinal studies or mortality-linked data, including NHANES, may include examining clinical outcomes for cardiovascular disease, including cardiovascular mortality, based on lipid concentrations present during childhood,” the authors conclude.

(JAMA. 2012;308[6]:591-600. Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: The laboratory analysis of the lipids described in this paper was funded by a National Heart, Lung, and Blood Institute, National Institutes of Health, Intra-agency Agreement. 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, August 7 at this link.

 Editorial: Declining Cholesterol Levels in U.S. Youths – A Reason for Optimism

Sarah D. de Ferranti, M.D., M.P.H., of Harvard Medical School and Boston Children’s Hospital, Boston, comments on the findings of this study in an accompanying editorial.

“Further research is needed to investigate the hypothesized contributors to change in childhood and adolescent lipid levels. Better understanding is needed about dietary trends and physical activity during childhood, areas that were not explored in the study by Kit et al but could be assessed using NHANES data. However it seems clear that population-wide efforts to alter cardiovascular disease [CVD] risk have potential to influence health risks. Examples of other interventions that could have positive population-level effects on health include taxation of carbonated beverages, improved access to water in schools and in the workplace, and environmental changes to promote daily physical activity. Improvements in child and adolescent lipid values over the past 2 decades are significant and may portend improved CVD outcomes for the future, but much work should be done to better understand the changes and to build upon them.”

(JAMA. 2012;308[6]:621-622. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. de Ferranti reports receipt of grants or pending grants from the National Institutes of Health/National Heart, Lung, and Blood Institute; payment for lectures including service on speakers bureaus from the Pediatric Endocrine Society, the Pediatric Rheumatology Society, and Covidien; and receipt of royalties from UpToDate.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 31, 2012

Study Evaluates Association of Pertussis Vaccine Type and Administration With Reports of Pertussis Cases

Similar to North America, Australia is experiencing a sustained pertussis epidemic, with the highest incidence rates in Queensland during 2011 in children age 6 to 11 years. The recent changes in pertussis epidemiology may be related to a shift in vaccines from diphtheria-tetanus-whole cell pertussis (DTwP) to diphtheria-tetanus-acellular pertussis (DTaP) because of a lower rate of adverse events. Sarah L. Sheridan, B.Med., M.App.Epid., and colleagues with the University of Queensland, Brisbane, Australia, conducted a study to compare pertussis reporting rates by primary course vaccination in the 1998 birth cohort in Queensland.

As reported in a Research Letter, of 58,233 children born in 1998 identified in the Queensland vaccination register, 40,494 (69.5 percent) received at least 3 doses of any pertussis-containing vaccine during the first year from a Queensland vaccine service provider and were included in the analysis. Overall, 267 first pertussis cases were reported from this cohort between 1999 and 2011; 2 second reports were excluded. The researchers found that children who received a 3-dose DTaP primary course had higher rates of pertussis than those who received a 3-dose DTwP primary course in the pre-epidemic and outbreak periods. Among those who received mixed courses, rates in the current epidemic were highest for children receiving DTaP as their first dose.

(JAMA. 2012;308[5]:454-456. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Curbing the Opioid Epidemic in the United States – The Risk Evaluation and Mitigation Strategy

Lewis S. Nelson, M.D., of the New York University School of Medicine, and Jeanmarie Perrone, M.D., of the University of Pennsylvania, Philadelphia, discuss the use of a risk evaluation and mitigation strategy (REMS) to help deal with the problem of the “opioid epidemic” in the United States. REMS is a U.S. Food and Drug Administration-required strategy to manage a known or potential serious risk associated with a drug or biological product.

“Prescriber and patient education alone will likely prove insufficient to assuage the concerns of patients with chronic noncancer pain, who fear the reduced availability of opioid pain relievers, and public health advocates, who fear the excessive use of these drugs. Although at its core the opioid epidemic may be iatrogenic, additional regulation may be needed to help ensure more informed and appropriate prescribing. The REMS approach, if implemented appropriately and followed correctly, may be an important component for addressing the opioid epidemic in the United States.”

(JAMA. 2012;308[5]:457-458. Available pre-embargo to the media at https://media.jamanetwork.com)

Potential Consequences of Reforming Medicare Into a Competitive Bidding System

Zirui Song, Ph.D., of Harvard Medical School, Boston, and colleagues write that premium support (or vouchers), based on competitive bidding, may offer a fiscal solution if Affordable Care Act (ACA) reforms fail, but at the cost of making Medicare beneficiaries responsible for solving Medicare’s fiscal crisis.

“Success of the ACA can make premium support less risky by lowering traditional Medicare costs and helping to monitor and improve quality in private plans. Without ACA improvements, beneficiaries must pay more for traditional Medicare or join a private plan. Given the current fiscal pressures, this may be acceptable, but it is a major shift from traditional Medicare that may have deleterious consequences.”

(JAMA. 2012;308[5]:457-458. Available pre-embargo to the media at https://media.jamanetwork.com)

Integrating Public Health and Primary Care Systems – Potential Strategies From an IOM Report

Bruce E. Landon, M.D., M.B.A., of Harvard Medical School, Boston, and colleagues examine reasons there may be progress in integrating public health and primary care.

“The efforts of the primary care clinician and the public health official on behalf of the patients and communities they jointly serve must be increasingly coordinated, complementary, mutually accountable, well informed by data, and comprehensive. The policy, practice, and information environments are now conducive to achieving the elusive goal of a transformed, robust, and equitable population health system.”

(JAMA. 2012;308[5]:461-462. Available pre-embargo to the media at https://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, JULY 31, 2012

Media Advisory: To contact corresponding author Peter K. Smith, M.D., call Debbe Geiger at 919-660-9461 or email debbe.geiger@dm.duke.edu. To contact editorial author Lawrence J. Dacey, M.D., M.S., call David Corriveau at 603-653-1978 or email David.A.Corriveau@hitchcock.org.

CHICAGO – Although there have been questions regarding the safety and durability of endoscopic vein graft harvest for coronary artery bypass graft (CABG) surgery, an analysis of data of more than 200,000 patients who underwent CABG surgery found no evidence of a long-term increased risk of death with endoscopic vein graft harvesting compared to open vein-graft harvesting, according to a study in the August 1 issue of JAMA. The authors did find that the endoscopic technique was associated with a significant reduction in wound complications.

“In the mid-1990s, surgeons began using endoscopic vein-graft harvesting techniques as an alternative to large, incision-based open vein-graft harvesting to improve postoperative discomfort and incision-site complications,” according to background information in the article. “The perceived advantages of endoscopic vein-graft harvesting led to wide-spread adoption of the technique, and the devices have been used in the majority of the more than 400,000 CABG surgery procedures performed at U.S. surgical centers each year.” In 2009, a study that included 3,000 patients called into question the safety of the endoscopic vein-graft harvesting technique, finding that patients who received this procedure had higher 3-year mortality than those receiving open vein-graft harvesting technique.

Judson B. Williams, M.D., M.H.S., of Duke University Medical Center, Durham, N.C., and colleagues conducted a study to assess use of the endoscopic vein-graft harvesting technique in CABG surgery and the risk of death, heart attack, and repeat revascularization. The observational study included 235,394 Medicare patients undergoing isolated CABG surgery between 2003 and 2008 at 934 surgical centers participating in the Society of Thoracic Surgeons (STS) national database. The STS records were linked to Medicare files to allow longitudinal assessment (median [midpoint] 3-year follow-up) through December 31, 2008.

Based on Medicare Part B coding, 52 percent of patients received endoscopic vein-graft harvesting during CABG surgery. The researchers found no significant differences between the cumulative incidence rate for mortality through 3 years for the endoscopic (13.2 percent [12,429 events]) and open (13.4 percent [13,096 events]) vein-graft harvest groups. There were also no significant differences between the cumulative incidence through 3 years for the composite of death, heart attack, or revascularization among the endoscopic vs. open vein-graft harvest groups (19.5 percent [18,419 events] vs. 19.7 percent [19,232 events]).

Endoscopic vein-graft harvesting was associated with lower harvest site wound complications relative to open vein-graft harvesting (3.0 percent vs. 3.6 percent).

“Our study found that endoscopic vein-graft harvesting was the most commonly used technique for vein-graft harvesting, with approximately 70 percent of CABG surgery cases in the STS Adult Cardiac Surgery Database using this technique in 2008, the most recent year examined. After adjustment for baseline clinical factors, no evidence was found of increased long-term mortality or the composite of death, myocardial infarction, or revascularization associated with endoscopic vs. open vein-graft harvesting in isolated patients undergoing CABG surgery. Consistent with previous randomized comparisons, use of endoscopic vein-graft harvesting was associated with a significant reduction in wound complications relative to the open procedures,” the authors conclude.

(JAMA. 2012;308[5]:475-484. Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Endoscopic Vein-Graft Harvest Is Safe for CABG Surgery

In an accompanying editorial, Lawrence J. Dacey, M.D., M.S., of the Dartmouth-Hitchcock Medical Center, Lebanon, N.H., comments on the findings of this study.

“Physicians tend to do what is best for their patients. Patient satisfaction is markedly better with endoscopic vein-graft harvesting. Patients who have had both an endoscopic and open vein-graft harvest marvel at the difference in reduced pain and time of healing with endoscopic vein-graft harvesting. This conclusive study by Williams et al provides information to say with certainty that the benefits of endoscopic vein-graft harvesting in short-term patient-centered outcomes are not associated with an increased risk of important adverse long-term outcomes. And that is something to be thankful for.”

(JAMA. 2012;308[5]:475-484. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 31, 2012

Media Advisory: To contact corresponding author Sapna Syngal, M.D., M.P.H., call Jessica Maki at 617-534-1603 or email jmaki3@partners.org. To contact editorial co-author Hemant K. Roy, M.D., call Jim Anthony at 847-570-6132 or email janthony@northshore.org.

CHICAGO – Among patients with multiple colorectal polyps, the prevalence of certain gene mutations varied considerably by polyp count, according to a study in the August 1 issue of JAMA.

“Patients with multiple colorectal adenomas [polyps] may carry germline [those cells of an individual that have genetic material that could be passed to offspring] mutations in the APC or MUTYH genes,” according to background information in the article. The authors write that guidelines for when genetic evaluation should be performed in individuals with multiple colorectal adenomas vary, and data to support such guidelines are limited.

Shilpa Grover, M.D., M.P.H., of Brigham and Women’s Hospital, Boston, and colleagues conducted a study to evaluate the frequency of APC and MUTYH mutations by the number of colorectal adenomas among individuals who had undergone clinical genetic testing. The researchers also studied the relationship between the number of adenomas and age at diagnosis of adenoma and colorectal cancer and the prevalence of pathogenic APC or MUTYH mutations.

The study included 8,676 individuals who had undergone full gene sequencing between 2004 and 2011. Individuals with a certain mutation of the MUTYH gene (Y179C and G396D) underwent full MUTYH gene sequencing. APC and MUTYH mutation prevalence was evaluated by the number of polyps.

Colorectal adenomas were reported in 7,225 individuals; 1,457 with classic polyposis (100 adenomas or more) and 3,253 with attenuated (diminished) polyposis (20-99 adenomas). “The prevalence of pathogenic APC and biallelic [pertaining to both alleles (both alternative forms of a gene)] MUTYH mutations was 95 of 119 (80 percent) and 2 of 119 (2 percent), respectively, among individuals with 1,000 or more adenomas, 756 of 1,338 (56 percent) and 94 of 1,338 (7 percent) among those with 100 to 999 adenomas, 326 of 3,253 (10 percent) and 233 of 3,253 (7 percent) among those with 20 to 99 adenomas, and 50 of 970 (5 percent) and 37 of 970 (4 percent) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses,” the authors write.

The researchers note that their evaluation of individuals who underwent genetic testing because of a personal or family history suggestive of a familial polyposis syndrome suggests that genetic evaluation for APC and MUTYH mutations may be considered in individuals with 10 or more adenomas. “However, our results are derived from a selected cohort of high-risk individuals and need to be validated in larger populations of unselected patients.”

“The mutation probabilities reported here may assist clinicians in their decision to recommend genetic evaluation and counsel patients undergoing genetic testing. However, it remains important to also consider the limitations of genetic testing at present, because one-third of patients with a classic familial adenomatous polyposis [FAP; a polyposis syndrome resulting from mutations in the APC gene characterized by multiple colorectal polyps] phenotype are found to not carry a mutation in either the APC or MUTYH gene. Such individuals should undergo periodic re-evaluation as other susceptibility genes are identified.”

(JAMA. 2012;308[5]:485-492. Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: APC Gene Testing for Familial Adenomatosis Polyposis

“At this juncture, clinicians need to carefully consider the effect of a positive or negative test result on management of patient care prior to making decisions regarding genetic testing,” write Hemant K. Roy, M.D., and Janardan D. Khandekar, M.D., of the NorthShore University HealthSystem, Evanston, Il., in an accompanying editorial.

“Appropriate patient education and informed consent prior to testing is mandatory, highlighting the integral nature of genetic counseling. Until development of more robust genomic technologies for FAP detection, complementary approaches including careful assessment of family history and biomarkers may have utility. Furthermore, these considerations for FAP may serve as a model for evaluating the wider issues associated with practicing medicine at the front lines of the genomic revolution.”

(JAMA. 2012;308[5]:514-515. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 31, 2012

Media Advisory: To contact James A. Blumenthal, Ph.D., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

CHICAGO – Patients with chronic heart failure who participated in exercise training had modest reductions in symptoms of depression after 12 months, compared with usual care, according to a study in the August 1 issue of JAMA.

“An estimated 5 million people in the United States have heart failure, and more than 500,000 new cases are diagnosed annually,” according to background information in the article. Clinical depression is a common co-existing illness, affecting as many as 40 percent of patients with heart failure, with up to 75 percent of patients reporting elevated depressive symptoms. Depression also is associated with worse clinical outcomes in a variety of cardiac patient populations. “Some evidence suggests that aerobic exercise may reduce depressive symptoms, but to our knowledge the effects of exercise on depression in patients with heart failure have not been evaluated,” the authors write.

James A. Blumenthal, Ph.D., of Duke University Medical Center, Durham, N.C., and colleagues conducted a study to assess the effects of exercise on depressive symptoms and to determine whether reduced depressive symptoms were associated with improved clinical outcomes. The randomized controlled trial involved 2,322 stable patients treated for heart failure at 82 medical clinical centers in the United States, Canada, and France. A measure of depressive symptoms was gauged via a questionnaire (Beck Depression Inventory II [(BDI-II]). Depressive scores ranged from 0 to 59; scores of 14 or higher are considered clinically significant. Participants were randomized between April 2003 and February 2007 to receive either supervised aerobic exercise (goal of 90 min/week for months 1-3 followed by home exercise with a goal of ≥ 120 min/week for months 4-12) or to education and usual guideline-based heart failure care.

The median (midpoint) BDI-II score at study entry was 8; 28 percent of the sample had BDI-II scores of 14 or higher. Depression scores were available for 2,322 participants at the beginning of the study, 2,019 at month 3 and 1,738 at month 12. The researchers found that the adjusted 3-month BDI-II average score was 8.95 for the aerobic exercise group and 9.70 for usual care (a difference of -0.76). The adjusted BDI-II score at month 12 was 8.86 for the aerobic exercise group and 9.54 for usual care (a difference of -0.68).

The authors observed similar results when they examined the treatment effects within the subset of patients with clinically significant depressive symptoms (baseline BDI-II scores >14), with BDI-II scores at 3 and 12 months lower for patients in the aerobic exercise group than for patients in usual care group.

Patients within the aerobic exercise group who reported greater adherence to the exercise prescription achieved relatively larger reductions in depressive symptoms, although the absolute reduction was small.

The researchers also observed that elevated depressive symptoms were associated with more than a 20 percent increase in risk for all-cause mortality and hospitalizations and that the increased risk was independent of antidepressant use and established risk factors in patients with heart failure including age and disease severity.

(JAMA. 2012;308[5]:465-474. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 31, 2012

Media Advisory: To contact corresponding author Anne L. Coleman, M.D., Ph.D., call Elaine Schmidt at 310-794-2272 or email eschmidt@mednet.ucla.edu.

CHICAGO – Medicare patients 65 years and older who underwent cataract surgery had a lower odds of hip fracture 1 year after the procedure when compared with patients with cataract who did not have cataract surgery, according to a study in the August 1 issue of JAMA.

Visual impairment has been found to be strongly associated with an increased risk of fractures, a significant cause of illness and death in the elderly population. “Specifically, vision plays an important role in providing a reference frame for postural balance and stability, and cataract-induced changes in vision have been found to be associated with postural instability,” according to background information in the article. “Furthermore, cataracts have been found to be the most common cause of fracture-related visual impairment, with untreated cataract causing up to 49 percent of visual impairment in patients with femoral neck fractures related to decreased vision.” Despite the association of poor vision and cataracts with increased fall and fracture risk, only a limited number of studies have examined the influence of cataract surgery on fall incidence in visually impaired adults.

Victoria L. Tseng, M.D., of the Warren Alpert Medical School of Brown University, Providence, R.I., and colleagues examined the association between cataract surgery and fracture incidence at 1-year. The study included a 5 percent random sample of Medicare Part B beneficiaries with cataract who received and did not receive cataract surgery from 2002 through 2009. Analyses were adjusted for various factors.

There were 1,113,640 Medicare beneficiaries 65 years and older with a diagnosis of cataract between 2002 and 2009 in the 5 percent random sample. Of these patients, the majority were female (60 percent) and white (88 percent). Of patients with cataract, 410,809 (36.9 percent) underwent cataract surgery during the study period. During this period, the overall 1-year fracture incidence was 1.3 percent (n = 13,976) for hip fractures. Analysis of the data indicated that cataract surgery was associated with a 16 percent decrease in the adjusted odds of hip fracture 1 year after the procedure. “In patients with severe cataract, the association between cataract surgery and lower odds of hip fracture was even stronger, with a 23 percent reduction in the adjusted odds of hip fracture in the cataract surgery group compared with the cataract diagnosis group,” the authors write.

Osteoporosis was the most common fracture-related comorbidity (co-existing illness) (12.1 percent). The most common ocular comorbidity was glaucoma (19.1 percent).

“Cataract surgery may be associated with lower odds of subsequent fracture in patients aged 65 years and older in the U.S. Medicare population. Future prospective studies using standardized registries of patients with cataracts will help further elucidate the association between cataract surgery and fracture risk. Cataract surgery has already been demonstrated to be a cost-effective intervention for visual improvement, with an estimated cost per quality-adjusted life-year gained for cataract surgery in the first eye of $2,023 in the United States and $2,727 in the second eye. The results in this study suggest the need for further investigation of the additional potential benefit of cataract surgery as a cost-effective intervention to decrease the incidence of fractures in the elderly,” the researchers conclude.

(JAMA. 2012;308[5]:493-501. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by the Center for Eye Epidemiology, Jules Stein Eye Institute. 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, July 31 at this link.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) SUNDAY, JULY 22, 2012

Use of Hydroxychloroquine Does Not Slow HIV Disease Progression Among Patients Not Taking Antiretroviral Therapy

Nicholas I. Paton, M.D., F.R.C.P., of the MRC Clinical Trials Unit, London, and colleagues conducted a study to examine whether hydroxychloroquine decreases immune activation and inflammation and subsequently slows the progression of early HIV disease. Hydroxychloroquine is a drug that has immunomodulatory and anti-inflammatory properties and has been reported to have anti-HIV properties in vitro.

“International HIV treatment guidelines recommend that antiretroviral therapy should be started when the CD4 cell count reaches 350 cells/µL, but resource limitations prevent implementation of this recommendation in many countries. An inexpensive, safe, and well-tolerated intervention that slowed the rate of decline of CD4 cells (and thereby delayed the time of starting combination antiretroviral therapy) would therefore be attractive,” according to background information in the article.

The randomized, placebo-controlled trial was performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/µL. Patients received hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks.

The researchers found that “hydroxychloroquine did not decrease immune activation but had a detrimental effect on CD4 cell count and increased HIV viral replication in patients with chronic HIV infection who were not receiving antiretroviral therapy. Alternative interventions are needed to reduce immune activation and disease progression in early HIV infection.”

(JAMA. 2012;308[4]:353-361. Available pre-embargo to the media at https://media.jamanetwork.com)

To contact Nicholas I. Paton, M.D., F.R.C.P., email nick.paton@ctu.mrc.ac.uk.

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 Liver Disease Stage Associated With Risk of Liver-Related Complications and Death Among Persons Infected With HIV and Hepatitis C

Berkeley N. Limketkai, M.D., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues conducted a study to determine the rates of end-stage liver disease (ESLD), hepatocellular carcinoma (HCC), or death (all-cause and liver-related mortality) among human immunodeficiency virus/hepatitis C virus coinfected adults.

“Hepatitis C virus (HCV) coinfection occurs frequently in persons infected with the human immunodeficiency virus (HIV) because of shared routes of acquisition,” according to background information in the article. “Human immunodeficiency virus accelerates hepatitis C virus disease progression; however, the effect of liver disease stage and antiviral therapy on the risk of clinical outcomes is incompletely understood.”

The study included 638 coinfected adults (80 percent black, 66 percent men) receiving care at the Johns Hopkins HIV clinic and receiving a liver biopsy and who were prospectively monitored for clinical events between July 1993 and August 2011 (median [midpoint] follow-up, 6 years). Histological specimens were analyzed for hepatic fibrosis stage.

The researchers found that patients experienced a graded increased risk in incidence of clinical outcomes based on baseline hepatic fibrosis stage. “Importantly, we found that HIV treatment with antiretroviral therapy, higher CD4 cell count, and effective HCV treatment were associated with significantly lower risk of clinical outcomes including those related to liver disease in some cases. As such, our findings have potential implications with respect to liver disease staging and initiation of antiviral therapy for coinfected persons.”

(JAMA. 2012;308[4]:370-378. Available pre-embargo to the media at https://media.jamanetwork.com)

To contact corresponding author Mark S. Sulkowski, M.D., call David March at 410-955-1534 or email dmarch1@jhmi.edu.

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Patients With HIV Appear More Likely To Have Increased Inflammation of Arterial Walls, Which Increases Risk For Cardiovascular Disease

Sharath Subramanian, M.D., of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues examined whether arterial wall inflammation is increased in patients with HIV compared with patients not infected with HIV with similar cardiac risk factors.

“Coronary artery disease (CAD) is significantly increased in patients infected with human immunodeficiency virus (HIV), but the specific mechanisms remain unknown,” according to background information in the article.

The study, which included 81 participants, was conducted from November 2009 through July 2011. Twenty-seven participants with HIV without known cardiac disease underwent a cardiac imaging test (¹⁸fluorine-2-deoxy-D-glucose positron emission tomography [¹⁸F-FDG-PET]) for assessment of arterial wall inflammation and coronary computed tomography scanning for coronary artery calcium. The HIV group was compared with 2 separate non-HIV control groups. One control group (n=27) was matched to the HIV group for age, sex, and Framingham risk score (FRS; a measure of cardiovascular risk) and had no known atherosclerotic disease (non-HIV FRS-matched controls). The second control group (n=27) was matched on sex and selected based on the presence of known atherosclerotic disease (non-HIV atherosclerotic controls).

The researchers found that HIV infection was associated with a high degree of inflammation within the arterial wall, even in patients with low FRS and well-controlled viremia. “These findings advance our understanding of the unique pathophysiology and predilection to early increased CVD among patients infected with HIV …” the authors write. “These data have clinical relevance and suggest that patients with HIV with chronic infection have significant vascular inflammation, and thus added CVD risk, beyond that estimated by traditional risk factors. This information should now be considered in determining optimal monitoring and CVD prevention strategies for this group.”

(JAMA. 2012;308[4]:379-386. Available pre-embargo to the media at https://media.jamanetwork.com)

To contact corresponding author Steven K. Grinspoon, M.D., call Sue McGreevey at 617-724-2764 or email smcgreevey@partners.org.

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Proportion of Patients Receiving Antiretroviral Therapy With Sustained Viral Suppression Increases Over Past Decade

Baligh R. Yehia, M.D., M.S.H.P., M.P.P., of the University of Pennsylvania Perelman School of Medicine, Philadelphia, and colleagues conducted a study to examine the change in and determinants of sustained viral suppression over time in HIV-infected adults receiving antiretroviral therapy (ART).

As reported in a Research Letter, the study included HIV-infected adults who initiated care at 12 high-volume HIV clinics that are part of the HIV Research Network (HIVRN). Clinics are located in the Northeastern (n = 6), Midwestern (n = l), Southern (n = 2), and Western (n = 3) sections of the United States. Patients were offered enrollment in the HIVRN. A total of 32,483 patients received care at the 12 clinics between 2001 and 2010.

The researchers found that the percentage of patients receiving ART with sustained viral suppression increased from 45 percent in 2001 to 72 percent in 2010. “Sustained viral suppression was lower for blacks and injection drug users during all 10 years. Older individuals and those with private insurance were more likely to have sustained viral suppression compared with younger patients and those with Medicaid, Medicare, or who were uninsured.”

The authors write that new drugs and combination fixed-dose tablets have enhanced the efficacy, safety, and tolerability of regimens. “Better access to care and adherence to treatment may also have contributed to improved virologic suppression.”

(JAMA. 2012;308[4]:339-342. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

HIV/AIDS in 1990 and 2012 – From San Francisco to Washington, D.C.

Robert Steinbrook, M.D., of the Yale School of Medicine, New Haven, Conn., examines the changes in treatments and policies for HIV/AIDS that have occurred since the last time the International AIDS Conference was held in the U.S., in 1990, to this month’s conference in Washington, D.C.

Dr. Steinbrook discusses the successes and disappointments over this time period, including the advent of highly active antiretroviral therapy, and the absence of an AIDS vaccine.

(JAMA. 2012;308[4]:345-346. Available pre-embargo to the media at https://media.jamanetwork.com)

The Future of HIV Prevention in the United States

Jonathan Mermin, M.D., M.P.H., and Kevin A. Fenton, M.D., Ph.D., of the Centers for Disease Control and Prevention, Atlanta, write that in the last 15 years, there’s been a 60 percent increase of the number of people in the U.S. living with HIV, to 1.1 million people. “The increasing number of people who can potentially transmit HIV makes prevention more difficult.”

In this Viewpoint, the authors discuss challenges and strategies of HIV prevention efforts in the U.S. “The United States has an opportunity to shift from supporting hundreds of different HIV prevention approaches to objectively assessing current HIV strategies, focusing on more cost-effective activities, and conducting research that will establish the groundwork for the future. This shift should help improve the effectiveness of HIV prevention efforts, reduce HIV incidence, and ultimately increase the possibility of achieving an AIDS-free America.”

(JAMA. 2012;308[4]:347-348. Available pre-embargo to the media at https://media.jamanetwork.com)

Aging and HIV-Related Cognitive Loss

Farrah J. Mateen, M.D., of Johns Hopkins University, Baltimore, and Edward J. Mills, Ph.D., of the University of Ottawa, Ontario, Canada, write that cognitive disorders related to HIV remain an important burden of disease and disability worldwide, and that conservative estimates from better resourced countries suggest that the number of individuals of all ages living with HIV-related cognitive disorders will increase 5- to 10- fold by 2030.

The authors add that complicating HIV-related neurocognitive disorders is older age, which is the major risk factor for multiple forms of cognitive decline. They discuss strategies needed to address the issues related to aging and HIV-related cognitive decline. “An improved understanding of cognitive function in individuals with HIV infection would promote a better understanding of the epidemic of cognitive decline and provide an opportunity for scientific and community discussion on interventions that can be offered in a culturally relevant manner.”

(JAMA. 2012;308[4]:349-350. Available pre-embargo to the media at https://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 EARLY RELEASE: 10 A.M. (ET) SUNDAY, JULY 22, 2012

Media Advisory: To contact Anthony S. Fauci, M.D., call Kathy Stover at 301-402-1663 or email Kathy.stover@nih.gov.

WASHINGTON, D.C. – Ending the global HIV/AIDS pandemic may be possible by implementing a multifaceted global effort that expands testing, treatment, and prevention programs, as well as meets the scientific challenges of developing an HIV vaccine and possibly a cure, according to a Viewpoint in the July 25 issue of JAMA, a theme issue on HIV/AIDS.

Anthony S. Fauci, M.D., Director, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Md., presented the article at a JAMA media briefing at the International AIDS Conference.

Dr. Fauci and co-author Gregory K. Folkers, M.S., M.P.H., also of the NIAID, write that “since the first cases of what is now known as AIDS were reported in 1981, an entire generation has grown up under the constant cloud of this modern-day plague. Across the globe, more than 34 million people are living with the human immunodeficiency virus (HIV), the virus that causes AIDS, including approximately 1.2 million individuals in the United States. HIV/AIDS has been responsible for the deaths of an estimated 30 million individuals.” They add that although the rate of new HIV infections has declined or stabilized in many countries, the disease continues to exact an enormous toll: 1.8 million deaths in 2010 alone, and grief and hardship for countless families and communities.

Because powerful interventions have been developed and scientifically proven effective, the fight against HIV/AIDS is currently viewed with considerably more optimism than in past years, the authors write. “If these tools are made widely available to those who need them, an AIDS-free generation may be possible—that is, today’s children could one day live in a world in which HIV infections and deaths from AIDS are rare.”

Among the most important interventions is combination antiretroviral therapy, which significantly improves the health and longevity of individuals infected with HIV. “Since the advent of antiretroviral therapy, the annual number of deaths due to AIDS has decreased by two-thirds in the United States. Globally, an estimated 700,000 lives were saved in 2010 alone due to the increased availability of antiretroviral therapy in low- and middle-income countries,” the authors write. “Important challenges remain—notably finding the resources and developing the infrastructure to provide antiretroviral therapy to the estimated 8 million individuals with HIV infection who need these drugs but are not receiving them.”

The authors add that antiretroviral therapy can also prevent HIV infection by reducing the amount of virus in an infected person’s blood and other body fluids, making it less likely that the virus will be transmitted to others. Also, antiretroviral therapy is highly effective in blocking mother-to-child HIV transmission.

Other important interventions include medical male circumcision, which offers a highly effective and durable way to protect heterosexual men from HIV infection; and potentially, pre-exposure prophylaxis with antiretroviral medications, which have shown promise in reducing an individual’s risk of acquiring HIV infection.

“Each of these treatment and prevention strategies has a strong evidence base; with further refinement and scale-up and also when used in combination, they could have an extraordinary effect on decreasing the trajectory of the HIV pandemic.”

According to the authors, researchers are maintaining focus on 2 key scientific challenges that remain: the development of a vaccine and a cure. They write that modest success in a large-scale clinical trial of an HIV vaccine, promising results in animal models, and advances in structure-based vaccine design suggest that an HIV vaccine is feasible. The prospect of an HIV cure remains challenging.

The authors conclude that ending the global HIV/AIDS pandemic “will require a global commitment of resources involving additional donor countries, strengthening health care systems overall, and fostering greater ownership by host countries of HIV/AIDS effort, including investing more in the health of their people. With collective and resolute action now and a steadfast commitment for years to come, an AIDS-free generation is indeed within reach.”

(JAMA. 2012;308[4]:343-344. Available pre-embargo to the media at https://media.jamanetwork.com)

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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EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) SUNDAY, JULY 22, 2012

Media Advisory: To contact H. Irene Hall, Ph.D., call the National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention press office at 404-639-8895 or email NCHHSTPMediaTeam@cdc.gov.

WASHINGTON, D.C. – An examination of the characteristics of persons born outside the United States diagnosed with HIV while living in the U.S. finds that, compared to U.S.-born persons with HIV, they are more likely to be Hispanic or Asian, and to have a higher percentage of HIV infections attributed to heterosexual contact, according to a study appearing in JAMA being published online.

H. Irene Hall, Ph.D., of the Centers for Disease Control and Prevention, Atlanta, presented the findings of the study at a JAMA media briefing at the International AIDS Conference.

“Persons born outside the United States comprise approximately 13 percent of the total U.S. population and represent a varied group of people, including students, skilled workers, family members of U.S. citizens, undocumented migrants, naturalized citizens, and refugees,” according to background information in the article. “Although more than 95 percent of persons with HIV in the world live outside the United States, an understanding of HIV infection in persons born outside but living in the United States allows for both a new perspective on HIV in this country as well as a better understanding of the health status and health education needs of persons born outside the United States.” The authors add that it can be difficult for persons born outside the United States to learn about HIV prevention, access HIV testing, and obtain timely medical care because of language and cultural barriers.

Dr. Hall and colleagues examined the demographic, geographic, and risk factor characteristics of U.S.-born and persons born outside the U.S. who received a diagnosis of HIV while living in the U.S. from 2007 through 2010 in 46 states and 5 U.S. territories, as reported to the National HIV Surveillance System. The category of persons were defined as persons born outside the United States and its territories was inclusive of naturalized citizens.

The researchers found that from 2007 through 2010, a total of 191,697 persons received a diagnosis of HIV. Of these, 30,995 (16.2 percent) were born outside the United States. The 4 states (California, Florida, New York, and Texas) reporting the highest numbers of persons born outside the U.S. and diagnosed with HIV were also the top 4 states with HIV cases overall. The majority of HIV cases occurred in males (n = 124,863 [77.7 percent] among U.S.-born males vs. n = 22,773 [73.5 percent] among males born outside the United States).

Regarding race/ethnicity, the researchers found that the proportion of persons born outside the United States varied by category. “Of the 55,574 HIV diagnoses in whites, 1,841 (3.3 percent) were in persons born outside the U.S.; of 86,547 diagnoses in blacks, 8,614 (10.0 percent) were in persons born outside the U.S. Of the 42,431 HIV diagnoses in Hispanics, 17,913 (42.2 percent) were in persons born outside the U.S. Of 3,088 HIV diagnoses in Asians, 1,987 (64.3 percent) were in persons born outside the U.S.”

Overall, 39.4 percent of HIV diagnoses in persons born outside the United States (men and women combined) were attributed to heterosexual contact; for U.S.-born persons, 27.2 percent was due to heterosexual contact.  For both males born outside the U.S. and U.S.-born men, the majority of HIV diagnoses were in men who have male-to-male sexual contact.

Of the 25,255 persons diagnosed with HIV with a specified country or region of birth outside the United States, the most common region of birth origin was Central America (including Mexico; n = 10,343 [41.0 percent]), followed by the Caribbean (n = 5,418; 21.5 percent), Africa (n = 3,656; 14.5 percent), Asia (n = 1,995; 7.9 percent), and South America (n = 1,929; 7.6 percent).

The researchers note that the date of first entry into the United States is not collected on the HIV case report form, so it is not possible to know whether HIV infection preceded or followed immigration.

“These findings demonstrate the diversity of the HIV-infected population born outside the United States, presenting many clinical and public health challenges,” the authors conclude.

(doi:10.1001/JAMA.2012.9046. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The Centers for Disease Control and Prevention funds all states and the District of Columbia to conduct HIV surveillance and selected areas to conduct HIV incidence surveillance and provides technical assistance to all funded areas. The 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 10 a.m. ET Sunday, July 22 at this link.

Editorial: HIV Infection Among Persons Born Outside the United States

Mitchell H. Katz, M.D., of the Los Angeles County Department of Health Services, and Deputy Editor, Archives of Internal Medicine, writes in an accompanying editorial that the findings of this study “suggests that persons born outside the United States who reside in the United States are a heterogeneous group.”

“This study and other studies suggest that these persons are in need of appropriate education and outreach, testing and treatment, and mental health services including specialized services for those who experience traumatic events in their home countries or during the immigration process, substance treatment for those addicted to drugs, as well as HIV care for those who are infected. Although these lessons may apply regardless of country of origin for HIV-infected persons, the effectiveness of these messages and interventions will require culturally relevant delivery to each specific population of immigrants.”

(doi:10.1001/JAMA.2012.8670. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Katz reported serving as a consultant to ETR Associates Inc., and receiving royalties for a chapter on HIV/AIDS in Current Medical Diagnosis and Treatment.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) SUNDAY, JULY 22, 2012

Media Advisory: To contact Howard D. Strickler, M.D., M.P.H., call Deirdre Branley at 347-266-9204 or email sciencenews@einstein.yu.edu.

WASHINGTON, D.C. – HIV-infected and uninfected women with normal cervical cytology (Pap test) and a negative test result for oncogenic (tumor inducing) human papillomavirus DNA at study enrollment had a similar risk of cervical precancer and cancer after 5 years of follow-up, according to a study in the July 25 issue of JAMA, a theme issue on HIV/AIDS.

Howard D. Strickler, M.D., M.P.H., of the Albert Einstein College of Medicine of Yeshiva University, New York, presented the findings of the study at a JAMA media briefing at the International AIDS Conference.

“U.S. cervical cancer screening guidelines for human immunodeficiency virus (HIV)-uninfected women 30 years or older have recently been revised, increasing the suggested interval between Papanicolaou (Pap) tests from 3 years to 5 years among those with normal cervical cytology results who test negative for oncogenic human papillomavirus (HPV). Whether a 3-year or 5-year screening interval could be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown,” according to background information in the article.

Dr. Strickler and colleagues conducted a study to examine the 3-year and 5-year risk of cervical precancer and cancer defined by cytology (i.e., high-grade squamous intraepithelial lesion or greater [HSIL+]) and histology (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), in HIV-infected women (n = 420) and HIV-uninfected women (n = 279). The participants, who at the beginning of the study had a normal Pap test result and were negative for oncogenic HPV, were enrolled in a multi-institutional U.S. cohort of the Women’s Interagency HIV Study, between October 2001 and September 2002, with follow-up through April 2011. Semiannual visits at 6 clinical sites included Pap testing and, if indicated, cervical biopsy.

Overall, no oncogenic HPV was detected in 369 (88 percent) of the HIV-infected women and 255 (91 percent) of the HIV-uninfected women with normal cervical cytology at enrollment. Two cases of HSIL+ were observed during the 5 years of observation, 1 among the HIV-uninfected women and 1 among the HIV-infected women with a CD4 cell count of 500 cells/µL or greater. Overall, the cumulative incidence of HSIL+ was 0.3 percent in HIV-infected women and 0.4 percent in HIV-uninfected women.

Based on a total of 15 cases, the authors found that the cumulative incidence of CIN-2+ over 5 years of follow-up was 2 percent in HIV-infected women with CD4 cell count less than 350 cells/µL, 2 percent in those with CD4 cell count of 350 to 499 cells/µL, 6 percent in those women with CD4 cell count of 500 cells/µL or greater, and 5 percent in HIV-uninfected women.

When the researchers combined the data among HIV-infected women, they found that the overall 5-year cumulative incidence of CIN-2+ in HIV-infected women was 5 percent. “Of the CIN-2+ cases, 2 were CIN-3 (an HIV-infected woman with a baseline CD4 cell count of 350-499 cells/µL, and an HIV-uninfected woman). The overall 5-year cumulative incidence of CIN-3+ was 0.5 percent in HIV-infected women and 0.7 percent in HIV-uninfected women. No cancers were observed.”

“In summary, the results of this prospective study suggest that HIV-infected women undergoing long-term clinical follow-up who are cytologically normal and oncogenic HPV-negative have a risk of cervical precancer similar to that in HIV-uninfected women through 5 years of follow-up. Additional observational studies or a randomized clinical trial may be necessary before clinical guideline committees consider whether to expand current recommendations regarding HPV co-testing to HIV-infected women. More broadly, the current investigation highlights the potential for a new era of molecular testing, including HPV as well as other biomarkers, to improve cervical cancer screening in HIV-infected women,” the authors conclude.

(JAMA. 2012;308[4]:362-369. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) SUNDAY, JULY 22, 2012

Media Advisory: To contact Melanie A. Thompson, M.D., email drmt@mindspring.com, or contact Donna Jacobsen, Executive Director of IAS-USA at DJacobsen@iasusa.org or 415-544-9400.

WASHINGTON, D.C. – Included in the 2012 International Antiviral Society-USA panel recommendations for human immunodeficiency virus (HIV) patient care is that all adult patients, regardless of CD4 cell count, should be offered antiretroviral therapy (ART), according to an article in the July 25 issue of JAMA, a theme issue on HIV/AIDS. Other new recommendations include changes in therapeutic options and modifications in the timing and choice of ART for patients with an opportunistic illness such as tuberculosis.

Melanie A. Thompson, M.D., of the AIDS Research Consortium of Atlanta, presented the findings of the article at a JAMA media briefing at the International AIDS Conference.

“Since the first antiretroviral drug was approved 25 years ago, improvements in the potency, tolerability, simplicity, and availability of ART have resulted in dramatically reduced numbers of opportunistic diseases and deaths where ART is accessible,” according to background information in the article. “New trial data and drug regimens that have become available in the last 2 years warrant an update to guidelines for ART in HIV-infected adults in resource-rich settings.”

Dr. Thompson and colleagues with the International Antiviral Society-USA panel conducted a review of the medical literature to identify relevant evidence published since the last report (2010), as well as data that had been published or presented in abstract form at scientific conferences in the past 2 years. The revised guidelines reflect new data regarding recommendations of when to initiate ART, new options for initial and subsequent therapy, ART management in the setting of special conditions, new approaches to monitoring treatment success and quality, and managing antiretroviral failure.

Among the primary recommendations of the panel are that treatment is recommended for all adults with HIV infection. The researchers found that there is no CD4 cell count threshold at which starting therapy is contraindicated, but the strength of the recommendation and the quality of the evidence supporting initiation of therapy increase as the CD4 cell count decreases and when certain concurrent conditions are present. Patients should be monitored for their CD4 cell count, and also HIV-1 RNA levels, ART adherence, HIV drug resistance, and quality-of-care indicators.

Initial regimens that are recommended include 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine) plus a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir or darunavir), or an integrase strand transfer inhibitor (raltegravir). “The aim of therapy continues to be maximal, lifelong, and continuous suppression of HIV replication to prevent emergence of resistance, facilitate optimal immune recovery, and improve health” the authors write. Alternatives in each class are recommended for patients with or at risk of certain concurrent conditions, including cardiovascular disease, reduced kidney function, or tuberculosis.

The primary reasons for switching regimens include virologic, immunologic, or clinical failure and drug toxicity or intolerance. Switching regimens in virologically suppressed patients to reduce toxicity, improve adherence and tolerability, and avoid drug interactions can be done by switching 1 or more agents in the regimen. “Confirmed treatment failure should be addressed promptly and multiple factors considered,” the researchers write.

“Although it is crucial to intensify efforts to find a cure for persons who are already infected and an effective vaccine for those who are not, many of the tools needed to control the HIV/AIDS pandemic are already at hand. Critical components of the tool kit to eradicate AIDS include expanded HIV testing, increased focus on engagement in HIV care, early and persistent access to ART, and attention to improving ART adherence. These must occur in the context of strategies to address social determinants of health, including the elimination of stigma and discrimination,” the authors conclude.

(JAMA. 2012;308[4]:387-402. Available pre-embargo to the media at https://media.jamanetwork.com)

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

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 17, 2012

Is It Time to Replace the Tuberculin Skin Test With a Blood Test?

“Recent mathematical tuberculosis (TB) transmission modeling has shown that substantial improvements in addressing latent tuberculosis infection (LTBI) will be needed to eliminate TB before the 22nd century,” writes Philip A. LoBue, M.D., and Kenneth G. Castro, M.D., of the Centers for Disease Control and Prevention, Atlanta. They add that effective management of LTBI has been hampered by limitations of both treatment regimens and diagnostic tools, and that there have been efforts at finding a replacement for the tuberculin skin test, which despite its many limitations has been the mainstay of LTBI diagnosis. In this Viewpoint, the authors compare the advantages and disadvantages of TB testing methods currently available.

(JAMA. 2012;308[3]:241-242. Available pre-embargo to the media at https://media.jamanetwork.com)

Understanding Health Care as a Complex System – The Foundation for Unintended Consequences

Lewis A. Lipsitz, M.D., of Harvard Medical School, Boston, writes that “to help guide future policies and avoid the unanticipated consequences of regulation, policy makers and physicians need to understand health care as a complex system and apply the principles of complexity science to achieve its goals.”

“The U.S. health care system will need to continue to depart from a mechanical, regulatory approach to health care policy and move toward a complex systems approach that permits creative self-organization. This may be accomplished by removing structural boundaries between health care professionals, aligning their goals, enabling experimentation, and establishing simple rules to help limit costs.”

(JAMA. 2012;308[3]:243-244. Available pre-embargo to the media at https://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, JULY 17, 2012

Media Advisory: To contact Bruce E. Landon, M.D., M.B.A., call David Cameron at 617-432-0441 or email david_cameron@hms.harvard.edu. To contact editorial co-author Elliott S. Fisher, M.D., M.P.H., call Annmarie Christensen at 603-653-0897 or email Annmarie.Christensen@dartmouth.edu.

CHICAGO – Physicians tend to share patients with colleagues who have similar personal traits and practice styles, and there is substantial variation in physician network characteristics across geographic areas, according to a study in the July 18 issue of JAMA.

Physicians are embedded in informal networks that result from their sharing of patients, information, and behaviors. “These informal information-sharing networks of physicians differ from formal organizational structures (such as a physician group associated with a health plan, hospital, or independent practice association) in that they do not necessarily conform to the boundaries established by formal structures,” according to background information in the article. “The potential influence of informal networks of physicians on decision making has been understudied despite the potential importance of these networks in day-to-day practice.”

Bruce E. Landon, M.D., M.B.A., of Harvard Medical School, Boston, and colleagues conducted a study to identify professional networks among physicians, examine how such networks vary across geographic regions, and determine factors associated with physician connections. Using methods adopted from social network analysis, Medicare administrative data from 2006 were used to study 4,586,044 Medicare beneficiaries seen by 68,288 physicians practicing in 51 hospital referral regions (HRRs). Distinct networks depicting connections between physicians (defined based on shared patients) were constructed for each of the 51 HRRs. The randomly sampled HRRs are distributed across all regions of the country and include urban and rural locations. The average physician age was 49 years and about 80 percent were male. Among the Medicare patients, the average age was 71 years and 40 percent were male.

Substantial variation was observed across HRRs. The number of included physicians ranged from 135 in Minot, N.D., (1,568 ties) to 8,197 in Boston (392,582 ties). The average adjusted degree (number of other physicians each physician was connected to per 100 Medicare beneficiaries) across all HRRs was 27.3. Patterns varied by physician specialty as well. Physicians with ties to each other were far more likely to be based at the same hospital (69.2 percent of unconnected physician pairs vs. 96.0 percent of connected physician pairs). Connected physician pairs also were more likely to be in close geographic proximity. The average distance for connected pairs was 13.1 miles vs. 24 miles.

“Characteristics of physicians’ patient populations also were associated with the presence of ties between physicians.  Across all racial and ethnic groups, connected physicians had more similar racial compositions of their patient panels than unconnected physicians. For instance, connected physician pairs had an average difference of 8.8 points in the percentage of black patients in their 2 patient panels compared with a difference of 14.0 percentage points for unconnected physician pairs. Similarly, differences in mean [average] patient age and percentage of Medicaid patients also were smaller for connected physicians than unconnected physicians. Medical comorbidities [co-existing illnesses] were also more similar, suggesting that connected physicians had more similar patients in terms of clinical complexity than unconnected physicians,” the authors write. “Physicians thus tend to cluster together along attributes that characterize their own backgrounds and the clinical circumstances of their patients.”

“It has long been known that physician behavior varies across geographic areas, yet our understanding of the factors that contribute to these geographic differences is incomplete. Our findings suggest that variation according to network attribute might help explain health care variation across geographic areas, particularly given what is known about how networks function.”

“In conclusion, we used novel methods to define social networks among physicians in geographic areas based or shared patients, examined how such networks vary across different geographic regions, and identified physician and patient population factors that are associated with physician patient-sharing relationships. This approach might have useful applications for policy makers seeking to influence physician behavior (whether related to accountable care organizations or innovation adoptions) because it is likely that physicians are strongly influenced by their network of relationships with other physicians,” the researchers write.

(JAMA. 2012;308[3]:265-273. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by a grant from the National Institute on Aging. Dr. Barnett was supported by a Doris Duke Charitable Foundation Clinical Research Fellowship and a Harvard Medical School Research Fellowship. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Social Networks in Health Care – So Much to Learn

In an accompanying editorial, Valerie A. Lewis, Ph.D., and Elliott S. Fisher, M.D., M.P.H., of Dartmouth Medical School, Hanover, N.H., discuss the importance of networks in health care.

“As advances in biomedicine enhance the effectiveness and complexity of the medical interventions required to treat acute and chronic illness, it is becoming clear that meeting physicians’ professional responsibility to each patient will require new ways of working together. Evidence from fields outside medicine, summarized in Putnam’s ‘Bowling Alone,’ concludes that stronger connections within a given group (such as physicians) and across groups (such as between physicians, nurses, and administrators) can help create the trust and shared values that are crucial to organizational success and individual fulfillment. Further research along the lines developed by Landon and colleagues should help bring useful insights to health care.”

(JAMA. 2012;308[3]:294-296. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 17, 2012

Media Advisory: To contact Michael W. Fried, M.D., call Tom Hughes at 919-966-6047 or email tahughes@unch.unc.edu.

CHICAGO – Use of the botanical product silymarin, an extract of milk thistle that is commonly used by some patients with chronic liver disease, did not provide greater benefit than placebo for patients with treatment-resistant chronic hepatitis C virus (HCV) infection, according to a study in the July 18 issue of JAMA.

Chronic hepatitis C virus infection affects almost 3 percent of the global population and may lead to cirrhosis, liver failure, and liver cancer. A large proportion of patients do not respond to certain treatments for this infection, and many others cannot be treated because of co-existing illnesses. “Thus, alternative medications with disease-modifying activity may be of benefit,” according to background information in the article. Thirty-three percent of patients with chronic HCV infection and cirrhosis reported current or past use of silymarin for the treatment of their disease. Clinical studies that have evaluated milk thistle for a variety of liver diseases have yielded inconsistent results.

Michael W. Fried, M.D., of the University of North Carolina, Chapel Hill, and colleagues conducted a study to assess the use of silymarin for treating chronic HCV infection. The multicenter, placebo-controlled trial was conducted at 4 medical centers in the United States. Participants included 154 persons with chronic HCV infection and serum alanine aminotransferase (ALT; an enzyme that reflects liver function) levels of 65 U/L or greater who were previously unsuccessfully treated with interferon-based therapy. Enrollment began in May 2008 and was completed in May 2010, with the last follow-up visit completed in March 2011. Participants were randomly assigned to receive 420-mg silymarin, 700-mg silymarin, or matching placebo administered 3 times per day for 24 weeks. The primary outcome measure for the study was a serum ALT level of 45 U/L or less (considered within the normal range) or less than 65 U/L, provided this was at least a 50 percent decline from baseline values. Secondary outcomes included changes in ALT levels, HCV RNA levels, and quality-of-life measures.

At the end of treatment, only 2 participants in each treatment group achieved the prespecified primary end point. The percentages of participants who achieved the primary end point were 3.8 percent in the placebo group, 4.0 percent in the 420-mg silymarin group, and 3.8 percent in the 700-mg silymarin group. The researchers also found that there was no statistically significant difference across treatment groups when changes in serum ALT levels from the beginning of the study to end of treatment were analyzed. Also, average serum HCV RNA levels did not change significantly during the 24 weeks of therapy.

There were no significant changes in physical or mental health components of quality-of-life scores, in chronic liver disease health-related quality-of-life assessments, or in depression scores in any group. Frequency of adverse events reported by individual patients also did not differ significantly among the treatment groups.

“In summary, oral silymarin, used at higher than customary doses, did not significantly alter biochemical or virological markers of disease activity in patients with chronic HCV infection who had prior treatment with interferon-based regimens,” the authors conclude.

(JAMA. 2012;308[3]:274-282. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 17, 2012

Media Advisory: To contact Gregg C. Fonarow, M.D., call Rachel Champeau at 310-794-2270 or email RChampeau@mednet.ucla.edu. To contact editorial co-author Tobias Kurth, M.D., Sc.D., email tobias.kurth@univ-bordeaux.fr.

CHICAGO – Adding stroke severity to a hospital 30-day mortality model based on claims data for Medicare beneficiaries with acute ischemic stroke was associated with improvement in predicting the risk of death at 30 days and changes in performance ranking regarding mortality for a considerable proportion of hospitals, according to a study in the July 18 issue of JAMA.

“Increasing attention has been given to defining the quality and value of health care through reporting of process and outcome measures. National quality profiling efforts have begun to report hospital-level performance for Medicare beneficiaries, including 30-day mortality rates, for common medical conditions, including acute myocardial infarction [heart attack], heart failure, and community-acquired pneumonia,” according to background information in the article. Stroke is among the leading causes of death, disability, hospitalizations, and health care expenditures in the United States. “There is increasing interest in reporting risk-standardized outcomes for Medicare beneficiaries hospitalized with acute ischemic stroke, but whether it is necessary to include adjustment for initial stroke severity has not been well studied.”

Gregg C. Fonarow, M.D., of the University of California, Los Angeles, and colleagues conducted a study to evaluate the degree to which hospital outcome ratings and the ability to predict 30-day mortality are altered after including initial stroke severity in a claims-based risk model for hospital 30-day mortality for acute ischemic stroke. For the study, data were analyzed from 782 Get With The Guidelines-Stroke participating hospitals on 127,950 fee-for-service Medicare beneficiaries with ischemic stroke. The patients had a score documented for the National Institutes of Health Stroke Scale (NIHSS, a 15-item neurological examination scale with scores from 0 to 42, with higher scores indicating more severe stroke) between April 2003 and December 2009. The median (midpoint) age was 80 years, 57 percent were women, and 86 percent were white. Performance of claims-based hospital mortality risk models with and without inclusion of NIHSS scores for 30-day mortality was evaluated and hospital rankings from both models were compared. The NIHSS median score in this overall population was 5, and the median hospital-level NIHSS score was 5.

There were 18,186 deaths (14.5 percent) within the first 30 days, including 7,430 deaths during the index hospitalization (in-hospital mortality, 5.8 percent). The median hospital-level 30-day mortality rate was 14.5 percent. The researchers found that the hospital mortality model with NIHSS scores had significantly better discrimination than the model without. Also, other index scores demonstrated substantially more accurate classification of hospital 30-day mortality after the addition of NIHSS score to the claims model. The model with NIHSS exhibited better agreement between observed and predicted mortality rates.

Analysis of data indicated that more than 40 percent of hospitals identified in the top or bottom 5 percent of hospital risk-adjusted mortality would have been reclassified into the middle mortality range using a model adjusting for NIHSS score compared with a model without NIHSS score adjustment. “Similarly, when considering the top 20 percent and bottom 20 percent ranked hospitals, close to one-third of hospitals would have been reclassified,” the authors write.

“These findings highlight the importance of including a valid specific measure of stroke severity in hospital risk models for mortality after acute ischemic stroke for Medicare beneficiaries. Furthermore, this study suggests that inclusion of admission stroke severity may be essential for optimal ranking of hospital with respect to 30-day mortality.”

“As public reporting and value-based purchasing policies increase for outcome measures, it is important to recognize the effect that using models with less than ideal discrimination and calibration has on the ranking of hospitals and the lack of correlation among ranking by models that do and do not adjust for critical risk determinants,” the researchers write.

(JAMA. 2012;308[3]:257-264. Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Comparing Hospitals on Stroke Care – The Need to Account for Stroke Severity

In an accompanying editorial, Tobias Kurth, M.D., Sc.D., of the University of Bordeaux, France, and Mitchell S. V. Elkind, M.D., M.S., of Columbia University, New York, write that the results of this study “clearly highlight the importance of incorporating information on stroke severity when conducting health outcomes research in stroke.”

“Excluding this information will lead to incorrect ranking of hospital performance by failing to consider that hospitals care for different patient populations. The influence of stroke severity on these outcome measures, moreover, seems different from that of measures of severity in other conditions. For other cardiovascular diseases, risk adjustment using demographic characteristics and claims-derived comorbid conditions may sufficiently account for the underlying case mix. Ischemic stroke is a much more heterogeneous condition than ischemic heart disease and is characterized by multiple subtypes, etiologies, and diverse outcomes. The assumption that what is true of myocardial infarction is also true of stroke, therefore, is flawed, as the present data underscore. The particular characteristics of stroke have to be taken into consideration by clinicians, insurance companies, and policy makers when comparing disease-specific health outcomes.”

(JAMA. 2012;308[3]:292-293. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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