EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 14, 2014

Media Advisory: To contact corresponding author Andrew T. Hattersley, D.M., email a.t.hattersley@exeter.ac.uk. To contact editorial author Jose C. Florez, M.D., Ph.D., call Mike Morrison at 617-724-6425 or email mdmorrison@partners.org.

Chicago – Despite having mild hyperglycemia for approximately 50 years, patients with a mutation in the gene encoding the enzyme glucokinase had a low prevalence of clinically significant vascular complications, findings that provide insights into the risks associated with isolated mild hyperglycemia, according to a study in the January 15 issue of JAMA.

“In both type 1 and type 2 diabetes, hyperglycemia [abnormally high blood sugar] is associated with microvascular complications over time. Intensive treatment to lower blood glucose levels reduces the development of microvascular complications,” according to background information in the article. Certain patients with glucokinase (GCK) mutations have mild fasting hyperglycemia from birth, resulting in an elevated glycated hemoglobin (HbA_1c) level that mimics recommended levels for type 1 and type 2 diabetes.

Anna M. Steele, Ph.D., of the University of Exeter, United Kingdom, and colleagues assessed the prevalence and severity of microvascular and macrovascular complications in patients with GCK mutations to provide additional information about the relationship between current glycemic targets and diabetes-related complications. The study, conducted in the United Kingdom between August 2008 and December 2010, included 99 GCK mutation carriers (median [midpoint] age, 49 years), 91 nondiabetic, nonmutation carrier relatives (control) (median age, 52 years), and 83 individuals with young-onset type 2 diabetes (YT2D), diagnosed at age 45 years or younger (median age, 55 years). Median HbA_1c was 6.9 percent in patients with the GCK mutation, 5.8 percent in controls, and 7.8 percent in patients with YT2D.

The prevalence of clinically significant microvascular complications (such as retinopathy, nephropathy, and neuropathy) was low in patients with a GCK mutation (1 percent) and the control group (2 percent). In contrast, 36 percent of the YT2D group had evidence of clinically significant microvascular disease. Thirty percent of patients with GCK had retinopathy compared with 14 percent of controls and 63 percent of patients with YT2D.

Neither patients with GCK nor controls had proteinuria (the presence of excessive protein in the urine), and microalbuminuria (an increase in the urinary excretion of the protein albumin that cannot be detected by a conventional test) was rare, whereas 10 percent of YT2D patients had proteinuria and 21 percent had microalbuminuria. Neuropathy was rare in patients with GCK and controls but present in 29 percent of YT2D patients. Patients with GCK had a low prevalence of clinically significant macrovascular complications (4 percent; such as heart attack, ischemic heart disease, stroke) that was not significantly different from controls (11 percent), and lower in prevalence than patients with YT2D (30 percent).

The presence of ischemic heart disease was low in the GCK and control group, while higher in YT2D patients (16 percent). No patients in either the GCK or control groups had experienced a stroke compared with 4 of 83 patients (5 percent) in the YT2D group.

“Patients with a GCK mutation have a low prevalence of clinically significant microvascular and macrovascular complications despite their lifelong hyperglycemia. In these patients, an average of nearly 50 years of isolated hyperglycemia within current target ranges for diabetes control has a negligible association with complication development,” the authors conclude.

(doi:10.1001/jama.2013.283980; 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: Insights From Monogenic Diabetes and Glycemic Treatment Goals for Common Types of Diabetes

Jose C. Florez, M.D., Ph.D., of Massachusetts General Hospital, Boston, comments on the findings of this study in an accompanying editorial.

“… this study by Steele et al sheds light on the extent to which decades of isolated mild hyperglycemia promote diabetes complications, and with key caveats expressed here [within the editorial], this study supports current treatment goals and lays the groundwork for more extended follow-up of this unique population,” Dr. Florez writes. “Overall, it is clear that despite the low frequency of glucokinase maturity-onset diabetes of the young, knowledge of its natural course has implications for the management of common forms of diabetes, and it illustrates how clinical insights gained from the study of monogenic [pertaining to one gene] syndromes can improve understanding of complex diseases.”

(doi:10.1001/jama.2013.283981; 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. Florez reported having received consulting fees from Eli Lilly, Pfizer, and Novartis.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 14, 2014

Media Advisory: To contact corresponding author John N. Primrose, M.D., F.R.C.S., email j.n.primrose@soton.ac.uk.

Chicago – Among patients who had undergone curative surgery for primary colorectal cancer, the screening methods of computed tomography and carcinoembryonic antigen each provided an improved rate of surgical treatment of cancer recurrence compared with minimal follow-up, although there was no advantage in combining these tests, according to a study in the January 15 issue of JAMA.

Colorectal cancer is the third most common cancer worldwide, with 1.24 million cases reported to the International Agency for Research on Cancer in 2008. Traditionally, patients who have had curative surgery for colorectal cancer undergo regular follow-up for at least 5 years to detect recurrence, a common practice based on limited evidence, according to background information in the article.

John N. Primrose, M.D., F.R.C.S., of the University of Southampton, England, and colleagues assessed detection of recurrence using two common screening methods: measurement of blood carcinoembryonic antigen (CEA; a glycoprotein used as a tumor marker), and computed tomography (CT). They randomized 1,202 patients from 39 hospitals in England to 1 of 4 groups: CEA only (n = 300), CT only (n = 299), CEA+CT (n = 302), or minimum follow-up (n = 301).

Cancer recurrence was detected in 199 participants (16.6 percent) during the period of observation for recurrence (average 4.4 years), and 5.9 percent of participants with recurrence underwent surgery for cure (recurrence detected early enough via follow-up test that surgery can still be performed for cure). The researchers found that surgical treatment of recurrence with curative intent was higher in each of the 3 more intensive follow-up groups compared with the minimum follow-up group. Compared with minimum follow-up, the absolute difference in the number treated with curative intent in the CEA group was 4.4 percent, 5.7 percent in the CT group, and 4.3 percent in the CEA+CT group.

The number of deaths was nonsignificantly higher in the more intensive follow-up groups compared with the minimum follow-up group, as was the number of disease-specific colorectal cancer deaths. “More than two-thirds of the patients treated surgically with curative intent were still alive at a median [midpoint] follow-up of just over 4 years postrecurrence, suggesting that 5-year survival may be more than the 40 percent previously reported,” the authors write. They note that if there is a survival advantage to any strategy, it is likely to be small, but either test is better than no follow-up testing.

“The benefits of follow-up appear to be independent of diagnostic stage (because although there are fewer recurrences with better-stage tumors, they are more likely to be curable), suggesting that stage-specific follow-up strategies may not be necessary. However, thorough staging investigation at the end of primary treatment to detect residual disease is still important because a large number of ‘recurrences’ reported in routine series are probably residual disease that should be detected and treated before embarking on follow-up.”

(doi:10.1001/jama.2013.285718; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The project was funded by the UK National Institute for Health Research Health Technology Assessment program. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Rose reports board membership with GP Update Ltd. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 7, 2014

Media Advisory: To contact Linda Sarna, Ph.D., R.N., call Laura Perry at 818-212-6226 or email Lperry@sonnet.ucla.edu.

Chicago – A survey of health care professionals finds that in 2010-2011, current smoking among this group, except for licensed practical nurses, was lower than the general population, and that the majority had never smoked, according to a study in the January 8 issue of JAMA.

Smoking by health care professionals is a barrier to tobacco interventions with patients. From 2003 to 2006-2007, smoking prevalences among health care professionals demonstrated no significant declines, according to background information in the article.

Linda Sarna, Ph.D., R.N., of the University of California, Los Angeles, and colleagues conducted a study to assess changes in smoking status among health care professionals. The researchers obtained publicly available data from self-respondents to the Tobacco Use Supplement to the Current Population Survey to compare smoking prevalences among health care professionals from 2003 to 2010-2011. Occupations included physicians, registered nurses, licensed practical nurses, pharmacists, respiratory therapists and dental hygienists. Smoking status was defined as never smokers, former smokers, and current smokers.

The 2010-2011 survey data from 2,975 health care professionals indicated that approximately 8 percent were current smokers, ranging from 2 percent among physicians to 25 percent among licensed practical nurses (the rate of current smoking among the general population is 16 percent). There was a decline in prevalence of current smoking among these health care professionals from 2003 to 2010-2011, but the only group with a significant decline in prevalence of current smoking from 2006-2007 to 2010-2011 and from 2003 to 2010-2011 was registered nurses (from 11 percent to 7 percent; a 36 percent decline).

The only significant changes in proportions of those who quit by profession from 2006-2007 to 2010-2011 were among registered nurses (a 13 percent increase), and among licensed practical nurses (a 30 percent decrease).

“Recent declines in smoking among health care professionals may reflect the impact of national tobacco control policies and efforts focused on reducing smoking among registered nurses. After little change in prevalence from 2003 to 2006-2007, the drop in smoking among registered nurses was more than twice that of the 13 percent decrease in the population, and the proportion who have quit was higher than the general population estimate (53.62 percent). Continued smoking and diminished quitting among licensed practical nurses remains a serious concern,” the authors write.

(doi:10.1001/jama.2013.284871; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This study was funded in part by a University of California, Los Angeles School of Nursing endowment to the lead author. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Sarna reports consulting for the International Society for Nurses in Cancer Care and receiving grant funding from Pfizer Independent Grants for Learning and Change. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 7, 2014

Media Advisory: To contact A. Eden Evins, M.D., M.P.H., email Kristen Chadwick at kschadwick@partners.org.

Chicago – Among smokers with schizophrenia or bipolar disease who achieved initial smoking abstinence with a standard 12-week course of the smoking cessation drug varenicline, an additional 40 weeks of treatment resulted in abstinence rates that were three times higher than patients who received placebo, according to a study in the January 8 issue of JAMA.

Although tobacco smoking among adults has declined by 55 percent in the United States since 1965, smoking prevalence among adults with serious mental illness remains higher now than it was in the general population in 1965. Six million of the 11.4 million adults (53 percent) with serious mental illness smoke tobacco (individuals with mental illness smoke at rates approximately twice that of adults without mental disorders). Relatively small trials have reported pharmacologic cessation aids increase initial abstinence rates over behavioral treatment alone for smokers with schizophrenia, suggesting behavioral treatment alone is ineffective for smoking cessation in this population. “Standard courses of pharmacotherapeutic cessation aids improve short-term abstinence, but most who attain abstinence relapse rapidly after discontinuation of pharmacotherapy,” according to background information in the article.

A. Eden Evins, M.D., M.P.H., of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues evaluated the efficacy of longer-term varenicline use and cognitive behavioral therapy (CBT) in smokers with serious mental illness. The trial included 247 smokers with schizophrenia or bipolar disease who received varenicline for 12-weeks and CBT; 87 met abstinence criteria to enter the relapse prevention intervention.

Participants who had 2 weeks or more of continuous abstinence at week 12 of treatment were randomly assigned to receive CBT and varenicline or placebo from weeks 12 to 52. Participants then discontinued study treatment and were followed up to week 76. Eighty-two percent (33 of 40) of those assigned to varenicline and 60 percent (28 of 47) of those receiving placebo remained in the study from weeks 12 through 52.

The researchers found that 24 of 40 patients (60 percent) in the extended-duration varenicline group achieved a biochemically verified (via exhaled carbon monoxide) abstinence rate at week 52 vs. 9 of 47 patients (19 percent) in the placebo group. From weeks 12 through 52, 45 percent of patients achieved continuous abstinence in the varenicline group vs. 15 percent in the placebo group. After treatment discontinuation, by week 76, 30 percent of patients in the varenicline group vs. 11 percent in the placebo group had been continuously abstinent since randomizations at week 12 (for a total of 16 months). Participants assigned to maintenance varenicline had higher continuous-abstinence rates at every post-randomization visit during the 40 weeks of relapse-prevention treatment.

Treatment assignment did not have an effect on severity of psychiatric symptoms, on self-report of overall health, body mass index, or on nicotine withdrawal symptoms.

The authors write that maintenance treatment as indicated in this study “may reduce the high prevalence of tobacco dependence and reduce the heavy burden of smoking-related morbidity and mortality in those with serious mental illness.”

(doi:10.1001/jama.2013.285113; 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, JANUARY 7, 2014

Media Advisory: To contact Jon O. Ebbert, M.D., M.Sc., call Kelley Luckstein at 507-284-5005 or email luckstein.kelley@mayo.edu.
Chicago – Among cigarette smokers, the combined use of the smoking cessation medications varenicline and bupropion, compared with varenicline alone, resulted in better rates of smoking abstinence at 12 weeks, but rates were similar after one year, according to a study in the January 8 issue of JAMA.

Smoking accounts for 62 percent of deaths among female smokers and 60 percent of deaths among male smokers. Innovative pharmacotherapeutic approaches to tobacco-dependence treatment need investigation to reduce smoking-related death and disability, according to background information in the article. “Exploration of combination therapy with existing drugs may provide the best opportunity to advance treatment in the absence of any new pharmacotherapies for tobacco dependence.”

Jon O. Ebbert, M.D., M.Sc., of the Mayo Clinic, Rochester, Minn., and colleagues investigated the efficacy of combination pharmacotherapy with varenicline and bupropion SR (sustained-release) for smoking cessation, compared with varenicline alone (monotherapy). The trial included 315 adults who completed the study. Participants were randomized to 12 weeks of varenicline and bupropion SR or varenicline and placebo. There was follow-up through week 52.

The primary outcome was abstinence rates at week 12, defined as prolonged abstinence (no smoking from 2 weeks after the target quit date) and 7-day point-prevalence abstinence (no smoking past 7 days). Outcomes were biochemically confirmed.

Combination therapy was associated with significantly higher prolonged smoking abstinence rates at 12 (53.0 percent vs. 43.2 percent) and 26 weeks (36.6 percent vs. 27.6 percent) compared with varenicline alone. No significant differences were observed in prolonged smoking abstinence rates between the 2 groups at 52 weeks (30.9 percent vs. 24.5 percent).

No significant differences were observed between the 2 groups at any time point for 7-day point-prevalence smoking abstinence rates.

Anxiety was reported more commonly with combination therapy than with varenicline monotherapy (7.2 percent vs. 3.1 percent), as were depressive symptoms (3.6 percent vs. 0.8 percent).

“Among cigarette smokers, combined use of varenicline and bupropion, compared with varenicline alone, resulted in an increase in prolonged abstinence but not 7-day point-prevalence at 12 and 26 weeks; neither outcome was significantly different at 52 weeks. Further research is required to determine the role of combination treatment in smoking cessation,” the authors conclude.

(doi:10.1001/jama.2013.283185; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: The clinical trial was supported by a National Institutes of Health grant (primary investigator, Dr. Ebbert). Medication (varenicline) was provided by Pfizer. 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, JANUARY 7, 2014

Media Advisory: To contact Benjamin Lê Cook, Ph.D., M.P.H., call David Cecere at 617-591-4044 or email dcecere@challiance.org.
Chicago – In recent years, the decline in smoking among individuals with mental illness was significantly less than among those without mental illness, although the rates of quitting smoking were greater among those receiving mental health treatment, according to a study in the January 8 issue of JAMA.

“Despite significant progress made in reducing tobacco use within the general population, individuals with mental illness smoke at rates approximately twice that of adults without mental disorders and comprise more than half of nicotine-dependent smokers,” according to background information in the article. Mental illness is associated with higher levels of nicotine dependence, intensity of smoking, and smoking severity (i.e., number of cigarettes/week). Tobacco cessation efforts have focused on the general population rather than individuals with mental illness.

Benjamin Lê Cook, Ph.D., M.P.H., of the Harvard Medical School/Cambridge Health Alliance, Cambridge, Mass., and colleagues used nationally representative surveys of U.S. residents to compare trends in smoking rates between adults with and without mental illness and across multiple disorders (2004-2011 Medical Expenditure Panel Survey [MEPS]) and compared rates of smoking cessation among adults with mental illness who did and did not receive mental health treatment (2009-2011 National Survey of Drug Use and Health [NSDUH]).The MEPS sample included 32,156 respondents with mental illness (reporting severe psychological distress, probable depression, or receiving treatment for mental illness) and 133,113 without mental illness. The NSDUH sample included 14,057 lifetime smokers with mental illness.

The researchers found that adjusted smoking rates declined significantly from 2004 to 2011 among individuals without mental illness, decreasing from 19.2 percent to 16.5 percent, but did not change significantly among those with mental illness, decreasing only from 25.3 percent to 24.9 percent. “… the fact that smoking rates for individuals receiving mental health care have not experienced the same rates of decline as the general population suggests limited adoption of integrated treatments and ongoing barriers to cessation treatment in mental health care settings.”

The rate of quitting smoking among individuals who received mental health treatment was 37.2 percent, significantly higher than the 33.1 percent quit rate among those who did not receive mental health treatment. Receiving any mental health treatment significantly increased the probability of having quit.

“These results suggest that smokers can quit and remain abstinent from cigarettes during mental health treatment and that this is a promising setting to promote smoking cessation. It also indicates the importance of assisting smokers with mental illness in overcoming barriers to accessing mental health care (e.g., insuring the uninsured, increasing the supply of mental health care professionals, improving linkages between primary care and mental health care) as a means to address smoking-related harm,” the authors write.

“The mechanisms that support persistently higher rates of smoking among individuals with mental illness are complex and remain understudied. Patients with mental illness may attribute greater benefits and reward value to smoking compared with patients without psychiatric disorders or may experience more difficult life circumstances, higher negative affect, or a relative lack of alternative rewards. Identifying new interventions to address mechanisms specific to this population should be a priority for tobacco control policy.”

(doi:10.1001/jama.2013.284985; 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 (Dr. Cook, principal investigator) and the William F. Milton Fund. 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, JANUARY 7, 2014

Media Advisory: To contact corresponding author Christopher J.L. Murray, M.D., D.Phil., call Rhonda Stewart at 206-897-2863 or email stewartr@uw.edu.
Chicago – Since 1980, the global prevalence of daily tobacco smoking has declined by an estimated 25 percent for men and 42 percent for women, although because of population growth, the number of smokers has increased (41 percent for males; 7 percent for females), along with a 26 percent increase in the number of cigarettes consumed, according to a study in the January 8 issue of JAMA.

“Given the importance of tobacco as a risk to health, monitoring the distribution and intensity of tobacco use is critical for identifying priority areas for action and evaluating progress. Early efforts to estimate smoking prevalence were based on limited data for many developing countries,” according to background information in the article. “Despite improvements in data availability, information on trends has not been synthesized in a systematic and consistent way.”

Marie Ng, Ph.D., of the Institute for Health Metrics and Evaluation, University of Washington, Seattle, and colleagues conducted a study to estimate levels and trends in the prevalence of smoking by age and sex and consumption of cigarettes for 187 countries from 1980 to 2012. Nationally representative sources that measured tobacco use were systematically identified. Survey data that did not report daily tobacco smoking were adjusted using the average relationship between different definitions.

The researchers found that between 1980 and 2012, the estimated prevalence of daily tobacco smoking for men declined from 41 percent to 31 percent; for women, there was a decline from 10.6 percent to 6.2 percent. Global progress in reducing the prevalence of smokers appeared to fall into 3 phases for both men and women: modest progress from 1980 to 1996, followed by a decade of more rapid global progress, then a slowdown in reductions from 2006 to 2012, with an apparent increase since 2010 for men. This deceleration in the global trend was in part due to increases in the number of smokers since 2006 in several large countries including Bangladesh, China, Indonesia and Russia.

While prevalence declined, because of the growth in population older than 15 years of age, there has been a continuous increase in the number of men and women who smoke daily, increasing from 721 million in 1980 to 967 million in 2012, with a 41 percent increase in the number of male daily smokers and a 7 percent increase for female smokers. Between 1980 and 2012, the number of cigarettes consumed worldwide increased by 26 percent.

Prevalence rates exhibited substantial variation across age, sex, and countries, with rates below 5 percent for women in some African countries to more than 50 percent for men in countries such as Indonesia, Armenia, Laos, Papua New Guinea and Russia. The number of cigarettes per smoker per day also varied widely across countries.

“Although in several countries substantial uncertainty remains in monitoring tobacco exposure and estimating the disease burden associated with it, there can be no doubt that both are large. Policies and strategies to improve global health must include comprehensive efforts to control tobacco use, as envisaged under the Framework Convention on Tobacco Control. But implementation of policies is not enough; countries, and the global health community, need to collect timely, reliable, and detailed information on the effect of those policies, particularly among vulnerable populations and those being directly targeted by the tobacco industry. If global tobacco control is to benefit from concerted policy action, population-level surveillance of tobacco use and its health effects needs to be strengthened and routinely used to evaluate the impact of tobacco control strategies,” the authors write.

“Although many countries have implemented control policies, intensified tobacco control efforts are particularly needed in countries where the number of smokers is increasing.”

(doi:10.1001/jama.2013.284692; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2.0. This study is supported by a grant from the Bill & Melinda Gates Foundation and the State of Washington. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Lopez reports consultancy for the Institute for Health Metrics and Evaluation. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 7, 2014

Media Advisory: To contact Theodore R. Holford, Ph.D., call Helen Dodson at 203-436-3984 or email helen.dodson@yale.edu.
Chicago – Researchers estimate that tobacco control in the U.S. since 1964 has been associated with the avoidance of an estimated 8 million premature smoking-attributable deaths, with the beneficiaries of these avoided early deaths having gained, on average, nearly 2 decades of life, according to a study in the January 8 issue of JAMA. The authors add that smoking-attributable death occurred in approximately 17.7 million people during this time period, and that efforts must continue to reduce the effect of smoking on the nation’s death toll.

“January 2014 marks the 50th anniversary of the first surgeon general’s report on smoking and health. The report inaugurated efforts to reduce cigarette smoking and its effects on health. Those efforts by governments, voluntary organizations, and the private sector—education on smoking’s dangers, increases in cigarette taxes, smoke-free air laws, media campaigns, marketing and sales restrictions, lawsuits, and cessation treatment programs—have comprised the nation’s tobacco control efforts,” according to background information in the article.

Theodore R. Holford, Ph.D., of the Yale University School of Public Health, New Haven, Conn., and colleagues conducted a study to model reductions in smoking-related mortality associated with implementation of tobacco control since 1964. Smoking histories for individual birth cohorts that actually occurred and under likely scenarios had tobacco control never emerged were estimated. National mortality rates and mortality rate ratio estimates from analytical studies of the effect of smoking on mortality yielded death rates by smoking status. Actual smoking-related mortality from 1964 through 2012 was compared with estimated mortality under no tobacco control. National Health Interview Surveys yielded cigarette smoking histories for the U.S. adult population in 1964-2012.

The model estimated that a total of 17.7 million smoking-attributable deaths occurred between 1964 and 2012. Overall, an estimated reduction of 8.0 million premature smoking-attributable deaths (or “lives saved”) were associated with tobacco control during this time period (5.3 million men and 2.7 million women). More than half of these, 4.4 million, occurred before age 65 years. The estimated number of lives saved each year has increased steadily over time.

From 1964-2012, it is estimated that overall, a gain of 157 million years of life was associated with tobacco control, 111 million for men and 46 million for women. “This suggests that individuals who avoided a premature smoking-related death gained 19.6 years of life on average (157 million years divided by 8.0 million lives saved),” the authors write.

For the population as a whole, life expectancy for men at age 40 years has increased 7.8 years. Without tobacco control, the estimated increase would have been 5.5 years. “Hence, 2.3 years or 30 percent of improved life expectancy for men is projected to be associated with tobacco control. In women, life expectancy at age 40 years increased 5.4 years, but without tobacco control, it would have been projected to increase by only 3.8 years. Tobacco control appears to be associated with 1.6 years of the improvement in life expectancy for women or 29 percent of the gain.”

“Tobacco control has made a unique and substantial contribution to public health over the past half century. This study provides a quantitative perspective to the magnitude of that contribution.”

“Despite the success of tobacco control efforts in reducing premature deaths in the United States, smoking remains a significant public health problem,” the researchers write. “Today, a half century after the surgeon general’s first pronouncement on the toll that smoking exacts from U.S. society, nearly a fifth of U.S. adults continue to smoke, and smoking continues to claim hundreds of thousands of lives annually. No other behavior comes close to contributing so heavily to the nation’s mortality burden. Tobacco control has been a great public health success story but requires continued efforts to eliminate tobacco-related morbidity and mortality.”

(doi:10.1001/jama.2013.285112; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded in part by the National Cancer Institute. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, January 7 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 31, 2013

Media Advisory: To contact Tuomo J. Meretoja, M.D., Ph.D., email tuomo.meretoja@fimnet.fi.

 
Chicago – In a study that included more than 800 women who had undergone surgery for breast cancer, the majority reported some level of pain 12 months after surgery, and factors associated with pain included chronic preoperative pain, chemotherapy, preoperative depression and pain in the area to be operated, according to a study appearing in the January 1 issue of JAMA.

“Persistent pain following breast cancer treatments remains a significant clinical problem despite improved treatment strategies. Data on factors associated with persistent pain are needed to develop prevention and treatment strategies and to improve the quality of life for breast cancer patients,” according to background information in the article.

Tuomo J. Meretoja, M.D., Ph.D., of Helsinki University Central Hospital, Helsinki, Finland, and colleagues examined the prevalence and severity and factors associated with chronic pain after breast cancer surgery and treatments. The study included 860 patients younger than 75 years with nonmetastasized breast cancer treated at the Helsinki University Central Hospital in 2006-2010. A questionnaire was sent to patients 12 months after surgery, with assessments of presence and intensity of pain.

At 12 months after surgery, 34.5 percent of the patients reported no pain, 49.7 percent mild pain, 12.1 percent moderate pain, and 3.7 percent severe pain. The factors associated with pain at 12 months were chronic preoperative pain, preoperative pain in the area to be operated, axillary lymph node dissection, preoperative depression, chemotherapy and radiotherapy.

“These findings may be useful in developing strategies for preventing persistent pain following breast cancer treatment. To identify patients who would benefit from preventive interventions, a risk assessment tool is needed,” the authors write.

(doi:10.l001/jama.2013.278795; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 31, 2013

Media Advisory: To contact Maurice W. Dysken, M.D., call Ralph Heussner at 612-467-3012 or email Ralph.Heussner@va.gov. To contact editorial co-author Denis A. Evans, M.D., email Deb Song at Deb_Song@rush.edu.

 
Chicago – Among patients with mild to moderate Alzheimer disease, a daily dosage of 2,000 IUs of vitamin E, compared to placebo, was effective in slowing functional decline and in reducing caregiver time in assisting patients, according to a study appearing in the January 1 issue of JAMA.

Alpha tocopherol, a fat-soluble vitamin (E) and antioxidant, has been studied in patients with moderately severe Alzheimer disease (AD) and in participants with mild cognitive impairment (MCI) but has not been studied in patients with mild to moderate AD. In patients with moderately severe AD, vitamin E was shown to be effective in slowing clinical progression. The drug memantine has been shown to be effective in patients with AD and moderately severe dementia, according to background information in the article.

Maurice W. Dysken, M.D., of the Minneapolis VA Health Care System, and colleagues examined the effectiveness and safety of vitamin E, memantine, and the combination for treatment of functional decline in patients with mild to moderate AD who were taking an acetylcholinesterase inhibitor (a chemical that increases the level and duration of action of the neurotransmitter acetylcholine). The trial included 613 patients at 14 Veterans Affairs medical centers. Participants received either 2,000 IU/day of vitamin E (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). Change in functional decline was gauged via the Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78).

Over the average follow-up time of 2.3 years, participants receiving vitamin E had slower functional decline than those receiving placebo, with the annual rate of decline in ADLs reduced by 19 percent. This treatment effect translates into a clinically meaningful delay in progression in the vitamin E group of 6.2 months. Neither memantine nor the combination of vitamin E and memantine showed clinical benefit in this trial.

In addition, caregiver time was reduced by about 2 hours per day in the vitamin E group.

All-cause death and safety analyses showed a difference only on the serious adverse event of “infections or infestations” with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants).

The authors write that the current study is one of the largest and longest treatment trials in patients with mild to moderate AD, and that it provides information on reported safety issues of vitamin E, with results from previous trials resulting in decreased prescribing for patients with AD. “In contrast to the conclusion drawn from a 2005 meta-analysis of vitamin E, which showed that high-dose vitamin E (≥ 400 IU/d) may increase the risk of all-cause mortality, we found no significant increase in mortality with vitamin E. The annual mortality rate was 7.3 percent in the alpha tocopherol group vs. 9.4 percent for the placebo group.”

The researchers note that decline in functioning in AD is increasingly recognized as an important determinant of both patient quality of life and social and economic costs. “In the current study, the placebo group lost approximately 3 units more on the ADCS-ADL Inventory than the alpha tocopherol group. A loss of this magnitude could translate into either the complete loss of being able to dress or bath independently, for example, or losing independence on any 3 different ADLs. Because vitamin E is inexpensive, it is likely these benefits are cost-effective as alpha tocopherol improves functional outcomes and decreases caregiver burden.”

(doi:10.l001/jama.2013.282834; 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.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, December 31 at this link.

Editorial: Vitamin E, Memantine, and Alzheimer Disease

Denis A. Evans, M.D., of Rush University Medical Center, Chicago, and colleagues comment on the findings of this study in an accompanying editorial.

“Many features of the trial by Dysken et al reflect the best in trials of AD therapy, especially its size, duration, and separation from commercial motivation. However, as with almost all previous AD trials, the therapeutic effect seen was modest and more relevant to AD symptoms and consequences than to reversal of the disease process. The importance of treating patients with AD is clear, but finding the best balance between treatment and prevention efforts is challenging for this grim disease affecting millions of people from all developed countries.”

“Considering the difficulties inherent in trying to treat rather than prevent very high-prevalence diseases and the limitations thus far of the therapeutic efforts for people with AD, shifting to more emphasis on prevention seems warranted.”

(doi:10.l001/jama.2013.282835; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 24, 2013

Media Advisory: To contact John L. Berk, M.D., call Jenny Eriksen Leary at 617-638-6841 or email jenny.eriksen@bmc.org.

Chicago – Among patients with familial amyloid polyneuropathy, a lethal, genetic neurodegenerative disease, use of the nonsteroidal anti-inflammatory agent diflunisal compared with placebo for 2 years reduced the rate of progression in neurological impairment and preserved quality of life, according to a study appearing in the December 25 issue of JAMA.

Familial amyloid polyneuropathy is characterized by progressive neurologic deficits and disability which prove fatal if left untreated. Fewer than 10,000 people are estimated to be clinically affected worldwide, according to background information in the article. Diflunisal showed potential benefit in a phase 1 study.

John L. Berk, M.D., of the Boston University School of Medicine, and colleagues, pursuing the NIH mission to repurpose old drugs, randomized 130 patients from Sweden, Italy, Japan, England, and the United States to receive diflunisal (n=64) or placebo (n=66) twice daily for 2 years to determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy.

Patients randomized to diflunisal exhibited less progression of polyneuropathy than those assigned to placebo. The inhibitory effect of diflunisal on neuropathy progression was detectable at 1 and 2 years, and at 2 years, 29.7 percent of the diflunisal group compared to 9.4 percent of the placebo group exhibited neurological stability. Physical quality of life stabilized from the beginning of the study to 2 years in those assigned to diflunisal treatment while decreasing in the placebo group.

The authors write that their trial is pivotal for several reasons: it is the first randomized trial involving a broad cross-section of the spectrum of disease; it provides invaluable natural history data on the rate of neurological disease progression; and it establishes that diflunisal, a low-cost treatment, is well tolerated by familial amyloid polyneuropathy patients with a spectrum of neuropathy.

“Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy.”

(doi:10.l001/jama.2013.283815; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 24, 2013

Media Advisory: To contact Henry P. Parkman, M.D., call Kathleen Duffy at 267-800-4359 or email Kathleen.Duffy@tuhs.temple.edu.

Chicago – Among patients with idiopathic (of unknown cause) gastroparesis, use of the antidepressant nortriptyline compared with placebo for 15 weeks did not result in improvement in overall symptoms, according to a study appearing in the December 25 issue of JAMA. Gastroparesis is a disease of the muscles of the stomach or the nerves controlling the muscles that causes the muscles to stop working, which can result in inadequate grinding of food by the stomach and poor emptying of food from the stomach into the intestine.

Gastroparesis remains a challenging syndrome to manage, with few effective treatments and a lack of rigorously controlled trials. One possible approach to treatment is based on the hypothesis that some of the symptoms (e.g., nausea, pain) arise because of changes in certain nerves. Tricyclic antidepressants are a category of drug often used to treat refractory (not yielding readily to treatment) symptoms of nausea, vomiting, and abdominal pain, according to background information in the article.

Henry P. Parkman, M.D., of Temple University, Philadelphia, and colleagues randomized 130 patients with idiopathic gastroparesis to nortriptyline (n = 65) or placebo (n = 65) to determine whether treatment with the tricyclic antidepressant nortriptyline would result in improvement of symptoms. Study drug dose was increased at 3-week intervals. The primary outcome measure was a decrease in the patient’s Gastroparesis Cardinal Symptom Index (GCSI) score of at least 50 percent on 2 consecutive visits during 15 weeks of treatment.

The researchers found that the proportion of patients experiencing symptomatic improvement on 2 visits did not differ between the treatment groups: 15 (23 percent) in the nortriptyline group vs. 14 (21 percent) in the placebo group. There were also no treatment group differences in measures of nausea, fullness or early satiety, or bloating.  Treatment was stopped more often in the nortriptyline group (29 percent) than in the placebo group (9 percent), but numbers of adverse events were not different.

“Our results raise general doubts about the utility of tricyclic antidepressants in low doses as a strategy for the treatment of idiopathic gastroparesis,” the authors conclude.

(doi:10.l001/jama.2013.282833; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This trial, from the Gastroparesis Clinical Research Consortium, is supported by National Institute of Diabetes and Digestive and Kidney Diseases grants. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 24, 2013

Media Advisory: To contact Chinazo O. Cunningham, M.D., M.S., call Kim Newman at 718-430-3101 or email Sciencenews@einstein.yu.edu.

Chicago – A survey of opioid treatment programs finds that the proportion offering on-site testing for human immunodeficiency virus (HIV) and sexually transmitted infections (STIs) declined substantially between 2000 and 2011, despite guidelines recommending routine opt-out HIV testing in all health care settings, according to a study appearing in the December 25 issue of JAMA.

“Opioid dependence is a risk factor for HIV, STIs, and hepatitis C virus (HCV) infection. Opioid treatment programs, which provide treatment to more than 300,000 opioid-dependent individuals in the United States, are well-positioned to offer testing for these infectious diseases to a high-risk population. They were among the first venues to offer HIV testing and are more likely to offer HIV, STI, and HCV testing than other drug treatment programs. Private for-profit opioid treatment programs are increasingly widespread and such programs offer on-site HIV testing less often than nonprofit and public programs. However, with the 2006 national recommendations for routine opt-out HIV testing, we hypothesized that the percentage of programs offering on-site testing for HIV, STIs, and HCV would increase,” the authors write.

Marcus A. Bachhuber, M.D., and Chinazo O. Cunningham, M.D., M.S., of the Albert Einstein College of Medicine, New York, analyzed data from a survey sent to directors of drug treatment facilities and tabulated the percentage of opioid treatment programs offering on-site HIV, STI, and HCV testing from 2000 to 2011.

The number of U.S. opioid treatment programs increased from 849 in 2000 to 1,175 in 2011. The percentage of programs operating as for-profit businesses increased from 43 percent to 54 percent, nonprofits decreased from 43 percent to 36 percent, and public programs decreased from 14 percent to 10 percent. From 2000 to 2011, the absolute number of programs offering testing for HIV, STIs, and HCV increased but the percentage offering on-site testing for HIV declined by 18 percent and for STIs by 13 percent. There was no change for HCV testing. More than 75 percent of public programs offered on-site testing for each infection, with no change over time.

“Declines were most pronounced in for-profit programs, suggesting that persons enrolled in these programs may be at increased risk for delayed diagnosis and continued transmission of HIV, STIs, and HCV,” the authors write.

“Opioid treatment programs are important venues for offering testing to high-risk individuals. As the number of for-profit opioid treatment programs increases, and the opioid, HIV, and HCV epidemics continue to intersect, further work is needed to understand and reverse declines in offering on-site testing.”

(doi:10.l001/jama.2013.278456; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by grants from the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Cunningham’s husband was recently employed by Pfizer Pharmaceuticals and is currently employed by Quest Diagnostics. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 24, 2013

Media Advisory: To contact Scott W. Powers, Ph.D., call Jim Feuer at 513-636-4656 or email Jim.Feuer@cchmc.org. To contact editorial author Mark Connelly, Ph.D., call Jessica Salazar at 816-346-1346 or email jmsalazar@cmh.edu.

Chicago – Among children and adolescents with chronic migraine, the use of cognitive behavioral therapy (CBT) resulted in greater reductions in headache frequency and migraine-related disability compared with headache education, according to a study appearing in the December 25 issue of JAMA.

“In adults, more than 2 percent of the population has chronic migraine and in children and adolescents the prevalence is up to 1.75 percent. In pediatric patients who seek care in headache specialty clinics, up to 69 percent have chronic migraine; however, there are no interventions approved by the U.S. Food and Drug Administration for the treatment of chronic migraine in young persons. As a result, current clinical practice is not evidence-based and quite variable,” according to background information in the article.

Scott W. Powers, Ph.D., of Cincinnati Children’s Hospital Medical Center, and colleagues randomized 135 participants (79 percent female) 10 to 17 years of age diagnosed with chronic migraine (≥ 15 days with headache/month) and a Pediatric Migraine Disability Assessment Score (PedMIDAS) greater than 20 points (disability score range: 0-10 for little to none, 11-30 for mild, 31-50 for moderate, >50 for severe) to CBT (n = 64) or headache education (n = 71). The study was conducted in the Headache Center at Cincinnati Children’s Hospital between October 2006 and September 2012; 129 participants completed 20-week follow-up and 124 completed 12-month follow-up. The interventions consisted of 10 CBT or 10 headache education sessions involving equivalent time and therapist attention; CBT included training in pain coping, modified to include a biofeedback component. Each group received amitriptyline; follow-up visits were conducted at 3, 6, 9, and 12 months.

On average, at the beginning of the trial, participants reported 21 of 28 days with a headache and a PedMIDAS of 68 points, indicating a severe grade of disability. From pretreatment to posttreatment, CBT resulted in a decrease of 11.5 headache days vs. 6.8 days with headache education. At 12-month follow-up, 86 percent of CBT participants had a 50 percent or greater reduction in days with headache vs. 69 percent of the headache education group; 88 percent of CBT participants had a PedMIDAS of less than 20 points (mild to no disability) vs. 76 percent of the headache education group.

“Now that there is strong evidence for CBT in headache management, it should be routinely offered [to younger people] as a first-line treatment for chronic migraine along with medications and not only as an add-on if medications are not found to be sufficiently effective. Also, CBT should be made more accessible to patients by inclusion as a covered service by health insurance as well as testing of alternate formats of delivery, such as using online or mobile formats, which can be offered as an option if in-person visits are a barrier,” the authors write.

(doi:10.l001/jama.2013.282533; 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.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, December 24 at this link.

Editorial: Cognitive Behavioral Therapy for Treatment of Pediatric Chronic Migraine

System barriers may affect the likelihood of CBT being implemented as a first-line treatment for pediatric chronic migraine, writes Mark Connelly, Ph.D., of Children’s Mercy Hospitals and Clinics, Kansas City, in an accompanying editorial.

“Creative means of delivering CBT for pediatric chronic migraine (e.g., via telehealth or Internet-based programs, using behavioral health consultants in primary care offices) will be necessary for reducing current access and referral barriers that could be encountered by many families and physicians. Widening the availability of interdisciplinary models of training and treatment delivery also will be important for helping ensure that children with chronic migraine routinely receive combination therapies rather than being referred for psychological therapy only after other approaches fail.”

“Ideally with the efforts of the health care community and other relevant stakeholders, the suggestion by Powers et al to consider CBT along with medication as a first-line treatment for chronic migraine in children will be implemented into practice well before the typical translation gap. Additional studies are warranted, however, to identify methods of preventing chronic migraine development and to determine the medications and combination therapies that further maximize improvements in health and quality of life outcomes for children and adolescents with chronic migraine.”

(doi:10.l001/jama.2013.282534; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 24, 2013

Media Advisory: To contact Edna B. Foa, Ph.D., call Steve Graff at 215-349-5653 or email Stephen.Graff@uphs.upenn.edu. To contact Sean Perrin, Ph.D., email sean.perrin@psy.lu.se.

Chicago – Adolescents girls with sexual abuse-related posttraumatic stress disorder (PTSD) experienced greater benefit from prolonged exposure therapy (a type of therapy that has been shown effectiveness for adults) than from supportive counseling, according to a study appearing in the December 25 issue of JAMA.

“Adolescence is a unique developmental stage that is associated with increased exposure to traumatic events that can lead to PTSD,” according to background information in the article. “Prolonged exposure therapy is the most studied evidence-based, theory-driven treatment for adults with PTSD, but it is rarely provided to adolescents because of concern that it may exacerbate PTSD symptoms or the belief that patients must master coping skills before exposure can safely be provided.” Prolonged exposure therapy is a form of behavior therapy and cognitive behavioral therapy, characterized by re-experiencing the traumatic event through remembering it and engaging with, rather than avoiding, reminders of the trauma (triggers).

Edna B. Foa, Ph.D., of the University of Pennsylvania, Philadelphia, and colleagues hypothesized that a prolonged exposure program modified for adolescents (prolonged exposure-A) would be superior to supportive counseling in reducing interviewer-assessed PTSD severity, rate of PTSD diagnosis, self-reported PTSD severity and depression, and improving general functioning. The trial included 61 adolescent girls with PTSD; counselors who had not previously administered prolonged exposure therapy provided the treatments in a community mental health clinic. Participants were randomized to receive fourteen 60- to 90-minute sessions of prolonged exposure therapy (n = 31) or supportive counseling (n = 30). Follow-up was 12 months.

Participants who received prolonged exposure showed greater improvement in PTSD symptoms and were more likely to lose their PTSD diagnosis and be classified as good responders than those who received supportive counseling. Also, participants who received prolonged exposure demonstrated greater improvement in depressive symptoms and functioning than those who received supportive counseling. The superiority of prolonged exposure over supportive counseling was also evident at 12-month follow-up.

“An important clinical implication of these results is the feasibility of disseminating and implementing prolonged exposure-A in community mental health clinics for adolescents who are motivated to participate in treatment. Prolonged exposure-A was successfully implemented by counselors with no prior training in evidence-based treatments and with relatively little supervision from experts. This is important because the need for evidence-based treatment of PTSD far exceeds the availability of these services,” the authors write.

(doi:10.l001/jama.2013.282829; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was conducted with support from the National Institute of Mental Health awarded to Dr. Foa. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Prolonged Exposure Therapy for PTSD in Sexually Abused Adolescents

Sean Perrin, Ph.D., of Lund University, Lund, Sweden, comments on the findings of this study in an accompanying editorial.

“Findings from the current report by Foa et al should allay therapist concerns about any potential harmful effects of exposure and the need for extensive preparation of the patient for exposure. The heightened arousal that accompanies exposure to traumatic reminders in session usually dissipates within a few sessions and leads to rapid reductions in symptoms between sessions. Thus, the heightened arousal that many therapists fear causing by leading the patients through exposure exercises is an expected and integral part of the recovery progress.”

“In the future, greater efforts are needed to increase awareness about the safety, tolerability, and effectiveness of treatments like prolonged exposure. Research is also needed to determine the minimum amount of training and supervision for therapists to effectively deliver prolonged exposure and similar exposure-focused treatments to patients with PTSD and other anxiety disorders.”

(doi:10.l001/jama.2013.283944; 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. (CT) WEDNESDAY, DECEMBER 18, 2013

Media Advisory: To contact corresponding author Paul A. James, M.D., call Molly Rossiter at 319-356-7127 or email molly-rossiter@uiowa.edu.

Chicago – A new guideline for the management of high blood pressure, developed by an expert panel and containing nine recommendations and a treatment algorithm (flow chart) to help doctors treat patients with hypertension, was published online by JAMA.

Hypertension is the most common condition seen in primary care and leads to heart attack, stroke, kidney failure, and death if not detected early and treated appropriately. “Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults,” according to information in the article.

The report, the “2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults,” is from panel members appointed to the Eighth Joint National Committee.

The guideline addresses three questions related to high BP management:

1) At what BP should medication be started in patients with hypertension?

2) What BP goal should patients achieve to know they are enjoying proven health benefits from their medication?

3) What are the best choices for medications to begin treatment for high blood pressure?

The nine recommendations in the guideline answer those three questions. In summary, “There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years.”

“There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes.”

The authors emphasize important differences from the past versions of the guideline. For development of these recommendations, “evidence was drawn from randomized controlled trials (RCTs), which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important health outcomes,” the authors write. These guidelines also sought to establish “similar treatment goals for all hypertensive populations except when evidence … supports different goals for a particular subpopulation.”

Also, rather than defining hypertension, the panel addressed threshold blood pressure for starting treatment. The report recommends beginning treatment for people aged 60 and older at a blood pressure of 150/90, and treating to below that level based on trial evidence, but the authors emphasize that “this evidence-based guideline has not redefined high BP and the panel believes that the 140/90 mm Hg definition from Joint National Committee 7 remains reasonable.” Lifestyle interventions should be used for everyone with blood pressures in this range.

They add that with each strategy, clinicians should regularly assess BP, encourage evidence-based lifestyle and adherence interventions, and adjust treatment until goal BP is attained and maintained. “For all persons with hypertension, the potential benefits of a healthy diet, weight control, and regular exercise cannot be overemphasized. These lifestyle treatments have the potential to improve BP control and even reduce medication needs.”

“The recommendations from this evidence-based guideline from panel members appointed to the Eighth Joint National Committee (JNC 8) offer clinicians an analysis of what is known and not known about BP treatment thresholds, goals, and drug treatment strategies to achieve those goals based on evidence from RCTs. However, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient. We hope that the algorithm will facilitate implementation and be useful to busy clinicians. The strong evidence base of this report should inform quality measures for the treatment of patients with hypertension,” the authors conclude.

(doi:10.l001/jama.2013.284427; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Assessing the Trustworthiness of the Guideline for Management of High Blood Pressure in Adults

Harold C. Sox, M.D., of the Dartmouth Institute for Health Policy and Clinical Practice, Hanover, N.H., calls attention to the fact that the 2014 hypertension guideline did not undergo specialty society review as was originally planned, and he addresses the trustworthiness of the guideline, and guidelines in general, in an editorial.

He asks “First, what are the key elements of trustworthiness in a guideline? Second, how does this guideline measure up? Third, what is the role of expert review of guidelines? Fourth, what is the pathway to guidelines that the public can trust?”

He ultimately concludes that the panel of guideline authors, by agreeing to share its record of the review process with anyone who asks, meets the standard of transparency and review that proper guideline development now requires. “A rigorous, transparent process for developing and reviewing guidelines matters a great deal because guidelines are increasingly driving the practice of medicine.”

(doi:10.l001/jama.2013.284429; 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.

Media Advisory: To contact Harold C. Sox, M.D., call K. Derik Hertel at 603-650-1211 or email kenneth.d.hertel@dartmouth.edu.

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Editorial: Updated Guidelines for Management of High Blood Pressure – Recommendations, Review, and Responsibility

Howard Bauchner, M.D., Editor in Chief, JAMA, Chicago, and colleagues comment on the production of guidelines.

“Producing guidelines in the United States has become increasingly more complicated and contentious. This likely reflects the strongly held beliefs of many stakeholders, including physicians and patients. For instance, the Infectious Diseases Society of America was embroiled in complicated legal proceedings after producing guidelines for the management of Lyme disease. There was a great deal of reaction from health professionals and the public after the U.S. Preventive Services Task Force released updated recommendations regarding mammography screening in women. Recently, in June 2013, the NHLBI announced its decision to discontinue its participation in the development of clinical guidelines, including the hypertension guideline. (Accordingly, as the authors clearly indicate, ‘This report is therefore not an NHLBI sanctioned report and does not reflect the views of NHLBI.’) Instead, the NHLBI has partnered with and shifted the responsibility for generating guideline products to selected specialty organizations, such as the American College of Cardiology and the American Heart Association, whose recently released guidelines on assessment of cardiovascular risk and treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk have been met with controversy.”

“Rigorously developed, thoroughly reviewed, evidence-based, trustworthy guidelines are critical to advance clinical medicine and improve health, and biomedical journals have a responsibility to disseminate important guidelines in an objective manner. We are pleased to publish the ‘2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults’ from the panel members appointed to the Eighth Joint National Committee (JNC8). We anticipate debate and discussion about the clinical application of these recommendations and the related policy issues. JAMA welcomes this responsibility, and indeed, embraces the opportunity to provide evidence-based recommendations to help clinicians improve the care of their patients.”

(doi:10.l001/jama.2013.284432; 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.

Media Advisory: To contact corresponding author Phil B. Fontanarosa, M.D., M.B.A., call Jim Michalski at 312-464-5785 or email Jim.Michalski@jamanetwork.org.

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Editorial: Recommendations for Treating Hypertension – What Are the Right Goals and Purpose?

Eric D. Peterson, M.D., M.P.H., of Duke University Medical Center, Durham, N.C., and colleagues write in an accompanying editorial that “while it is likely that there will be considerable controversy in hypertension treatment for the foreseeable future, several critical next steps are needed.”

“First, larger RCTs need to compare different BP thresholds in diverse patient populations. Ideally, these investigations would be conducted using the evolving strategies of practical clinical trials designs to improve their efficiency and real-world generalizability. Second, there is an important need to create a national consensus group to draft an updated comprehensive practice guideline that would harmonize the hypertension guideline with other cardiovascular risk guidelines and recommendations, thereby resulting in a more coherent overall cardiovascular prevention strategy. … Third, the process of translating practice guidelines into performance measures needs to be more deliberate. For example, performance measures derived from guidelines need to be cognizant of the potential unintended consequences if treatment goals are set too strict or adherence to these is too rigid. Finally, once the right targets for BP thresholds are determined, patients and physicians need to work together to consistently achieve these new goals.”

(doi:10.l001/jama.2013.284430; 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.

Media Advisory: To contact Eric D. Peterson, M.D., M.P.H., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 17, 2013

Media Advisory: To contact Steven P. Engebretson, D.M.D., M.S., M.S., call Elyse Bloom at 212-998-9910 or email dental.communications@nyu.edu.

Chicago – For persons with type 2 diabetes and chronic periodontitis, nonsurgical periodontal treatment did not result in improved glycemic control, according to a study appearing in the December 18 issue of JAMA.

Emerging evidence implicates inflammation in the development of type 2 diabetes. Chronic periodontitis, a destructive inflammatory disorder of the soft and hard tissues supporting the teeth, is a major cause of tooth loss in adults. Nearly half of the U.S. population older than 30 years is estimated to have chronic periodontitis, according to background information in the article. Individuals with diabetes are at greater risk for chronic periodontitis. Well-controlled diabetes is associated with less severe chronic periodontitis and a lower risk for progression of periodontitis, suggesting that level of glycemia is an important mediator of the relationship between diabetes and risk of chronic periodontitis. Limited evidence suggests that periodontal therapy may improve glycemic control.

Steven P. Engebretson, D.M.D., M.S., M.S., of New York University, New York, and colleagues examined whether nonsurgical periodontal therapy, compared with no therapy, reduces levels of glycated hemoglobin (HbA_lc) levels in persons with type 2 diabetes and moderate to advanced chronic periodontitis. The trial included 514 participants who were enrolled between November 2009 and March 2012 from diabetes and dental clinics and communities affiliated with 5 academic medical centers. The treatment group (n = 257) received scaling and root planing plus an oral rinse at baseline and supportive periodontal therapy at 3 and 6 months. The control group (n = 257) received no treatment for 6 months.

The researchers found that levels of HbA_lc did not change between baseline and the 3-month or 6-month visits in either the treatment or the control group, and the target 6-month reduction of HbA_lc level of 0.6 percent or greater was not achieved. There were no differences in HbA_lc levels across centers.

Periodontal measures improved in the treatment group compared with the control group at 6 months.

“This multicenter randomized clinical trial of nonsurgical periodontal treatment for participants with type 2 diabetes and chronic periodontitis did not demonstrate a benefit for measures of glycemic control. Although periodontal treatment improved clinical measures of chronic periodontitis in patients with diabetes, the findings do not support the use of nonsurgical periodontal treatment for the purpose of lowering levels of HbA_lc,” the authors conclude.

(doi:10.l001/jama.2013.282431; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 17, 2013

Media Advisory: To contact Eric J. Shiroma, M.Ed., M.S., call Jessica Maki at 617-525-6373 or email jmaki3@partners.org.

Chicago – Among 7,000 older women who wore an accelerometer to measure their movement, about two-thirds of their waking time was spent in sedentary behavior, most of which occurred in periods of less than 30 minutes, according to a study appearing in the December 18 issue of JAMA.

Recent studies suggest sedentary behavior may be a risk factor for adverse health outcomes. However, few data exist on how this behavior is patterned (e.g., does most sedentary behavior occur in a few long periods or in many short periods), according to background information in the article.

Eric J. Shiroma, M.Ed., M.S., of the Harvard School of Public Health, Boston, and colleagues examined details of sedentary behavior among 7,247 older women (average age, 71 years) who were asked to wear an accelerometer for 7 days during waking hours. Women wore the accelerometer for an average of 14.8 hours per day. The average percentage of wear time spent in sedentary behavior was 65.5 percent, equivalent to an average of 9.7 hours per day.

Total sedentary time increased and the number of periods of sedentary behavior and breaks per sedentary hour decreased as age and body mass index increased. Most sedentary time occurred in periods of shorter duration. Among the total number of sedentary bouts, the average percentage of bouts of at least 30 minutes was 4.8 percent, representing 31.5 percent of total sedentary time.

“If future studies confirm the health hazards of sedentary behavior and guidelines are warranted, these data may be useful to inform recommendations on how to improve such behavior,” the authors conclude.

(doi:10.l001/jama.2013.278896; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by research grants from the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs. Freedson and Trost are members of the Actigraph scientific advisory board. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 17, 2013

Media Advisory: To contact Sheila M. Rothman, Ph.D., call Whitney Adair at 212-342-5268 or email smr4@columbia.edu or wa2187@columbia.edu. To contact editorial co-author Steven Woloshin, M.D., M.S., call Mike Barwell at 603-653-1984 or email Michael.r.barwell@hitchcock.org.

Chicago – Eighteen medical communication companies (MCCs) received about $100 million from 13 pharmaceutical and one device company that released data in 2010, and all or most of the 18 MCCs were for profit, conducted continuing medical education programs, and tracked website behavior, with some 3^rd party information sharing, according to a study appearing in the December 18 issue of JAMA.

“Medical communication companies (MCCs) are among the most significant but least analyzed health care stakeholders. Supported mainly by drug and device companies, they are vendors of information to physicians and consumers and sources of information for industry. Known best for arranging continuing medical education (CME) programs, they also develop prelaunch and branding campaigns and produce digital and print publications,” according to background information in the article. The authors add that how MCCs share or protect physicians’ personal data requires greater transparency.

Sheila M. Rothman, Ph.D., of Columbia University, New York, and colleagues examined the financial relationships between MCCs and drug device companies and the characteristics of large MCCs and whether they accurately represent themselves to physicians. The researchers combined data from year 2010 grant registries of 14 pharmaceutical and device companies; grouped recipients into categories of MCCs, academic medical centers, disease-targeted advocacy organizations, and professional associations; and created a master list of 19,272 grants.

Of the 6,493 recipients of more than $657 million grant awards from drug and device companies, 363 were medical communication companies, which received 26 percent of the funding ($171 million), followed by 21 percent awarded to academic medical centers ($141 million) and 15 percent to disease-target advocacy organizations ($96 million). For-profit MCCs (n = 208) received 77 percent of funds. The top 5 percent (18 MCCs), almost all for-profit companies, received 59 percent of the funds ($102 million). Eighteen MCCs received more than $2 million each.

The top 18 MCCs offered continuing medical education: 14 offered live and 17 offered online CME courses. “Medical communication companies promoted online CME courses as a convenient and cost-free alternative to live CME courses. Physicians could access the site anywhere at any time. To enroll in the CME course, physicians had to provide personal information, such as name, e-mail address, specialty, and license number,” the authors write. Fourteen MCCs stated that they used ‘cookies’ and web ‘beacons to track physician web activity. Ten declared that they shared personal information with third parties. Eight stated that they did not share personal information, but almost all added exceptions for unnamed ‘educational partners’ and companies with which they worked or might merge.

“It appears that providing online CME courses is a common activity offered by MCCs, which allows them the opportunity to collect personal data and create digital profiles. Although MCCs did not elicit users’ explicit consent, they interpreted participating in a CME course and navigating the website as an implicit agreement to share information with third parties. It is possible that physicians using MCC websites do not appreciate the full extent of MCC-industry financial ties or are aware of data sharing practices.”

“Physicians who interact with MCCs should be aware that all require personal data from the physician and that some share these data with unnamed third parties,” the authors conclude.

(doi:10.l001/jama.2013.281638; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was funded by the Selz Foundation and the May and Samuel Rudin Foundation. Please see the article for additional information, including author contributions and affiliations, financial disclosures, etc.

Editorial: Medical Communication Companies and Continuing Medical Education

Lisa M. Schwartz, M.D., M.S., and Steven Woloshin, M.D., M.S., of the Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, N.H., comment on the findings of this study in an accompanying editorial.

“As evident by the substantial investment in medical communication companies as described in the report by Rothman et al, the pharmaceutical industry is invested in the continuing education of physicians and nonphysician prescribers alike. Past abuses by the industry have spawned policies by the Accreditation Council for Continuing Medical Education, medical schools, and government to enforce separation between education and promotion largely through greater disclosure and limiting money and gifts. Closing loopholes that allow medical communication companies to bypass some of these policies would be an important additional step in ensuring that marketing is not confused with education. Keeping physicians and other health care practitioners up to date with balanced evidence about the safe and effective use of prescription drugs is in everyone’s interest.”

(doi:10.l001/jama.2013.281640; 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. Drs. Schwartz and Woloshin reported that they are cofounders and shareholders of Informulary Inc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 10, 2013

Media Advisory: To contact corresponding author Douglas A. Corley, M.D., Ph.D., call Janet Byron at 510-891-3115 or email Janet.L.Byron@kp.org.

Chicago – Use for 2 or more years of proton pump inhibitors and histamine 2 receptor antagonists (two types of acid-inhibiting medications) was associated with a subsequent new diagnosis of vitamin B₁₂ deficiency, according to a study appearing in the December 11 issue of JAMA.

“Vitamin B₁₂ deficiency is relatively common, especially among older adults; it has potentially serious medical complications if undiagnosed. Left untreated, vitamin B₁₂ deficiency can lead to dementia, neurologic damage, anemia, and other complications, which may be irreversible,” according to background information in the article. Proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H₂RAs) suppress the production of gastric acid, which may lead to malabsorption of vitamin B₁₂, and they are among the most commonly used pharmaceuticals in the United States. However, few data exist about any association between long-term exposure to these medications and vitamin B₁₂ deficiency in large population-based studies.

Jameson R. Lam, M.P.H., of Kaiser Permanente, Oakland, Calif., and colleagues evaluated the relationship between the use of acid-suppressing prescription medications and vitamin B₁₂ deficiency within the Kaiser Permanente Northern California population. The researchers identified 25,956 patients having new diagnoses of vitamin B₁₂ deficiency between January 1997 and June 2011 and 184,199 patients without B₁₂ deficiency, and compared their exposure to acid inhibitors as observed via electronic pharmacy, laboratory, and diagnostic databases.

Among patients with a new diagnosis of vitamin B₁₂ deficiency, 3,120 (12.0 percent) were dispensed a 2 or more years’ supply of PPIs, 1,087 (4.2 percent) were dispensed a 2 or more years’ supply of H₂RAs (without any PPI use), and 21,749 (83.8 percent) had not received prescriptions for either PPIs or H₂RAs. Among control patients, 13,210 (7.2 percent) were dispensed a 2 or more years’ supply of PPIs, 5,897 (3.2 percent) were dispensed a 2 or more years’ supply of H₂RAs (without any PPI use), and 165,092 (89.6 percent) had not received prescriptions for either PPIs or H₂RAs.

Receiving 2 or more years’ supply of PPIs and H₂RAs was associated with increased risk for vitamin B₁₂ deficiency. Doses more than 1.5 PPI pills/day were more strongly associated with vitamin B₁₂ deficiency than were doses less than 0.75 pills/day.

The researchers found that the magnitude of the association was stronger in women and younger age groups with more potent acid suppression (PPIs vs. H₂RAs), and that the association decreased after discontinuation of use. There was no significant trend with increasing duration of use.

“We cannot completely exclude residual confounding [factors besides the drugs] as an explanation for these findings, but, at minimum, the use of these medications identifies a population at higher risk of B₁₂ deficiency, independent of additional risk factors. These findings do not recommend against acid suppression for persons with clear indications for treatment, but clinicians should exercise appropriate vigilance when prescribing these medications and use the lowest possible effective dose. These findings should inform discussions contrasting the known benefits with the possible risks of using these medications,” the authors conclude.

(doi:10.1001/jama.2013.280490; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was supported by a Kaiser Permanente Community Benefit grant. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Corley reported receiving a grant or grant pending from Wyeth/Pfizer. No other authors reported disclosures.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 10, 2013

Media Advisory: To contact Miguel-Angel Martinez-Garcia, M.D., Ph.D., email mianmartinezgarcia@gmail.com.

Chicago – Among patients with obstructive sleep apnea and hypertension that requires 3 or more medications to control, continuous positive airway pressure (CPAP) treatment for 12 weeks resulted in a decrease in 24-hour average and diastolic blood pressure and an improvement in the nocturnal blood pressure pattern, compared to patients who did not receive CPAP, according to a study appearing in the December 11issue of JAMA.

“Systemic hypertension is one of the most treatable cardiovascular risk factors. Between 12 percent and 27 percent of all hypertensive patients require at least 3 antihypertensive drugs for adequate blood pressure control and are considered patients with resistant hypertension. Patients with resistant hypertension are almost 50 percent more likely to experience a cardiovascular event than hypertensive patients without resistant hypertension, and the incidence of resistant hypertension is expected to increase,” according to background information in the article. Recent studies have shown that obstructive sleep apnea [OSA] may contribute to poor control of blood pressure and that a very high percentage (>70 percent) of resistant hypertension patients have OSA. Continuous positive airway pressure is the treatment of choice for severe or symptomatic OSA. “A meta-analysis suggests that CPAP treatment reduces blood pressure levels to a clinically meaningful degree, but whether this positive effect is more pronounced in patients with resistant hypertension is unclear because studies on this issue are scarce and based on single-center approaches.”

Miguel-Angel Martinez-Garcia, M.D., Ph.D., of the Hospital Universitario y Politecnico La Fe, Valencia, Spain, and colleagues assessed the effect of CPAP treatment on blood pressure levels and nocturnal blood pressure patterns of 194 patients with resistant hypertension and OSA. The trial was conducted in 24 teaching hospitals in Spain; data were collected from June 2009 to October 2011. The patients were randomly assigned to receive CPAP (n = 98) or no CPAP (control; n = 96) while maintaining usual blood pressure control medication.

When the changes in blood pressure during the study period were compared between study groups by intention-to-treat, the CPAP group achieved a 3.1 mm Hg greater decrease in 24-hour average blood pressure and 3.2 mm Hg greater decrease in 24-hour diastolic blood pressure, but the difference in change in 24-hour systolic blood pressure was not statistically significant compared to the control group. In addition, the percentage of patients displaying a nocturnal blood pressure dipper pattern (a decrease of at least 10 percent in the average night-time blood pressure compared with the average daytime blood pressure) at the 12-week follow-up was greater in the CPAP group than in the control group (35.9 percent vs. 21.6 percent). There was a positive correlation between hours of CPAP use and the decrease in 24-hour average blood pressure.

“Further research is warranted to assess longer-term health outcomes,” the authors conclude.

(doi:10.1001/jama.2013.281250; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 3, 2013

Media Advisory: To contact J. Randall Curtis, M.D., M.P.H., call Elizabeth Hunter at 206-616-3192 or email elh415@uw.edu. To contact editorial co-author Abraham Verghese, M.D., call Margarita Gallardo at 650-723-7897 or email mjgallardo@stanford.edu.

Chicago – Among internal medicine and nurse practitioner trainees, simulation-based communication skills training compared with usual education did not improve quality of communication about end-of-life care or quality of end-of-life care but was associated with a small increase in patients’ symptoms of depression, according to a study appearing in the December 4 issue of JAMA, a medical education theme issue.

“Observational studies have suggested that communication about end-of-life care is associated with decreased intensity of care, increased quality of life, and improved quality of dying. In addition, interventions that focus on communication about palliative and end-of-life care, using palliative care specialists, have demonstrated improved quality of life, decreased symptoms of depression, and reduced intensity of care at the end of life,” according to background information in the article. “Simulation-based training improves skill acquisition, but effects on patient-reported outcomes are unknown.”

J. Randall Curtis, M.D., M.P.H., of the University of Washington, Seattle, and colleagues conducted a trial to examine whether a communication skills-building workshop aimed at internal medicine (n = 391) and nurse practitioner (n = 81) trainees, using simulation during which trainees practiced skills associated with palliative and end-of-life care communication, had any effect on patient-, family-, and clinician-reported outcomes.  Participants were randomized to the 8-session, simulation-based, communication skills intervention (n = 232) or usual education (n = 240).

The primary outcome was patient-reported quality of communication (QOC). Secondary outcomes were patient-reported quality of end-of-life care (QEOLC) and depressive symptoms and family-reported QOC and QEOLC.

The researchers received 1,866 patient evaluations completed by 1,717 patients evaluating 345 trainees; and 936 surveys completed by 898 family respondents, evaluating 295 trainees. Analysis of the data indicated that the intervention was not associated with improvement in QOC or QEOLC. After adjustment, comparing intervention with control, there was no difference in the QOC or QEOLC score for patients or families, but it was associated with increased depression scores among patients of post-intervention trainees.

“These findings raise questions about skills transfer from simulation training to actual patient care and the adequacy of communication skills assessment,” the authors write.

(doi:10.l001/jama.2013.282081; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Improving Communication With Patients – Learning by Doing

In an accompanying editorial, Jeffrey Chi, M.D., and Abraham Verghese, M.D., of the Stanford University School of Medicine, Stanford, Calif., write that there are many possible reasons for the unexpected results of this study.

“Patients and families are not formally trained to evaluate communication skills. Additionally, the acquisition of skills was tested over the course of a 10-month period following workshop participation and not immediately following specific end-of-life discussions. It is possible that the improvement in participants’ skills was not enough to make a measurable difference to patients; conversely, it is possible that trainees did not recall training and so were not able to apply the communication skills.”

“The study by Curtis et al provides an important lesson about the nature of pedagogy [teaching or training] in medicine: new and innovative ways are needed to teach skills, and continued measurement, reassessment, and validation are needed to determine if those teaching methods have succeeded. The final arbiter is of course the patient and patient outcomes. Much work remains to be done.”

(doi:10.l001/jama.2013.281828; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 3, 2013

Media Advisory: To contact Richard P. Deane, M.B., B.Ch., email deaneri@tcd.ie.

Chicago – Among fourth-year medical students completing an 8-week obstetrics/gynecology clinical rotation, there was a positive association between attendance at clinical and tutorial-based activities and overall examination scores, according to a study appearing in the December 4 issue of JAMA, a medical education theme issue.

“Student attendance is thought to be an important factor in the academic performance of medical students on the basis that clinical contact and teaching are necessary to develop competence. Student attendance also has wider implications for institutions providing medical education. The educational value of clinical teaching is resource-dependent and expensive. Medical schools are increasingly challenged in providing clinical teaching in the face of increasing student numbers. In this context, medical schools must appraise the educational value of attendance at their clinical teaching programs,” according to background information in the article. “Previous studies evaluating the relationship between attendance and academic performance among medical students have been limited and related to classroom-based lectures only rather than clinical activities.”

Richard P. Deane, M.B., B.Ch., and Deirdre J. Murphy, M.D., of Trinity College, University of Dublin, Ireland, evaluated the relationship between student attendance and academic performance in a medical student obstetrics/gynecology clinical rotation during a full academic year (September 2011 to June 2012) at a university teaching hospital in Dublin. Students were expected to attend 64 activities (26 clinical activities and 38 tutorial-based activities) but attendance was not mandatory. All 147 fourth-year medical students who completed an 8-week obstetrics/gynecology rotation were included.

The average attendance rate was 89 percent (n = 57/64 activities). Male students (84 percent attendance) and students who failed an end-of-year examination previously (84 percent attendance) had significantly lower rates. The researchers found that both clinical attendance and tutorial-based attendance were positively correlated with overall examination score. The associations persisted after controlling for confounding factors (factors that can influence outcomes) of student sex, age, country of origin, previous failure in an end-of-year examination, and the timing of the rotation during the academic year.

Distinction grades (grades above the expected basic standard [i.e., demonstrated additional items for the competency tested]) were present only among students with attendance rates of 80 percent or higher. The odds of a distinction grade increased with each 10 percent increase in attendance. The majority of failure grades occurred in students with attendance rates lower than 80 percent.

The researchers write that further research is needed to understand whether the relationship found in this study is causal, and whether improving attendance rates can improve academic performance.

“If a causal relationship can be identified, interventions to preemptively target potential poor attenders should be investigated to avoid the cycle of persistent failure and remedial education among a subset of students from year to year. The effect of rapidly evolving electronic learning resources on attendance patterns should also be evaluated.”

(doi:10.l001/jama.2013.282228; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 3, 2013

Media Advisory: To contact David O. Warner, M.D., call Bryan Anderson at 507-284-5005 or email Anderson.bryan@mayo.edu.

Chicago – Among anesthesiology residents entering primary training from 1975 to 2009, 0.86 percent had a confirmed substance use disorder during training, with the incidence of this disorder increasing over the study period and the risk of relapse high, according to a study appearing in the December 4 issue of JAMA, a medical education theme issue.

Substance use disorder (SUD) is a serious public health problem, and physicians are susceptible. Anesthesiologists have ready access to potent substances such as intravenous opioids, although only indirect evidence exists that SUD is more common in anesthesiologists than in other physicians, according to background information in the article. “Formulation of policy and individual treatment plans is hampered by lack of data regarding the epidemiology and outcomes of physician SUD.”

David O. Warner, M.D., of the Mayo Clinic, Rochester, Minn., and colleagues examined the incidence and outcomes of SUD among anesthesiology residents in the United State. The analysis included physicians who began training in anesthesiology residency programs from July 1, 1975, to July 1, 2009 (n = 44,612). Follow-up for incidence was to the end of training, and for relapse was until December 31, 2010.

Of the 44,612 residents, 384 (0.86 percent) had SUD confirmed during training. During the study period, an initial high rate was followed by a period of lower rates in 1996-2002, but the highest rates occurred since 2003. The most common substance used was intravenous opioids, followed by alcohol, marijuana or cocaine, anesthetics/hypnotics, and oral opioids. Twenty-eight individuals (7.3 percent) died during the training period; all deaths were related to SUD.

The researchers estimated that approximately 43 percent of survivors experienced at least 1 relapse by 30 years after the initial episode. Rates of relapse and death did not depend on the category of substance used. Risk of relapse during the follow-up period was high, indicating persistence of risk after training. Risk of death was also high; at least 11 percent of those with evidence of SUD died of a cause directly related to SUD.

“To our knowledge, this report provides the first comprehensive description of the epidemiology and outcomes of SUD for any in-training physician specialty group, showing that the incidence of SUD has increased over the study period and that relapse rates are not improving,” the authors write.

“Despite the considerable attention paid to this issue, there is no evidence that the incidence and outcomes of SUD among these physicians are improving over time.”

(doi:10.l001/jama.2013.281954; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 3, 2013

Media Advisory: To contact James Guevara, M.D., M.P.H., call Dana Weidig at 267-426-6092 or email weidigd@email.chop.edu.

Chicago – From 2000 to 2010, the presence of a minority faculty development program at U.S. medical schools was not associated with greater underrepresented minority faculty representation, recruitment, or promotion, according to a study appearing in the December 4 issue of JAMA, a medical education theme issue.

“Minority physicians and scientists have been inadequately represented among medical school faculty when compared with their representation in the U.S. population. Although their representation has increased over time, underrepresented minority faculty are less likely to be promoted and spend a longer period in a probationary rank. In addition, underrepresented minority faculty have been less likely to hold senior faculty and administrative positions and less likely to receive National Institutes of Health research awards,” according to background information in the article. To increase the recruitment and retention of underrepresented minority faculty, a number of medical schools in recent years have developed minority faculty development programs. “Although it is clear that efforts to enhance diversity and inclusion are increasing, it is not clear whether minority faculty development programs are effective in general at enhancing the recruitment and retention of underrepresented minority faculty.”

James Guevara, M.D., M.P.H., of the Children’s Hospital of Philadelphia, and colleagues conducted a study to determine whether minority faculty development programs targeting underrepresented minority faculty are associated with increases in underrepresented minority faculty representation, recruitment, and promotion. The study consisted of an analysis of the Association of American Medical Colleges Faculty Roster, a database of U.S. medical school faculty, and included full-time faculty at schools located in the 50 U.S. states or District of Columbia and reporting data from 2000-2010.

Underrepresented minority faculty were defined as faculty self-reported to be black, Hispanic, Native American, Alaskan Native, Native Hawaiian, or Pacific Islander faculty.

The overall number of underrepresented minority faculty increased during the study period (from 6,565 (6.8 percent) in 2000 to 9,009 (8.0 percent) in 2010) as did the percentage of newly hired faculty self-reporting underrepresented minority status (from 9.4 percent in 2000 to 12.1 percent in 2010) and newly promoted (6.3 percent to 7.9 percent). Hispanic faculty members increased from 3.6 percent in 2000 to 4.3 percent in 2010, while black faculty members increased 3.2 percent to 3.4 percent.

Of 124 eligible schools, 36 (29 percent) were identified with a minority faculty development program in 2010. Schools with minority faculty development programs had a similar increase in percentage of underrepresented minority faculty as schools without minority faculty development programs (6.5 percent in 2000 to 7.4 percent in 2010 vs. 7.0 percent to 8.3 percent). After adjustment for faculty and school characteristics, minority faculty development programs were not associated with greater representation of minority faculty, recruitment, or promotion.

In subgroup analyses, minority faculty development programs that were present for ≥ 5 years and had more components were associated with greater increases in underrepresented minority faculty representation.

The researchers add that the percentage of underrepresented minority faculty increased modestly from 2000 to 2010 at U.S. medical schools.

“Although the definition of underrepresented minority is evolving to reflect local and regional perspectives, findings from this study demonstrate that faculty who are underrepresented in medicine, relative to the general population, have seen little increase in absolute or percentage representation across all schools during this time period, while the prevalence of individuals of underrepresented minority status in the general population had increased to greater than 30 percent by 2010,” the authors write.

“This relatively small increase may have been the result of an increase in the percentage of faculty hires that involve underrepresented minority faculty and efforts to increase the pipeline of medical school faculty.”

(doi:10.l001/jama.2013.282116; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by a New Connections grant from the Robert Wood Johnson Foundation. 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, DECEMBER 3, 2013

Media Advisory: To contact Amy J. Starmer, M.D., M.P.H., call Meghan Weber at 617-919-3110 or email Meghan.Weber@childrens.harvard.edu. To contact editorial author Leora Horwitz, M.D., M.H.S., call Helen Dodson at 203-436-3984 or email helen.dodson@yale.edu.

Chicago – Implementation of a multifaceted program to improve patient handoffs (change in staff caring for a patient) among physicians-in-training residents at a children’s hospital was associated with a reduction in medical errors and preventable adverse events, according to a study appearing in the December 4 issue of JAMA, a medical education theme issue.

Handoff miscommunications are a leading cause of medical errors. “The Agency for Healthcare Research and Quality (AHRQ) and the Accreditation Council for Graduate Medical Education (ACGME) have identified improving handoffs as a priority in U.S. nationwide efforts to improve patient safety. The ACGME now requires residency programs to provide formal instruction in handoffs. Despite these new requirements and the increasing frequency of handoffs as a result of reductions in resident-physician work hours, many institutions do not have robust procedures for training residents or ensuring high-quality handoffs,” according to background information in the article.

Amy J. Starmer, M.D., M.P.H., of Boston Children’s Hospital and Harvard Medical School, Boston, and colleagues examined whether introduction of a multifaceted handoff program was associated with a reduction in medical errors and preventable adverse events, fewer omissions of key data in written handoffs, improved verbal handoffs, and changes in resident-physician workflow. The study included 1,255 patient admissions (642 before and 613 after the intervention) involving 84 resident physicians (42 before and 42 after the intervention) on 2 inpatient units at Boston Children’s Hospital.

The intervention consisted of a 2-hour communication training session that included interactive discussion regarding best practices for verbal and written handoffs; the introduction of a mnemonic (a memory aid) to standardize verbal handoffs; the restructuring of verbal handoffs to include integration of interns’ and senior residents’ separate handoffs into a unified team handoff; relocation of handoff to a private and quiet space; and introduction of periodic handoff oversight by a chief resident or attending physician. In addition, for one unit, a computerized handoff tool was created that was integrated into the electronic medical record.

Following implementation of the intervention, medical errors decreased from 33.8 per 100 admissions to 18.3 per 100 admissions, and preventable adverse events decreased from 3.3 per 100 admissions to 1.5 per 100 admissions. The researchers found that there were fewer omissions of key handoff elements on printed handoff documents, especially on the unit that received the computerized handoff tool. Verbal handoffs were more likely to occur in a quiet and private location after the intervention.

“Implementation of the intervention was not associated with adverse effects on resident workflow: time spent on verbal handoffs did not change, and time spent at the computer did not increase; residents spent more time in the post-intervention period in direct contact with patients,” the authors write.

“Given the increasing frequency of handoffs in hospitals following resident work-hour reductions and the high frequency with which miscommunications lead to serious medical errors, disseminating high-quality handoff improvement programs has the potential for benefit. Further work to improve and standardize handoffs across specialties and settings may lead to improvement in the safety of patients in teaching hospitals nationwide.”

(doi:10.l001/jama.2013.281961; 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: Does Improving Handoffs Reduce Medical Error Rates?

Leora Horwitz, M.D., M.H.S., of the Yale School of Medicine, New Haven, Conn., comments on this study in an accompanying editorial.

“As hospitals and residency programs seek to manage increasing complexity and fragmentation without reverting to an archaic model of round-the-clock care, the focus will be on safe handoffs and mitigating discontinuity. The study by Starmer et al presents tantalizing evidence that improving handoffs can actually reduce harm to patients. In the meantime, while awaiting results from larger multi-institutional studies, it is reasonable to ensure that at least basic elements of safe handoffs are in place.”

(doi:10.l001/jama.2013.281827; 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, NOVEMBER 26, 2013

Media Advisory: To contact David Alain Wohl, M.D., call Lisa Chensvold at 919-843-5719 or email lisa_chensvold@med.unc.edu.

Chicago – An analysis indicates that the prevalence of undiagnosed human immunodeficiency virus (HIV) infection among state prison entrants in North Carolina was low, at 0.09 percent, according to a study appearing in the November 27 issue of JAMA.

“A substantial proportion of individuals infected with the human immunodeficiency virus in the United States enter a correctional facility annually. Therefore, incarceration presents an opportunity for HIV detection. Even though many states have adopted policies of mass HIV screening of inmates, the extent to which HIV testing on prison entry detects new infections is unclear,” according to background information in the article.

David Alain Wohl, M.D., of the University of North Carolina, Chapel Hill, and colleagues examined HIV prevalence among inmates entering a state prison system and the proportion known to state public health authorities as having previously tested HIV seropositive. Individuals were evaluated who entered the North Carolina Department of Public Safety (NC DPS) between June 2008 and April 2009. Testing entering inmates for HIV in North Carolina was voluntary; however, a state statute mandated screening for syphilis. Excess blood was batch tested for HIV antibodies. Before removing links to the inmate’s HIV test result, identifiers were used to merge prison test results with the North Carolina Department of Health and Human Services (NC DHHS) HIV testing database.

During the study period, 23,373 inmates entered the NC DPS. Of these inmates, 22,134 (94.7 percent) had HIV testing performed on blood remaining after syphilis testing. Testing of excess blood revealed that 320 inmates (1.45 percent) were HIV seropositive. Of those who tested HIV seropositive, 300 (93.8 percent) were known by the NC DHHS to be infected with HIV prior to incarceration. Therefore, 20 of 22,134, or 0.09 percent of tested inmates and not known to be infected previously.

“… in contrast to the perception that undiagnosed HIV infection is prevalent among incarcerated individuals, our results indicate that few new cases of HIV enter prison,” the authors write. “Other at-risk populations with higher levels of undiagnosed HIV infection may constitute a higher priority for screening for HIV than prisoners.”

(doi:10.l001/jama.2013.280740; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by a grant from the National Institute of Mental Health and from the University of North Carolina Center for AIDS Research. 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, NOVEMBER 26, 2013

Media Advisory: To contact Bjorn Pasternak, M.D., Ph.D., email bjp@ssi.dk. To contact editorial author Allan S. Brett, M.D., call Jeff Stensland at 803-777-3686 or email stenslan@mailbox.sc.edu.

Chicago – In contrast to findings of a recent study, researchers in Denmark did not find an association between use of a class of antibiotics known as fluoroquinolones (such as ciprofloxacin) and an increased risk of retinal detachment, according to a study appearing in the November 27 issue of JAMA.

Retinal detachment (a separation of the retina from its connection at the back of the eye) is an acute eye disorder that may lead to loss of vision despite prompt surgical intervention. A recent study found that use of fluoroquinolones was strongly associated with retinal detachment, reporting a 4.5-fold significantly increased risk for ongoing exposure. A possible mechanism was effects of the drug on connective tissue, according to background information in the article. “Given the prevalent use of fluoroquinolones, this could, if confirmed in the general population, translate to many excess cases of retinal detachment that are potentially preventable.”

Bjorn Pasternak, M.D., Ph.D., of the Statens Serum Institut, Copenhagen, Denmark, and colleagues used data from a nationwide register to investigate whether oral fluoroquinolone use was associated with increased risk of retinal detachment. The register had information about 748,792 episodes of fluoroquinolone use and 5,520,446 control episodes of nonuse, including data on participant characteristics, drugs used, and cases of retinal detachment with surgical treatment.

The fluoroquinolones used were ciprofloxacin (88.2 percent), ofloxacin (9.2 percent), fleroxacine (1.2 percent), moxifloxacin (0.8 percent), and others (0.7 percent).

Of 566 patients with retinal detachment, 72 were exposed to fluoroquinolones; 5 during current use (days 1-10), 7 during recent use (days 11-30), 14 during past use (days 31-60), and 46 during distant use (2-6 months). Among patients not exposed to fluoroquinolones, 494 cases occurred. Analysis of the data indicated that fluoroquinolone use compared with nonuse was not associated with increased risk of retinal detachment.

The authors write that given limited power, the study can only rule out more than a 3-fold relative increase in the risk of retinal detachment associated with current fluoroquinolone use. However, any differences in absolute risk are likely to have limited, if any, clinical significance: in terms of absolute risk, current use of fluoroquinolones would, in the worst-case scenario, account for no more than 11 additional cases of retinal detachment per 1,000,000 treatment episodes.

(doi:10.l001/jama.2013.280500; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by The Danish Medical Research Council. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Oral Fluoroquinolone Use and Retinal Detachment – Reconciling Conflicting Findings in Observational Research

Allan S. Brett, M.D., of the University of South Carolina School of Medicine, Columbia, S.C., comments in an accompanying editorial on the findings in studies regarding an association between fluoroquinolone use and retinal detachment.

“For the physician caring for an inpatient with an indication for fluoroquinolone therapy, retinal detachment should not cross the physician’s mind. But the next time an outpatient with no good indication for a quinolone asks for one ‘because I got better last time I took it,’ the physician might mention a remote possibility of retinal detachment among the many reasons for declining the request.”

(doi:10.l001/jama.2013.280501; 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, NOVEMBER 26, 2013

Media Advisory: To contact Bruno Mourvillier, M.D., email bruno.mourvillier@bch.aphp.fr.

Chicago – In a study of adults with severe bacterial meningitis, therapeutic hypothermia (reduction of body temperature) did not improve outcomes, and it may even have been harmful, according to a study appearing in the November 27 issue of JAMA.

Among adults with bacterial meningitis, the case fatality rate and frequency of neurologic complications are high, especially among patients with pneumococcal meningitis. In animal models of meningitis, moderate hypothermia has shown favorable effects, according to background information in the article.

Bruno Mourvillier, M.D., of the Universite Paris Diderot, Sorbonne Paris Cite, Paris, and colleagues examined the effect of induced hypothermia on outcomes in patients with severe bacterial meningitis. The study, conducted at 49 intensive care units in France, randomized 98 comatose adults to hypothermia (n = 49), comprising a loading dose of 4°C cold saline and cooling to 32°C to 34°C for 48 hours; or standard care (n = 49). The primary outcome measure was the score at 3 months on the Glasgow Outcome Scale, an assessment of physical function following cerebral injuries.

The trial was stopped early at the request of the data and safety monitoring board because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51 percent]) vs. the control group (15 of 49 patients [31 percent]). Pneumococcal meningitis was diagnosed in 77 percent of patients. At 3 months, 86 percent in the hypothermia group compared with 74 percent of controls had an unfavorable outcome.

After adjustment for factors that might explain the findings, mortality remained higher, although the increase was no longer statistically significant, in the hypothermia group. Subgroup analysis on patients with pneumococcal meningitis showed similar results. “Although there was a trend toward higher mortality and rate of unfavorable outcome in the hypothermia group, early stopping of clinical trials is known to exaggerate treatment effects, precluding firm conclusions about harm of therapeutic hypothermia in bacterial meningitis,” the authors write.

“In conclusion, our trial does not support the use of hypothermia in adults with severe meningitis. Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Our results may have important implications for future trials on hypothermia in patients presenting with septic shock or stroke. Careful evaluation of safety issues in these future and ongoing trials are needed.”

(doi:10.l001/jama.2013.280506; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 26, 2013

Media Advisory: To contact Marzia Lazzerini, Ph.D., email lazzerini@burlo.trieste.it.

Chicago – Among children and adolescents with Crohn disease not responding to treatment, use of the drug thalidomide resulted in improved clinical remission after 8 weeks of treatment compared with placebo, according to a study appearing in the November 27 issue of JAMA.

As many as 1.2 million people in Europe and more than half a million in the United States are estimated to have Crohn disease, a chronic inflammatory disease involving the digestive system.  Its incidence is increasing globally.  “About 25 percent of people with Crohn disease develop symptoms as children, and these cases are generally more severe than adult-onset cases. Resistance or intolerance to therapy is common in children with Crohn disease, with up to approximately 18 percent of cases requiring surgery within 5 years from disease onset,” according to background information in the article. Thalidomide is a drug used to treat inflammatory diseases of the skin and mucous membranes. Observational studies on thalidomide in patients with Crohn disease have reported encouraging results.

Marzia Lazzerini, Ph.D., of the Institute for Maternal and Child Health, Trieste, Italy and colleagues evaluated the efficacy and adverse effects of thalidomide in inducing clinical remission in children and adolescents with refractory (not responding to treatment) Crohn disease. The study included 56 children and was conducted August 2008-September 2012 in 6 pediatric care centers in Italy. Children were randomized to thalidomide or placebo once daily for 8 weeks. The primary measured outcomes were a reduction in the Pediatric Crohn Disease Activity Index (PCDAI) score of ≥ 25 percent or ≥ 75 percent at weeks 4 and 8 (clinical remission). Nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks.

The researchers found that clinical remission was achieved by more children treated with thalidomide (13/28 [46.4 percent] vs. 3/26 [11.5 percent]). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group. Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4 percent) subsequently reached remission at week 8. Overall, 31 of 49 children treated with thalidomide (63.3 percent) achieved clinical remission, and 32 of 49 (65.3 percent) achieved 75 percent response.

Average duration of clinical remission in the thalidomide group was 181 weeks vs. 6.3 weeks in the placebo group.

“These findings require replication to definitively determine the utility of this treatment,” the authors conclude.

(doi:10.l001/jama.2013.280777; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by the Italian Medicines Agency, on funds for Independent Research. The drug producer (Pharmion until 2009; Celgene after 2009) provided the study drug. 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, NOVEMBER 26, 2013

Media Advisory: To contact Marianna K. Baum, Ph.D., call Maydel Santana-Bravo at 305-348-1555 or email santanam@fiu.edu.

Chicago – Long-term (24-month) supplementation with multivitamins plus selenium for human immunodeficiency virus (HIV)-infected patients in Botswana in the early stages of disease who had not received antiretroviral therapy delayed time to HIV disease progression, was safe and reduced the risk of immune decline and illness, according to a study appearing in the November 27 issue of JAMA.

“Micronutrient deficiencies, known to influence immune function, are prevalent even before the development of symptoms of HIV disease and are associated with accelerated HIV disease progression. Micronutrient supplementation has improved markers of HIV disease progression (CD4 cell count, HIV viral load) and mortality in clinical trials; however, these studies were conducted either in the late stages of HIV disease or in pregnant women,” according to background information in the article.

Marianna K. Baum, Ph.D., of Florida International University, Miami, and colleagues examined whether specific supplemental micronutrients enhance the immune system and slow HIV disease progression during the early stages of the disease in antiretroviral therapy (ART)-naive adults. They randomized 878 HIV patients to supplementation with daily multivitamins (B vitamins and vitamins C and E), selenium alone, multivitamins with selenium, or placebo for 24 months. The vitamins (vitamins B, C and E, and the trace element selenium) are nutrients essential for maintaining a responsive immune system. Selenium may also have an important role in preventing HIV replication.

Participants receiving the combined supplement of multivitamins plus selenium had a lower risk compared to placebo of reaching a CD4 cell count 250/µL or less (a measure that is consistent with the standard of care in Botswana for initiation of ART at the time of the study). This supplement also reduced the risk of a combination of measures of disease progression (CD4 cell count ≤ 250/µL, AIDS-defining conditions, or AIDS-related death, whichever occurred earlier).

“This evidence supports the use of specific micronutrient supplementation as an effective intervention in HIV-infected adults in early stages of HIV disease, significantly reducing the risk for disease progression in asymptomatic, ART-naive, HIV-infected adults. This reduced risk may translate into delay in the time when the HIV-infected patients experience immune dysfunction and into broader access to HIV treatment in developing countries,” the authors conclude.

The researchers add that their “findings are generalizable to other HIV subtype C-infected cohorts in resource-limited settings where the provision of ART is being scaled up, rolled out, or not yet available to all in conditions similar to those in Botswana at the time of this study.”

(doi:10.l001/jama.2013.280923; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by the National Institute on Drug Abuse. 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 Early Release: 10:45 a.m CT Monday, November 18, 2013

Chicago – Horng H. Chen, M.B.B.Ch., of the Mayo Clinic, Rochester, Minn., and colleagues conducted a randomized trial to determine whether, as compared with placebo, the addition of low-doses of the drugs dopamine or nesiritide to diuretic therapy would enhance urine output and preserve kidney function in patients with acute heart failure and kidney dysfunction.

“Primary treatment goal in acute heart failure is to achieve adequate [urine output] while avoiding renal dysfunction and other adverse effects. Patients with acute heart failure and moderate or severe renal dysfunction are at risk for inadequate [urine output] and worsening renal function, both of which are associated with worse outcomes,” according to background information in the article. “Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance [urine output] and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested.”

The multicenter, clinical trial included 360 hospitalized participants with acute heart failure and renal dysfunction.

The researchers found that compared with placebo, low-dose dopamine had no effect on 72-hour cumulative urine volume (a measure of decongestion) or on a measure of kidney function. Similarly, low-dose nesiritide had no effect on these measures. There was no effect of low-dose dopamine or low-dose nesiritide on other urine measure, weight change, renal function, or clinical outcomes, compared with placebo.

“These findings do not support the use of low-dose dopamine or low-dose nesiritide as a renal adjuvant therapy in patients with acute heart failure and renal dysfunction,” the authors write.

(doi:10.l001/jama.2013.282190; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Horng H. Chen, M.B.B.Ch., call Traci Klein at 507-990-1182 or email Klein.traci@mayo.edu.

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Embargoed for Early Release: 3 p.m CT Monday, November 18, 2013

Chicago – Stephen J. Nicholls, M.B.B.S., Ph.D., of the South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, Australia, and colleagues determined the effects of varespladib, a drug that inhibits the enzyme secretory phospholipase A₂ on cardiovascular risk in patients with acute coronary syndrome (ACS; such as heart attack or unstable angina).

Despite contemporary therapies, patients with ACS face a substantial risk of early, recurrent adverse cardiovascular events. Increasing evidence supports a potential role of inflammation in the progression and clinical instability of coronary heart disease. Secretory phospholipase A₂ (sPLA₂) is an enzyme involved with inflammation and implicated in atherosclerosis. The results of some studies have stimulated interest in sPLA₂ inhibition as a cardioprotective strategy. The sPLA₂ inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown, according to background information in the article.

The trial was conducted at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America and included 5,145 patients randomized within 96 hours of presentation of an ACS to either 500-mg/d varespladib (n = 2,572) or placebo (n = 2,573) for 16 weeks (study termination on March 9, 2012). The participants also received atorvastatin and other established therapies. The primary efficacy measure was a composite of cardiovascular mortality, nonfatal heart attack, nonfatal stroke, and unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated.

At a prespecified interim analysis, including 212 patients with primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1 percent) treated with varespladib compared with 109 patients (5.1 percent) treated with placebo. Varespladib was associated with a greater risk of heart attack (78 [3.4 percent] vs. 47 [2.2 percent]). The composite secondary end point of cardiovascular mortality, heart attack, and stroke was observed in 107 patients (4.6 percent) in the varespladib group and 79 patients (3.8 percent) in the placebo group.

“The sPLA₂ inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS,” the authors write.

(doi:10.l001/jama.2013.282836; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Stephen J. Nicholls, M.B.B.S., Ph.D., email stephen.nicholls@sahmri.com.

Embargoed for Early Release: 9:00 a.m CT Monday, November 18, 2013

Chicago – Alan W. Heldman, M.D., of the University of Miami Miller School of Medicine, and colleagues conducted a study to examine the safety of transendocardial stem cell injection (TESI) with autologous mesenchymal stem cells and bone marrow mononuclear cells in patients with ischemic cardiomyopathy.

An effective proregenerative treatment for ischemic cardiomyopathy would address a major unmet need for many patients. An unresolved issue is whether mesenchymal stem cells have similar safety and possibly greater efficacy than bone marrow mononuclear cells, according to background information in the article.

The included 65 patients with ischemic cardiomyopathy and compared injection of mesenchymal stem cells (n=19) with placebo (n = 11) and bone marrow mononuclear cells (n = 19) with placebo (n = 10), with 1 year of follow-up. The primary measured outcome was treatment-emergent 30-day serious adverse event rate defined as a composite of death, heart attack, stroke, hospitalization for worsening heart failure, perforation (rupture), tamponade (compression of the heart due to collection of blood or fluid), or sustained ventricular arrhythmias.

No patient had treatment emergent-serious adverse event at day 30. Exploratory analyses of 1-year incidence of serious adverse events was 31.6 percent for mesenchymal stem cells, 31.6 percent for bone marrow cells, and 38.1 percent for placebo. Over 1 year, the Minnesota Living with Heart Failure score (a measure of quality of life) improved with mesenchymal stem cells and with bone marrow cells but not with placebo. The 6-minute walk distance increased with mesenchymal stem cells only.

“These results provide the basis for larger studies to provide definitive assessment of safety and to assess efficacy of this new therapeutic approach,” the authors write.

(doi:10.l001/jama.2013.282909; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact corresponding author Joshua M. Hare, M.D., call Lisa Worley at 305-458-9654 or email lworley2@med.miami.edu.

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Embargoed for Early Release: 9:00 a.m CT Monday, November 18, 2013

Chicago – Joseph Poole, M.D., Ph.D., of the Emory University School of Medicine, Atlanta, and colleagues studied whether therapy with granulocyte-macrophage colony stimulating factor (GM-CSF), an agent that functions as a white blood cell growth factor, would improve walking performance in patients with symptomatic peripheral artery disease (a form of vascular disease in which there is partial or total blockage of an artery, usually one leading to a leg or arm).

“Peripheral artery disease (PAD) affects more than 8 million individuals in the United States. Although exercise, smoking cessation, antiplatelet therapy, cilostazol [a medication for PAD], statins, and revascularization are used to treat PAD, men and women with PAD have significantly greater functional impairment and faster functional decline than those without PAD. Stem and progenitor cell (PC) therapy that promotes neoangiogenesis [formation of blood vessels] is an emerging treatment modality in PAD,” according to background information in the article. Progenitor cells are involved in vascular repair and regeneration.

The phase 2, placebo-controlled study included 159 patients with intermittent claudication (pain in leg muscles, aggravated by walking and caused by an insufficient supply of blood). Participants were randomized to received 4 weeks of subcutaneous (under the skin) injections of GM-CSF (leukine), 3 times a week (n = 80), or placebo (n = 79).

The researchers found that therapy with GM-CSF did not improve treadmill walking time, a measure of PAD severity at 3-month follow-up. “The improvement in a subset of secondary outcomes observed with GM-CSF suggests that GM-CSF may warrant further study in patients with claudication. In addition, further investigation is needed to investigate the variability of responsiveness to GM-CSF and its clinical significance.”

(doi:10.l001/jama.2013.282540; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Arshed A. Quyyumi, M.D., Ph.D., call Jennifer Johnson McEwen at 404-441-5929 or email jrjohn9@emory.edu.

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Embargoed for Early Release: 9:00 a.m CT Monday, November 18, 2013

Chicago – Michael H. Criqui, M.D., M.P.H., of the University of California, San Diego, and colleagues determined the independent associations of coronary artery calcium (CAC) volume and CAC density with cardiovascular disease events. An increasing body of evidence suggests that greater calcium density in plaques (measured by computed tomography) is associated with decreased CVD risk.

The study included 3,398 men and women from 4 race/ethnicity groups; non-Hispanic white, African-American, Hispanic, and Chinese. Participants were 45-84 years of age, free of known CVD at baseline, had CAC greater than 0 on their baseline CT, and were followed up through October 2010.

During a median (midpoint) of 7.6 years of follow-up, there were 175 CHD events and an additional 90 other CVD events for a total of 265 CVD events. Analysis of the data found that CAC volume was positively and independently associated with CHD and CVD risk. At any level of CAC volume, CAC density was inversely and significantly associated with CHD and CVD risk.

“The role of CAC density should be considered when evaluating current CAC scoring systems,” the authors write.

(doi:10.l001/jama.2013. 282535; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Michael H. Criqui, M.D., M.P.H., call Debra Kain at 619-543-6163 or email ddkain@ucsd.edu.

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Embargoed for Early Release: 3:00 p.m CT Sunday, November 17, 2013

Chicago – Jiang He, M.D., Ph.D., of the Tulane University School of Public Health and Tropical Medicine, New Orleans, and colleagues examined whether moderate lowering of blood pressure within the first 48 hours after the onset of an acute ischemic stroke would reduce death and major disability at 14 days or hospital discharge.

“Stroke is the second leading cause of death and the leading cause of serious, long-term disability worldwide. Clinical trials have documented that lowering blood pressure reduces the risk of stroke in hypertensive and normotensive patients with a history of stroke or transient ischemic attack. Although the benefit of lowering blood pressure for primary and secondary prevention of stroke has been established, the effect of immediate antihypertensive treatment in patients with acute ischemic stroke and elevated blood pressure is uncertain,” according to background information in the article.

The China Antihypertensive Trial in Acute Ischemic Stroke, a randomized controlled trial, was conducted among 4,071 patients with ischemic stroke within 48 hours of symptom onset and elevated systolic blood pressure. Patients were recruited from 26 hospitals across China between August 2009 and May 2013. Patients (n = 2,038) were assigned to receive antihypertensive treatment (aimed at lowering systolic blood pressure by 10 percent to 25 percent within the first 24 hours after randomization, achieving blood pressure less than 140/90 mm Hg within 7 days, and maintaining this level during hospitalization) or to discontinue all antihypertensive medications (control) during hospitalization (n = 2,033).

Average systolic blood pressure was reduced from 166.7 mm Hg to 144.7 mm Hg (-12.7 percent) within 24 hours in the antihypertensive treatment group and from 165.6 mm Hg to 152.9 mm Hg (-7.2 percent) in the control group within 24 hours after randomization. Average systolic blood pressure was 137.3 mm Hg in the antihypertensive treatment group and 146.5 mm Hg in the control group at day 7 after randomization. The primary outcome (a combination of death and major disability at 14 days or hospital discharge) did not differ between treatment groups (683 events [antihypertensive treatment] vs. 681 events [control]) at 14 days or hospital discharge. The secondary composite outcome of death and major disability at 3-month posttreatment follow-up did not differ between treatment groups.

These findings suggest that the decision to lower blood pressure with antihypertensive treatment in patients with acute ischemic stroke does not improve or worsen outcome and therefore should be based on individual clinical judgment, the authors write.

(doi:10.l001/jama.2013.282543; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Jiang He, M.D., Ph.D., call Arthur Nead at 504-247-1443 or email anead@tulane.edu. To contact co-corresponding author Yong-Hong Zhang, M.D., Ph.D., email yhzhang@suda.edu.cn.

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Embargoed for Early Release: 3:00 p.m CT Sunday, November 17, 2013

Chicago – Francis Kim, M.D., of Harborview Medical Center, Seattle, and colleagues evaluated whether early prehospital cooling (lowering body temperature) improved survival to hospital discharge and neurological outcome in cardiac arrest patients with or without ventricular fibrillation (VF).

Cardiac arrest can cause brain injury and many patients never awaken after resuscitation. Hypothermia is a promising treatment that can help brain recovery. “Hospital cooling improves outcome after cardiac arrest, but prehospital cooling immediately after return of spontaneous circulation may result in better outcomes,” according to background information in the article. “The optimal timing for induction of hypothermia is uncertain.”

For this trial, 1,359 patients (583 with VF and 776 without VF) with prehospital cardiac arrest and resuscitated by paramedics were assigned to standard care with or without prehospital cooling, accomplished by infusing up to 2 liters of 4°C normal saline as soon as possible following return of spontaneous circulation. Nearly all of the patients resuscitated from VF and admitted to the hospital received hospital cooling regardless of their randomization.

The intervention reduced core temperature by more than 1°C and patients reached the goal temperature about 1 hour sooner than in the control group. The researchers found that survival to hospital discharge was similar in the intervention and control groups among patients with VF (62.7 percent vs. 64.3 percent, respectively) and among patients without VF (19.2 percent vs. 16.3 percent, respectively). The intervention was also not associated with improved neurological status of full recovery or mild impairment at discharge for patients with or without VF.

“Although hypothermia is a promising strategy to improve resuscitation and brain recovery following cardiac arrest, the results of the current study do not support routine use of cold intravenous fluid in the prehospital setting to improve clinical outcomes,” the authors write.

(doi:10.l001/jama.2013.282173; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Francis Kim, M.D., call Leila Gray at 206-941-4506 or email leilag@uw.edu.

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Embargoed for Early Release: 1:00 p.m CT Sunday, November 17, 2013

Chicago – Sten Rubertsson, M.D., Ph.D., of Uppsala University, Sweden and colleagues assessed whether cardiopulmonary resuscitation (CPR) in which chest compressions are delivered with a mechanical device would result in superior 4-hour survival in patients with out-of-hospital cardiac arrest compared to CPR with manual chest compression.

“Many factors affect the chances of survival after cardiac arrest, including early recognition of arrest, effective CPR and defibrillation, and postresuscitation care. One important link is the delivery of high-quality chest compressions to achieve restoration of spontaneous circulation. The effectiveness of manual chest compressions depends on the endurance and skills of rescuers, and manual compressions provide only approximately 30 percent of normal cardiac output. Manual CPR is also limited by prolonged hands-off time, and its quality is particularly poor when it is administered during patient transport. Mechanical chest compression devices have therefore been developed to improve CPR,” according to background information in the article.  “A strategy using mechanical chest compressions might improve the poor outcome in out-of-hospital cardiac arrest, but such a strategy has not been tested in large clinical trials.”

This multicenter clinical trial, which included 2,589 patients with out-of-hospital cardiac arrest, was conducted between January 2008 and February 2013 in 4 Swedish, 1 British, and 1 Dutch ambulance services and their referring hospitals. Duration of follow-up was 6 months. Patients were randomized to receive chest compressions from a mechanical device combined with defibrillation during the compressions (n = 1,300) or manual CPR according to guidelines (n = 1,289). The mechanical chest compressions device had an integrated suction cup designed to deliver compressions according to resuscitation guidelines.

Four-hour survival was achieved in 307 patients (23.6 percent) with mechanical CPR and 305 (23.7 percent) with manual CPR. Among patients surviving at 6 months, 99 percent in the mechanical CPR group and 94 percent in the manual CPR group had good neurological outcomes.

“In patients with out-of-hospital cardiac arrest, mechanical chest compressions in combination with defibrillation during ongoing compressions provided no improved 4-hour survival vs. manual CPR according to guidelines. There was a good neurological outcome in the vast majority of survivors in both groups, and neurological outcomes improved over time,” the authors write.

(doi:10.l001/jama.2013.282538; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Sten Rubertsson, M.D., Ph.D., email sten.rubertsson@akademiska.se.

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Embargoed for Early Release: 11:00 a.m CT Sunday, November 17, 2013

Chicago – Jose Augusto Barreto-Filho, M.D., Ph.D., of the Federal University of Sergipe and the Clinica e Hospital Sao Lucas, Sergipe, Brazil, and colleagues assessed procedure rates and outcomes of surgical aortic valve replacement (AVR) among 82,755,924 Medicare fee-for-service beneficiaries between 1999 and 2011.

“Aortic valve disease in the United States is a major cardiovascular problem that is likely to grow as the population ages. Aortic valve replacement is the standard treatment even for very elderly patients despite its risks in this age group. With transcatheter aortic valve replacement emerging as a less invasive option, contemporary data from real-world practice are needed to provide a perspective on the outcomes that are being achieved with surgery,” according to background information in the article.

The primary measured outcomes for the study were procedure rates for surgical AVR alone and with coronary artery bypass graft (CABG) surgery, 30-day and 1-year mortality, and 30-day readmission rates.

The researchers found that rates of AVR increased between 1999 and 2011, including AVR without CABG surgery, while the rate of AVR with CABG surgery decreased during this time period.  Procedure rates increased in all age, sex, and race strata, most notably in patients 75 years or older.

Mortality decreased at 30 days (absolute decrease, 3.4 percent; adjusted annual decrease, 4.1 percent) per year and at 1 year (absolute decrease, 2.6 percent; adjusted annual decrease, 2.5 percent). Thirty-day all-cause readmission also decreased by 1.1 percent per year. In addition, AVR with CABG surgery decreased and women and black patients had lower procedure and higher mortality rates.

“These findings may provide a useful benchmark for outcomes of aortic valve replacement surgery for older patients eligible for surgery considering newer transcatheter treatments,” the authors write.

(doi:10.l001/jama.2013.282437; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact corresponding author Harlan M. Krumholz, M.D., S.M., call Karen N. Peart at 203-980-2222 or email karen.peart@yale.edu.

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Embargoed for Early Release: 11:00 a.m CT Sunday, November 17, 2013

Chicago – Michael J. Mack, M.D., of the Baylor Health Care System, Plano, Texas, and colleagues describe the experience in the U.S. with transcatheter aortic valve replacement (TAVR), including patient selection, procedural details, and in-hospital and 30-day outcomes following TAVR, a less invasive procedure than open heart-valve surgery for replacing the aortic valve in the heart.

In November 2011, the U.S. Food and Drug Administration (FDA) approved use of a valve that could be implanted using a catheter for TAVR for the treatment of severe, symptomatic aortic stenosis in patients with inoperable status. The label for the valve was expanded in September 2012 to include patients at high-risk but operable status. Since commercial approval, this first-to-U.S.-market TAVR device has been introduced to nearly 250 U.S. clinical sites. “Although the [initial] trials demonstrated efficacy of TAVR within a select cohort of patients and hospital centers, there are no data on dissemination and utilization patterns of this technology in routine clinical practice in the United States. Additionally, concerns persist regarding the safety and effectiveness of this novel technology as it moves beyond protocolized trial care and highly experienced centers and operators,” according to background information in the study.

For this study, the researchers gathered results from all eligible U.S. TAVR cases (n = 7,710) from 224 participating registry hospitals following the device commercialization (November 2011 – May 2013).  Successful device implantation occurred in 7,069 patients (92 percent). In-hospital mortality was 5.5 percent. Other major complications included stroke (2.0 percent), dialysis-dependent renal failure (1.9 percent), and major vascular injury (6.4 percent).

Median hospital stay was 6 days, with 4,613 patients (63 percent) discharged home. Among patients with available follow-up at 30 days (n = 3,133), mortality was 7.6 percent (noncardiovascular cause, 52 percent); stroke occurred in 2.8 percent, and new dialysis in 2.5 percent.

“This analysis represents the first public report from the U.S. national Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry and documents 2 major findings. First, postapproval commercial introduction of this new technology with an early-generation device has yielded success rates and complication patterns that are similar to those documented in carefully performed randomized trials. Second, the outcomes of procedures even with this early-generation approved device are similar to the global experience of TAVR, which now is based on second- and third-generation improved devices. These findings help address a lingering question of clinical outcomes with the first-generation TAVR device after controlled U.S. dissemination to a relatively narrow group of treatment centers,” the authors write. “Longer-term follow-up is essential to assess continued safety and efficacy as well as patient health status.”

(doi:10.l001/jama.2013.282043; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Michael J. Mack, M.D., call Susan Hall at 214-566-2589 or email Susan.Hall@baylorhealth.edu.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 11 a.m. CT Sunday, November 17 at this link.

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Embargoed for Early Release: 11:00 a.m CT Sunday, November 17, 2013

Chicago – Seth S. Martin, M.D., of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, and colleagues developed a method for estimating low-density lipoprotein cholesterol (LDL-C) levels that is more accurate than the standard measure.

Low-density lipoprotein cholesterol is the primary target for treatment in national and international clinical practice guidelines. Conventionally, LDL-C is estimated by the Friedewald equation, which estimates LDL-C as (total cholesterol) – (high-density lipoprotein cholesterol [HDL-C]) – (triglycerides/5) in mg/dL. The final term assumes a fixed ratio of triglyceride levels to very low-density lipoprotein cholesterol (TG:VLDL-C) of 5:1. “Applying a factor of 5 to every individual patient is problematic given variance in the TG:VLDL-C ratio across the range of triglyceride and non-HDL-C levels,” according to background information in the study.

The researchers used a sample of lipid profiles obtained from 2009 through 2011 from 1,350,908 children, adolescents, and adults in the United States.

From this large sample of lipid profiles, the authors created and validated a novel method to estimate LDL-C from the standard lipid profile, consisting of a 180-cell table (grid) of median TG:VLDL-C values based on triglyceride and non-HDL-C values. Rather than assuming a fixed factor of 5, it applies an adjustable factor for the TG:VLDL-C ratio based on triglyceride and non-HDL-C concentrations. “The greatest advantage occurs in classification of LDL-C concentrations lower than 70 mg/dL, especially in patients with elevated triglyceride concentrations. In addition to the novel analytic approach, a major strength of this study is its size, 3,015 times larger than the original Friedewald database.”

“These findings require external validation, as well as assessment of their clinical importance. The novel method could be easily implemented in most laboratory reporting systems at virtually no cost.”

(doi:10.l001/jama.2013.280532; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Seth S. Martin, M.D., call Ellen Beth Levitt at 410-598-4711 or email eblevitt@jhmi.edu.

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Embargoed for Early Release: 11:00 a.m CT Sunday, November 17, 2013

Chicago – Hany S. Abed, B.Pharm., M.B.B.S., of the University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia and colleagues evaluated the effect of a structured weight reduction program on atrial fibrillation symptoms.

“Atrial fibrillation has been described as the epidemic of the new millennium, with a projection that by 2050 there will be 12 million to 15 million affected individuals in the United States. In the United States, the direct economic cost of atrial fibrillation is estimated at $6 billion annually. Although population aging is regarded as an important contributor, obesity may account for a substantial proportion of the increasing prevalence,” according to background information in the article. Whether weight reduction and cardiometabolic risk factor management can reduce the burden of atrial fibrillation has not been known.

The study was conducted between June 2010 and December 2011 among overweight and obese patients with symptomatic atrial fibrillation. Patients underwent a median (midpoint) of 15 months of follow-up. Patients were randomized to weight management (intervention; n = 75) or general lifestyle advice (control; n = 75). Both groups underwent intensive management of cardiometabolic risk factors (hypertension, hyperlipidemia, glucose intolerance, sleep apnea, and alcohol and tobacco use).

The intervention group experienced greater reduction, compared with the control group, in weight (33 and 12.5 lbs., respectively,) and in atrial fibrillation, symptom severity, number of episodes, and cumulative duration in minutes.

“In this study, a structured weight management program for highly symptomatic patients with atrial fibrillation reduced symptom burden and severity and reduced antiarrhythmic use when compared with attempts to optimally manage risk factors alone,” the authors write.

(doi:10.l001/jama.2013.280521; Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact corresponding author Prashanthan Sanders, M.B.B.S., Ph.D., email prash.sanders@adelaide.edu.au.

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EMBARGOED FOR EARLY RELEASE: 9 A.M. (CT) SATURDAY, NOVEMBER 9, 2013

Media Advisory: To contact corresponding author Amit X. Garg, M.D., Ph.D., call Julia Capaldi at 519-685-8500, ext. 75616, or email julia.capaldi@lawsonresearch.com.

Chicago – Among older adults taking a calcium-channel blocker, simultaneous use of the antibiotic clarithromycin, compared with azithromycin, was associated with a small but statistically significant greater 30-day risk of hospitalization with acute kidney injury, according to a study published by JAMA. The study is being published early online to coincide with its presentation at the American Society of Nephrology’s Kidney Week 2013.

The commonly used antibiotics clarithromycin and erythromycin are clinically important inhibitors of the enzyme CYP3A4, while azithromycin is much less so. Calcium-channel blockers are metabolized by this enzyme. Blood concentrations of these drugs may rise to harmful levels when CYP3A4 activity is inhibited.  “Currently, the U.S. Food and Drug Administration warns that ‘serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates, which includes hypotension [abnormally low blood pressure] with calcium-channel blockers [that are] metabolized by CYP3A4.’ Yet, calcium-channel blockers and clarithromycin continue to be frequently coprescribed in routine care,” according to background information in the article. When hypotension occurs, the kidney is particularly prone to injury from poor circulation. “Despite this knowledge, the risk of acute kidney injury following coprescription of clarithromycin with a calcium-channel blocker is unknown.”

Sonja Gandhi, B.Sc., of Western University, London, Canada, and colleagues conducted a study to investigate the interaction between calcium-channel blockers (amlodipine, felodipine, nifedipine, diltiazem, or verapamil) and the antibiotic clarithromycin (n = 96,226), compared with azithromycin (n = 94,083), with a focus on acute kidney injury, among older adults (average age, 76 years).

Amlodipine was the most commonly prescribed calcium-channel blocker (more than 50 percent of patients).

The researchers found that coprescribing clarithromycin with a calcium-channel blocker was associated with a higher risk of hospitalization with acute kidney injury compared with coprescribing azithromycin (0.44 percent vs. 0.22 percent); in absolute terms, coprescription with clarithromycin resulted in a 0.22 percent higher incidence of hospitalization with acute kidney injury.

When examined by type of calcium-channel blocker, the risk of hospitalization with acute kidney injury was highest among patients coprescribed clarithromycin with nifedipine (absolute risk increase, 0.63 percent). Coprescription of a calcium-channel blocker with clarithromycin was also associated with a higher risk of hospitalization with hypotension (0.12 percent vs. 0.07 percent patients taking azithromycin; absolute risk increase, 0.04 percent) and all-cause mortality (1.02 percent vs. 0.59 percent patients taking azithromycin; absolute risk increase, 0.43 percent).

“Although the absolute increases in the risks were small, these outcomes have important clinical implications. Our results suggest that potentially hundreds of hospitalizations and deaths in our region may have been associated with this largely preventable drug-drug interaction. This burden on the health care system, given the high costs of managing acute kidney injury, might have been avoided,” the authors write.

“… our study highlights the need for quality improvement initiatives that will mitigate the clinical effects of such drug interactions. Potential strategies may include temporary cessation of the calcium-channel blocker for the duration of clarithromycin therapy or selection of a non-CYP3A4 inhibiting antibiotic (such as azithromycin) when clinically appropriate.”

(doi:10.l001/jama.2013.282426; 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: 9:30 A.M. (ET) TUESDAY, NOVEMBER 12, 2013

Media Advisory: To contact Ezekiel J. Emanuel, M.D., Ph.D., call Katie Delach at 215-349-5964 or email Katie.Delach@uphs.upenn.edu.

Washington, D.C. – The U.S. health care system needs a new, audacious goal: limit health care expenditure growth to the growth of national economy. “That is, by the end of the decade, health care costs per person will not grow faster than the economy as a whole,” writes Ezekiel J. Emanuel, M.D., Ph.D., of The Perelman School of Medicine and the Wharton School, University of Pennsylvania, Philadelphia, in a Viewpoint appearing in the November 13 issue of JAMA, a theme issue on critical issues in U.S. health care.

Dr. Emanuel presented the article at a JAMA media briefing at the National Press Club in Washington, D.C.

Dr. Emanuel writes that the health care system is in need of what author Jim Collins, a business strategist, called a big hairy audacious goal (BHAG): by 2020, per capita health care costs will increase no more than gross domestic product (GDP)+0 percent. Collins used the term BHAG “to define a kind of goal, like going to the moon, that can make an organization—or a nation—stretch beyond what it thought was possible to achieve remarkable things.”

“The goal of reining in per capita cost growth is clear and easily measured. It is not going to happen overnight; it is going to take at least until 2020 to achieve. Success is not guaranteed. During the last 50 years, only a few years in the mid 1990s have seen per capita cost growth track closely to the growth of the economy. But by the end of the decade, getting there is possible. Most importantly, if the effort is successful, the entire health care system will have been transformed.”

Dr. Emanuel notes that states have begun to adopt this BHAG. “In 2012, Massachusetts enacted another important health reform law to improve quality and reduce costs. It had a spending target of limiting health care cost growth to growth of the state economy—the equivalent of GDP+0 percent. Maryland and Arkansas have adopted similar cost-control goals.”

“So what will it take to get to the moon in health care? It will require substantially more focus on delivering care to the 10 percent of patients with chronic illness. It will require turning care delivery upside-down. Instead of focusing on care in the hospital, more outpatient monitoring of these patients, and more interventions at home, are necessary to keep them healthy and with fewer emergency department visits and hospitalizations. To achieve this requires electronic records with real-time tracking of leading physiologic indicators. It requires team-based care coordination between office, hospital, pharmacy, and home. It requires reducing the use of inappropriate interventions. If all this happens, the other goal that everyone believes is critical—improved quality of care—will be achieved.”

Dr. Emanuel concludes that most importantly, the goal of limiting U.S. health care expenditure growth to the growth of the national economy “will organize and focus energies and skills in a way that will permanently transform health care for the better. Ultimately, President Kennedy may have said it best: ‘”We choose to go to the moon in this decade and do the other things, not because they are easy, but because they are hard, because that goal will serve to organize and measure the best of our energies and skills, because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win.”’

(doi:10.l001/jama.2013. 281967; 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 payment for speaking engagements unrelated to this work.

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EMBARGOED FOR EARLY RELEASE: 9:30 A.M. (ET) TUESDAY, NOVEMBER 12, 2013

Media Advisory: To contact Joanne Lynn, M.D., M.A., M.S., call Ken Schwartz at 571-733-5709 or email Ken.schwartz@altarum.org.

Washington, D.C. – “The United States needs arrangements that allow elderly people to live with confidence, comfort, and meaningfulness at a cost that families can afford and the nation can sustain … Without significant structural changes in service delivery, an aging nation faces a future of substantial costs and needless pain and distress among those who are old,” writes Joanne Lynn, M.D., M.A., M.S., of the Center for Elder Care and Advanced Illness, Altarum Institute, Washington, D.C., in a Viewpoint appearing in the November 13 issue of JAMA, a theme issue on critical issues in U.S. health care.

Dr. Lynn presented the article at a JAMA media briefing at the National Press Club in Washington, D.C.

The current “care system” for an elderly person with self-care disability and numerous diagnoses “provides disjointed specialty services, ignores the challenges of living with disabilities, tolerates routine errors in medications and transitions, disdains individual preferences, and provides little support for paid or volunteer caregivers. This maladapted service delivery system now generates about half of the person’s lifetime costs for health care services, yet patients and families are left fearful and disoriented, with pain, discomfort, and distress.”

Dr. Lynn provides specific changes she contends are critical for improving care for this population, an approach she calls “MediCaring”. She writes that discussions about living with frailty now are virtually absent from popular media, political discussion, and professional education. “To counteract this shortcoming, reformers will need to generate discussion about the challenges of aging, disability, and death, along with the continuing opportunities to live meaningfully and comfortably. Medical  professionals, political leaders, and popular culture must generate vigorous discussion about how people live well with frailty and how best to die.”

“Each frail elderly person has unique resources, priorities, fears, medical issues, and aspirations, and each should be given an opportunity to evaluate his or her potential futures and to have an individualized plan for services. A multidisciplinary team should conduct an appropriately comprehensive assessment and work with the patient and family to generate a care plan that documents the patient’s goals and the chosen service strategies.”

“The service delivery system should encompass health care and long-term services and supports as equal partners,” Dr. Lynn writes. “A balanced system would give integrated multidisciplinary teams the tools and authority to match services with each frail person’s priority needs. … Today, a physician can order any drug for any Medicare patient at any cost—but that physician cannot order a substitute caregiver or adequate housing, except perhaps by arranging nursing home admission. The mismatch of service availability with the priorities of frail elderly people engenders high costs as well as frustration and heightened fear of decline and death for frail elders.”

Dr. Lynn also suggests that “by allowing localities to take a role in monitoring and managing their arrangements for supporting frail elders, the services could become more reliable and appropriate, and most or all of the funding for supplementing social services for people who cannot afford them could come from sharing in the savings from better health care.”

“Essential reforms include requiring development and use of comprehensive care plans; modifying medical care to ensure continuity, comprehensiveness, honesty about treatment goals, and comfort; bringing health care and long-term services and supports together into stable funding and management arrangements; and enabling some degree of local monitoring and control. Meeting the challenges of long lives requires substantial changes, quickly, in how people in the United States envision health care, community obligations, and the lives of frail older adults.”

(doi:10.l001/jama.2013.281923; 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: 9:30 A.M. (ET) TUESDAY, NOVEMBER 12, 2013

Media Advisory: To contact Hamilton Moses III, M.D., call Stephanie Desmon at 410-955-8665 or email sdesmon1@jhmi.edu.
Washington, D.C. – An examination of health care in the U.S. finds that despite the extraordinary economic success of many of its participants, the health care system has performed relatively poorly by some measures; and that outcomes have improved, but more slowly than in the past and more slowly than in comparable countries, according to an article in the November 13 issue of JAMA, a theme issue on critical issues in U.S. health care.

Hamilton Moses III, M.D., of the Alerion Institute, North Garden, Va., and the Johns Hopkins School of Medicine, presented the article at a JAMA media briefing at the National Press Club in Washington, D.C.

Dr. Moses and colleagues from The Boston Consulting Group and University of Rochester, using publicly available data, conducted an analysis to identify trends in health care, principally from 1980 to 2011. The areas they addressed included the economics of health care; the profile of people who receive care and organizations that provide care; and the value created in terms of objective health outcomes and perceptions of quality of care. In addition, they examined the potential factors driving change, including consolidation of insurers and health systems; health care information; and the patient as consumer.

Among the findings:

Economics and Outcomes

• In 2011, U.S. health care employed 15.7 percent (21 million people) of the workforce, with expenditures of $2.7 trillion, doubling since 1980 as a percentage of U.S. gross domestic product (GDP) to 17.9 percent.

Between 2000 and 2010, health care increased faster than any other industry (2.9 percent/year) but trailed government (3.3%/year); health’s proportion of GDP doubled between 1980 and 2011. Government funding increased from 31 percent in 1980 to 42 percent in 2011. Costs have tripled in real terms over the past 2 decades. However, the average rate of increase has declined consistently since the mid-1970s and sharply over the last decade.

• Despite the increases in resources devoted to health care, multiple health metrics, including life expectancy at birth and survival with many diseases, shows the United States trailing peer nations.

Contributors to Costs

In addition, the researchers note that findings from their analysis contradict several common assumptions:

• Price of professional services, drugs and devices, and administrative costs, not demand for services or aging of the population, produced 91 percent of cost increases since 2000.

• Personal out-of-pocket spending on insurance premiums and co-payments have declined from 23 percent to 11 percent since 1980.

• In 2011, chronic illnesses account for 84 percent of costs overall among the entire population, not only of the elderly. Chronic illness among individuals younger than 65 years accounts for 67 percent of spending.

Contributors to Change

The authors add that three factors have produced the most change:

• Consolidation, with fewer insurers and general hospitals (but more single-specialty hospitals and large physician groups) has produced financial concentration in health systems, insurers, pharmacies, and benefit managers;

• Information technology, in which investment has occurred but value is elusive;

• The patient as consumer, whereby influence is sought outside traditional channels, using social media, informal networks, new public sources of information, and self-management software.

These forces create a triangle of tension among patient aims for choice, personal attention, and unbiased guidance; physician aims for professionalism and autonomy; and public and private payer aims for aggregate economic value across large populations. “Measurements of cost and outcome (applied to groups) are supplanting individuals’ preferences. Clinicians increasingly are expected to substitute social and economic goals for the needs of a single patient.”

The researchers write that at the highest level, the U.S. health system is struggling to adapt to competing goals, desires, and expectations. “The conflict among patient desires, physician interests, and social policy is certain to increase. Those tensions will likely become a palpable force that may hinder care integration and inhibit other changes that favor improved outcome and savings. The usual approach is to address each constituency in isolation rather than optimizing efforts across them. The triangle will need to be reconciled. This is the chief challenge of the next decade.”

“A national conversation, guided by the best data and information, aimed at explicit understanding of choices, tradeoffs, and expectations, using broader definitions of health and value, is needed.”

(doi:10.l001/jama.2013.281425; 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.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 9:30 a.m. ET Tuesday, November 12 at this link.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) MONDAY, NOVEMBER 4, 2013

Media Advisory: To contact Nicholas J. Christian, Ph.D., email Allison Hydzik (HydzikAM@upmc.edu) or Cyndy McGrath (McGrathC3@upmc.edu) or call 412-647-9975.

In an analysis that included nearly 1,000 patients, self-reported weights following bariatric surgery were close to measured weights, suggesting that self-reported weights used in studies are accurate enough to be used when measured weights are not available, according to a Research Letter published online by JAMA.

“Obtaining standardized weights in long-term studies can be difficult. Self-reported weights are more easily obtained, but less accurate than those from a calibrated scale and may be inaccurately reported,” according to background information in the article.

Nicholas J. Christian, Ph.D., of the University of Pittsburgh Graduate School of Public Health, and colleagues investigated whether self-reported weights following bariatric surgery differed from weights obtained by study personnel using a standard scale. They used data collected between April 2010 and November 2012 at annual assessments from the Longitudinal Assessment of Bariatric Surgery-2, an observational cohort study of 2,458 adults undergoing an initial Roux-en-Y gastric bypass (RYGB), laparoscopic adjustable gastric band (LAGB), or other bariatric procedure at 10 centers. Participants were sent mailed questionnaires each year and asked to report their: (1) weight from last medical office or weight loss program visit (self-reported medical weight) and (2) last self-weighing (self-reported personal weight).

The final analysis included 988 participants, including 164 with a self-reported medical weight, 580 with a self-reported personal weight, and 244 with both self-reported weights. Across the 2 groups who self-reported weight, women and men underreported their weight by an average 2.2 lbs. or less and the degree of underreporting was not different between women and men. Self-reported medical weights were closer to measured weights than were self-reported personal weights for both women and men.

“Small differences between self-reported and measured weights were found and may be due to differences in clothing, inaccurate personal scales, time between measurements, or intentional misrepresentation,” the authors write. “Self-reported weights after bariatric surgery may be more accurate because participants who undergo surgery to lose weight may be especially attentive to their weight.”

(doi:10.l001/jama.2013.281043; 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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