EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 25, 2014

Media Advisory: To contact Signe Sorup, Ph.D., email sgs@ssi.dk. To contact editorial co-author David Goldblatt, M.B.Ch.B., Ph.D., email d.goldblatt@ucl.ac.uk.

Chicago – In a nationwide group of Danish children, receipt of the live measles, mumps, and rubella (MMR) vaccine on schedule after vaccination for other common infections was associated with a lower rate of hospital admissions for any infections, but particularly for lower respiratory tract infections, according to a study in the February 26 issue of JAMA.

Childhood vaccines are recommended worldwide, based on their protective effect against the targeted diseases.  However, studies from low-income countries show that vaccines may have nonspecific effects that reduce illness and death from non-targeted diseases, according to background information in the study. Such nonspecific effects of vaccines might also be important for the health of children in high-income settings.

Signe Sorup, Ph.D., of the Statens Serum Institut, Copenhagen, Denmark, and colleagues examined whether the live MMR vaccine was associated with lower rates of hospital admissions for infections among children in a higher-income setting (Denmark). The study included children 495,987 born 1997-2006 and followed from ages 11 months to 2 years. The recommended vaccination schedule was inactivated vaccine against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) administered at ages 3, 5, and 12 months; and MMR at age 15 months.

There were 56,889 hospital admissions for any type of infection among the children in the study. The researchers found that receiving the live MMR vaccine after the inactivated DTaP-IPV-Hib vaccine was associated with a lower rate of hospital admissions for any infection. The association was particularly strong for lower respiratory tract infections and for longer hospital admissions. Children who received DTaP-IPV-Hib after MMR had a higher rate of infectious disease admission.

“The coverage with MMR is suboptimal in many high-income countries; in the present study, about 50 percent of children were not vaccinated on time. Physicians should encourage parents to have children vaccinated on time with MMR and avoid giving vaccinations out of sequence, because the present study suggests that timely MMR vaccination averted a considerable number of hospital admissions for any infection between ages 16 and 24 months,” the authors write.

(doi:10.1001/jama.2014.470; 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: Nonspecific Effects of Vaccines

In an accompanying editorial, David Goldblatt, M.B.Ch.B., Ph.D., of the UCL Institute of Child Health and Great Ormond Street Children’s Hospital, London, and Elizabeth Miller, F.R.C.Path., of Public Health England, London, write that the WHO Strategic Advisory Group of Experts recently decided to revisit the issue of nonspecific effects of vaccines as part of its continued appraisal of important issues that could be relevant to inform global immunization policy.

“Systematic reviews of all available epidemiologic and immunologic evidence relevant to the issue of the nonspecific effects of vaccines on childhood mortality will be undertaken to decide whether current evidence is sufficient to lead to adjustments in policy recommendations or to warrant further scientific investigation. The study by Sorup et al is a further contribution to this body of literature. Although reanalysis of the available evidence is important, the ability to properly control for bias and confounding [factors that can influence outcomes] in observational studies is often limited, and without randomized controlled trials specifically designed to test the hypothesis, the issue of nonspecific effects of vaccines may remain subject to continuing debate.”

(doi:10.1001/jama.2014.471; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Goldblatt reported receiving grants from, and serving on advisory boards for, GlaxoSmithKline, Sanofi Pasteur, Merck, and Novartis and serving on an advisory board for Pfizer. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 25, 2014

Media Advisory: To contact Cynthia L. Ogden, Ph.D., email Jeff Lancashire (jhl1@cdc.gov) or the CDC press office (paoquery@cdc.gov) or call 301-458-4800.
Chicago – The prevalence of obesity remains high in the U.S., with about one-third of adults and 17 percent of children and teens obese in 2011-2012, according to a national survey study in the February 26 issue of JAMA.

Obesity and childhood obesity, in particular, are the focus of many preventive health efforts in the United States, including new regulations implemented by the U.S. Department of Agriculture for food packages; funding by the Centers for Disease Control and Prevention of state- and community-level interventions; and numerous reports and recommendations issued by the Institute of Medicine, the U.S. Surgeon General, and the White House, according to background information in the article.  Two articles published by the authors in JAMA in 2012 demonstrated that the prevalence of obesity leveled off between 2003-2004 and 2009-2010, but “given the focus of public health efforts on obesity, surveillance of trends in obesity remains important.”

Cynthia L. Ogden, Ph.D., and colleagues from the Centers for Disease Control and Prevention, Hyattsville, M.D., examined trends for childhood and adult obesity among 9,120 persons with measured weights and heights (or recumbent length) in the 2011-2012 nationally representative National Health and Nutrition Examination Survey.

The prevalence of high weight for recumbent length, a standard measure of weight among infants and toddlers from birth to age 2 years, was 8.1 percent in 2011-2012, with a difference between boys (5 percent) and girls (11.4 percent). For youth (2- to 19-years of age), 31.8 percent were either overweight or obese, and 16.9 percent were obese. Among adults, more than two-thirds (68.5 percent) were either overweight or obese, 34.9 percent were obese (body mass index [BMI] 30 or greater), and 6.4 percent were extremely obese (BMI 40 or greater).

Overall, there was no change from 2003-2004 through 2011-2012 in high weight for recumbent length among infants and toddlers or in obesity in 2- to 19-year-olds or adults. The prevalence of obesity among children 2 to 5 years of age decreased from 14 percent in 2003-2004 to just over 8 percent in 2011-2012, and increased in women age 60 years and older, from 31.5 percent to more than 38 percent.

The authors conclude that “obesity prevalence remains high and thus it is important to continue surveillance.”

(doi:10.1001/jama.2014.732; 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, FEBRUARY 18, 2014

Media Advisory: To contact corresponding author Claudia A. Steiner, M.D., M.P.H., call Alison Hunt at 301-427-1244 or email Alison.Hunt@ahrq.hhs.gov.
Chicago – In an analysis that included nearly 300,000 patients from eight states who underwent ambulatory surgery (surgery performed on a person who is admitted to and discharged from a hospital on the same day), researchers found that the rates of surgical site infections were relatively low; however, the absolute number of patients with these complications is substantial, according to a study in the February 19 issue of JAMA.

Surgical site infections are among the most common health care-associated infections, accounting for 20 percent to 31 percent of health care-associated infections in hospitalized patients, according to background information in the article. Although ambulatory surgeries represent a substantial portion of surgical health care, there is a lack of information on adverse events, including health care-associated infections.

Pamela L. Owens, Ph.D., of the Agency for Healthcare Research and Quality, Rockville, Md., and colleagues determined the incidence of clinically significant surgical site infections (CS-SSIs) following low- to moderate-risk ambulatory surgery in patients with low risk for surgical complications (defined as not seen in past 30 days in acute care, length of stay less than 2 days, no other surgery on the same day, and discharged home and no infection coded on the same day). The researchers used the 2010 Healthcare Cost and Utilization Project State Ambulatory Surgery and State Inpatient Databases for 8 states (California, Florida, Georgia. Hawaii. Missouri, Nebraska, New York, and Tennessee), representing one-third of the U.S. population. The analysis included 284,098 ambulatory surgical procedures (general surgery, orthopedic, neurosurgical, gynecologic, and urologic) in adult patients; rates were calculated for

14- and 30-day postsurgical acute care visits for CS-SSIs following ambulatory surgery.

The researchers found that the overall rate of postsurgical acute care visits within 14 days for CS-SSIs was relatively low (3.09 per 1,000 ambulatory surgical procedures). When the time frame was extended to 30 days, the rate increased to 4.84. Two-thirds (63.7 percent) of all visits for CS-SSI occurred within 14 days of the surgery; of those visits, 93.2 percent involved treatment in the inpatient setting.

The authors note that although the overall rate of CS-SSIs was low, because of the large number of ambulatory surgical procedures performed annually, in absolute terms, a substantial number of patients develop clinically significant postoperative infections. Most of these infections occurred within 2 weeks after surgery and resulted in hospital admission. “Our findings suggest that earlier access to a clinician or member of the surgical team (e.g., telephone check-in prior to 2 weeks) may help identify and treat these infections early and reduce overall morbidity.”

“Prior studies showing significant lapses in infection control practices at ambulatory surgery centers suggest that quality improvement efforts may facilitate reducing CS-SSIs following ambulatory surgery.”

(doi:10.1001/jama.2014.4; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by the Agency for Healthcare Research and Quality under a contract to Truven Health Analytics to develop and support the Healthcare Cost and Utilization Project. 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, FEBRUARY 18, 2014

Media Advisory: To contact David A. Hanauer, M.D., M.S., call Mary Masson at 734-764-2220 or email mfmasson@med.umich.edu.

Chicago – In a survey of a nationally representative sample of the U.S. population, 65 percent of respondents reported awareness of online physician ratings and about one-fourth reported usage of these sites, according to a study in the February 19 issue of JAMA.

“Patients are increasingly turning to online physician ratings, just as they have sought ratings for other products and services,” according to background information in the article. “Little is known about the public’s awareness and use of online physician ratings, and whether these sites influence decisions about selecting a physician.”

David A. Hanauer, M.D., M.S., of the University of Michigan Medical School, Ann Arbor, Mich., and colleagues surveyed the public in September 2012 about their knowledge and use of online ratings for selecting physicians. Sixty percent (2,137/3,563) of the sample responded. Twenty-one percent of respondents were 18 to 29 years of age; 17 percent, 30 to 39 years; 18 percent, 40 to 49 years; 19 percent, 50 to 59 years; and 26 percent, 60 years or older.

Among the findings of the survey:

Forty percent reported that physician rating sites were “very important” when choosing a physician, although rating sites were endorsed less frequently than other factors, including word of mouth from family and friends;

Awareness of online physician ratings (65 percent) was lower than for consumer goods such as cars (87 percent) and non-health care service providers (71 percent);

Among those who sought online physician ratings in the past year, 35 percent reported selecting a physician based on good ratings and 37 percent had avoided a physician with bad ratings;

For those who had not sought online physician ratings, 43 percent reported a lack of trust in the information on the sites.

The authors conclude that “rating sites that treat reviews of physicians like reviews of movies or mechanics may be useful to the public but the implications should be considered because the stakes are higher.”

(doi:10.1001/jama.2013.283194; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This research was conducted with the support of the C. S. Mott Children’s Hospital National Poll on Children’s Health, sponsored by the Department of Pediatrics and Communicable Diseases at the University of Michigan and the University of Michigan Health System. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 18, 2014

Media Advisory: To contact Anton P. Porsteinsson, M.D., call Julie Philipp at 585-275-1309 or email Julie_Philipp@urmc.rochester.edu. To contact editorial author Gary W. Small, M.D., call Rachel Champeau at 310-794-2270 or email rchampeau@mednet.ucla.edu.

Chicago – The use of the medication citalopram was associated with a reduction in agitation in patients with Alzheimer disease, although at the dosage used in the study, patients experienced mild cognitive and cardiac adverse effects that might limit the practical application of this medication at the dosage of 30 mg per day, according to a study in the February 19 issue of JAMA.

Agitation, which is common in patients with Alzheimer disease, is persistent, difficult to treat, costly, and associated with severe adverse consequences for patients and caregivers. Pharmacologic therapies have proven inadequate and antipsychotic drugs continue to be widely used for this condition despite serious safety concerns, including increased risk of death, and uncertain efficacy, according to background information in the article. Citalopram, an antidepressant drug frequently used in older individuals, has been proposed as an alternative to antipsychotic drugs for agitation and aggression in dementia, yet there is limited evidence for its efficacy and safety.

Anton P. Porsteinsson, M.D., of the University of Rochester School of Medicine and Dentistry, Rochester, N.Y., and colleagues randomized 186 patients with probable Alzheimer disease without major depression and clinically significant agitation from 8 academic centers in the United States and Canada to receive citalopram (n = 94) or placebo (n = 92) for 9 weeks. Both groups received psychological counseling and assistance.

Treatment with citalopram 30 mg per day led to a reduction in agitation, with a clinically relevant effect size: on one measure, 40 percent of citalopram-treated participants were judged to be much or very much improved vs 26 percent of those in the placebo group. The researchers did find a worsening of cognition and higher risk of ECG changes that could predispose to an abnormal heart rhythm in the citalopram group, and conclude that citalopram “cannot be generally recommended as an alternative treatment option at that dose.”

“An assessment of individual patient circumstances, including symptom severity, value of improvement, cognitive function and change, cardiac conduction, vulnerability to adverse effects, and effectiveness of behavioral interventions can help guide appropriate medication use in patients with marked agitation or aggression,” the authors add.

(doi:10.1001/jama.2014.93; 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, February 18 at this link.

Editorial: Treating Dementia and Agitation

Until more informative criteria are available for choosing a particular drug treatment for agitation, clinicians should continue to emphasize nonpharmacological strategies and opt for medications with caution, writes Gary W. Small, M.D., of the University of California, Los Angeles, in an accompanying editorial.

“In addition to educating caregivers and family members about the potential risks and benefits of particular medications, physicians should carefully document their treatment plans and aim for short-term treatment to minimize the possible added risks of long-term use. As demonstrated by the results of this study of citalopram, when behavioral interventions fail to improve agitation, multiple factors need consideration for selecting the best medication for an individual patient, including cardiac safety issues and evidence of efficacy from randomized controlled trials. Until more definitive treatments are available, the careful selection and monitoring of pharmacologic agents may help optimize the level of functioning and quality of life for some patients with dementia.”

(doi:10.1001/jama.2014.94; 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, FEBRUARY 18, 2014

Media Advisory: To contact Carlos A. Morillo, M.D., F.R.C.P.C., call Veronica McGuire at 905-525-9140, ext. 22169, or email vmcguir@mcmaster.ca. To contact editorial co-author Hugh Calkins, M.D., call Stephanie Desmon at 410-955-8665 or email sdesmon1@jhmi.edu.

 
Chicago – Among patients with untreated paroxysmal (intermittent) atrial fibrillation (AF), treatment with electrical energy (radiofrequency ablation) resulted in a lower rate of abnormal atrial rhythms and episodes of AF, according to a study in the February 19 issue of JAMA.

Arial fibrillation affects approximately 5 million people worldwide and is associated with an increased risk of stroke. Drug treatment is recommended by practice guidelines as a first-line therapy in patients with paroxysmal AF. “Radiofrequency ablation is an accepted therapy in patients for whom antiarrhythmic drugs have failed; however, its role as a first-line therapy needs further investigation,” according to background information in the article.

Carlos A. Morillo, M.D., F.R.C.P.C., of McMaster University, Hamilton, Canada, and colleagues compared ablation to drug treatment as first-line therapy in patients with paroxysmal AF who had not previously received treatment. The trial included 127 patients at 16 centers in Europe and North America; 61 patients received antiarrhythmic drug treatment and 66 radiofrequency ablation.

Recurrence of an atrial tachyarrhythmia lasting longer than 30 seconds (the primary measured outcome) occurred more often in the antiarrhythmic drug group than in the ablation group, 44 patients (72 percent) vs. 36 patients (55 percent). Asymptomatic AF was also observed more frequently with drug treatment, 11 patients (18 percent) compared with 6 patients (9 percent). Symptomatic recurrence of abnormal rhythm was more common with drug treatment, 36 patients (59 percent) in the antiarrhythmic drug group compared with 31 patients (47 percent) in the ablation group.

Quality of life was improved overall by both treatments but not significantly different between groups. No deaths or strokes were reported in either group; 4 cases of cardiac tamponade (the accumulation of a large amount of fluid [usually blood] near the heart that interferes with its performance) were reported in the ablation group.

The authors conclude that recurrence of an atrial tachyarrhythmia was frequent in both groups, and that when offering ablation as a therapeutic option to patients with paroxysmal AF who have not previously received antiarrhythmic drugs, the risks and benefits need to be discussed and treatment strategy individually recommended.

(doi:10.1001/jama.2014.467; 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: Has the Time Come to Recommend Catheter Ablation of Atrial Fibrillation as First-Line Therapy?

Hugh Calkins, M.D., of Johns Hopkins Hospital, Baltimore, Md., comments on the findings of this study in an accompanying editorial.

“Morillo and colleagues have made an important contribution in defining the safety, efficacy, and clinical role of catheter ablation of AF in treating symptomatic patients with paroxysmal AF. Their trial not only provides new and important information concerning the efficacy of AF ablation but also serves as another reminder of the potential complications of invasive therapies such as AF ablation.”

(doi:10.1001/jama.2014.468; 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, FEBRUARY 18, 2014

Media Advisory: To contact Nancy K. Latham, Ph.D., P.T., call Lisa Chedekel at 617-571-6370 or email chedekel@bu.edu.
Chicago – Among patients who had completed standard rehabilitation after hip fracture, the use of a home exercise program that included exercises such as standing from a chair or climbing a step resulted in improved physical function, according to a study in the February 19 issue of JAMA.

More than 250,000 people in the United States fracture their hip each year, with many experiencing severe long-term consequences. “Two years after a hip fracture, more than half of men and 39 percent of women are dead or living in a long-term care facility. Many of these patients are no longer able to independently complete basic functional tasks that they could perform prior to the fracture, such as walking 1 block or climbing 5 steps 2 years after a fracture,” according to background information in the article. The efficacy of a home exercise program with minimal supervision after formal hip fracture rehabilitation ends has not been established.

Nancy K. Latham, Ph.D., P.T., of Boston University, and colleagues randomized 232 functionally limited older adults who had completed traditional rehabilitation after a hip fracture to a home exercise hip rehabilitation program comprising functionally oriented exercises (such as standing from a chair, climbing a step) taught by a physical therapist and performed independently by the participants in their homes for 6 months (n = 120); or in-home and telephone-based cardiovascular nutrition education (n = 112).

Among the 232 randomized patients, 195 were followed up at 6 months and included in the primary analysis. The intervention group (n=100) showed improvement relative to the control group (n=95) in functional mobility on various measures. In addition, balance significantly improved in the intervention group compared with the control group at 6 months.

“The traditional approach to rehabilitation for hip fracture leaves many patients with long-term functional limitations that could be reduced with extended rehabilitation. However, it is unlikely that additional months of highly supervised rehabilitation can be provided to patients with hip fracture,” the authors write.

“Exercise programs are challenging for people to perform on their own without clear feedback about whether they are performing the exercises accurately and safely and without guidance as to how to change the exercises over time. The findings from our study suggest that [the approach used in this study] could be introduced to patients after completion of traditional physical therapy following hip fracture and may provide a more effective way for these patients to continue to exercise in their own homes. However, future research is needed to explore whether the interventions in this trial can be disseminated in a cost-effective manner in real clinical environments.”

(doi:10.1001/jama.2014.469; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by a grant from the National Institute of Nursing Research. All Thera-Band products were donated by Thera-Band. 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, FEBRUARY 11, 2014

Media Advisory: To contact Saad B. Omer, M.B.B.S., M.P.H., Ph.D., call Melva Robertson at 404-727-5692 or email melva.robertson@emory.edu.

Chicago – From 2009-2012, 36 bills introduced in 18 states sought to modify school immunization mandates, with the majority seeking to expand exemptions although none of the bills passed, according to a study in the February 12 issue of JAMA.

“School immunization mandates, implemented through state-level legislation, have played an important role in maintaining high immunization coverage in the United States,” according to background information in the article. Immunization mandates permit exemptions that vary from state to state in terms of type of exemption (e.g., religious, personal belief, medical). Certain types of exemptions (especially personal belief exemptions) and the ease of obtaining them can help predict the increased disease risk among exemptors themselves and in the communities in which they reside

Saad B. Omer, M.B.B.S., M.P.H., Ph.D., of Emory University, Atlanta, and colleagues analyzed legislation proposed from 2009 through 2012 at the state level to modify exemptions to school immunization requirements. The bills were classified into those that did or did not have a personal belief exemption (PBE). In addition, the researchers listed administrative requirements included in each bill, defined as one that would require action from the child’s parent or guardian beyond merely signing an exemption form. Bills were also classified as expanding or restricting exemptions.

Eighteen states introduced 1 or more exemption-related bills. Among 36 bills introduced, 15 contained no administrative requirements, 7 had 1 or 2 administrative requirements, and the remaining 14 contained between 3 and 5 administrative requirements.

Of 20 states with a current PBE, 5 saw a bill introduced to restrict exemptions and 1 saw a bill introduced to expand exemptions. Among the 30 states without a PBE, none saw a bill introduced to restrict exemptions and 13 saw a bill introduced to expand exemptions. Of the 36 bills introduced, 5 were categorized as restricting exemptions and 31 as expanding exemptions. None of the bills categorized as expanding exemptions were passed. Three of the 5 bills categorized as restricting exemptions were passed (Washington, California, and Vermont).

“Exemptions to school immunization requirements continue to be an issue for discussion and debate in many state legislatures,” the authors write.

(doi:10.1001/jama.2013.282869; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Hinman reported receiving institutional grant funding from the U.S. Centers for Disease Control and Prevention, the Bill & Melinda Gates Foundation, Novartis Vaccines, and the Merck Company Foundation. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 11, 2014

Media Advisory: To contact Kenneth J. Ottenbacher, Ph.D., call Molly Dannenmaier at 409-772-8790 or email mjdannen@utmb.edu; or Mechal Weiss at 212-642-7731, mechal.weiss@edelman.com.

 Chicago – Among rehabilitation facilities providing services to Medicare fee-for-service patients, 30-day hospital readmission rates vary, from about 6 percent for patients with lower extremity joint replacement to nearly 20 percent for patients with debility (weakness or feebleness), according to a study in the February 12 issue of JAMA.

The Centers for Medicare & Medicaid Services (CMS) recently identified 30-day hospital readmission as a national quality indicator for inpatient rehabilitation facilities; reporting will be required in 2014 by the CMS, according to background information in the article.

Kenneth J. Ottenbacher, Ph.D., of the University of Texas Medical Branch, Galveston, Texas, and colleagues conducted a study to determine 30-day readmission rates and factors related to readmission for patients receiving postacute inpatient rehabilitation. The study included records for 736,536 Medicare fee-for-service beneficiaries discharged from 1,365 inpatient rehabilitation facilities to the community between 2006 and 2011. Readmission rates were examined for the 6 most common reasons for receiving inpatient rehabilitation: stroke, lower extremity fracture, lower extremity joint replacement, neurologic disorders, brain dysfunction and debility.

Average rehabilitation length of stay was 12 days. The overall 30-day readmission rate was 11.8 percent, with rates ranging from 5.8 percent for patients with lower extremity joint replacement to 18.8 percent for patients with debility. Rates were highest in men, non-Hispanic blacks, and for persons with longer lengths of stay. Higher motor and cognitive ratings, indicating better patient function, were consistently related to lower readmission rates across all 6 categories. Rates were similar for rural vs urban facilities and freestanding vs hospital-based facilities.

Approximately 50 percent of patients rehospitalized within the 30-day period were readmitted within 11 days of discharge. The most common reasons for readmission (per diagnosis codes) were heart failure, urinary tract infection, pneumonia, septicemia (blood poisoning), nutritional and metabolic disorders, esophagitis (inflammation of the esophagus), gastroenteritis, and digestive disorders.

The authors write that Medicare is currently examining bundled payment models designed to improve quality and contain costs. “The payment options cover different periods and include multiple health care professionals and settings. In the context of bundled payment, what happens to patients during post-acute care becomes important in the management of resources, quality, cost, and readmissions. Recent research has demonstrated that most of the variation in Medicare spending across geographic areas is attributable to postacute care. Readmission will likely add to the cost variation.”

“Questions regarding the validity of readmission as a quality indicator are likely to increase as the accountability for readmission expands to include postacute care settings. Although readmission is an imperfect quality indicator, it has the potential to serve as a platform for efforts to improve patient transitions and care continuity associated with bundling and other initiatives proposed by the Affordable Care Act to reduce cost and improve health outcomes.”

(doi:10.1001/jama.2014.8; 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.

ama_toc_item id=”16419″]

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 11, 2014

Media Advisory: To contact corresponding author Xiaobin Wang, M.D., M.P.H., Sc.D., call Tim Parsons at 410-955-7619 or email tmparson@jhsph.edu. To contact editorial author Mark Hanson, D.Phil., F.R.C.O.G., email M.Hanson@soton.ac.uk.

Chicago – Researchers have found that preterm infants are more likely to have elevated insulin levels at birth and in early childhood compared to full-term infants, findings that provide additional evidence that preterm birth may be a risk factor for type 2 diabetes, according to a study in the February 12 issue of JAMA.

In the United States, 1 in 9 live births are preterm, and l in 5 live births among African Americans are preterm. “There is growing evidence that fetal and early life events may result in permanent metabolic alterations, such as type 2 diabetes and metabolic syndrome [a combination of risk factors that increase the risk for heart disease, diabetes, and stroke]. Although available studies in children and adults support the hypothesis that preterm birth may result in adverse metabolic alterations, it is unclear whether the observed association between preterm birth, later insulin resistance, and type 2 diabetes stems from alterations in insulin metabolism during the in utero [in the uterus] period or in early childhood,” according to background information in the article.

Guoying Wang, M.D., Ph.D., of the Johns Hopkins University Bloomberg School of Public Health, Baltimore, and colleagues tested the hypothesis that preterm birth is associated with elevated plasma insulin levels (indirect evidence of insulin resistance) at birth that persist into early childhood. The study included 1,358 children, born between 1998 and 2010, and followed-up from 2005 to 2012. Random plasma insulin levels were measured at birth and in early childhood.

The researchers found that plasma insulin levels were inversely associated with gestational age at birth and in early childhood. Average insulin levels at birth were 9.2 µIU/mL (micro international units per milliliter) for full term (≥ 39 weeks) and 18.9 µIU/mL for early preterm (<34 weeks) births. In early childhood, random plasma insulin levels were higher for early term, late preterm, and for early preterm both than those born full term.

“These findings provide additional evidence that preterm birth (and perhaps early term birth as well) may be a risk factor for the future development of insulin resistance and type 2 diabetes,” the authors write.

(doi:10.1001/jama.2014.1; 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: Understanding the Origins of Diabetes

In an accompanying editorial, Mark Hanson, D.Phil., F.R.C.O.G., of the University of Southampton and University Hospital Southampton, United Kingdom, writes that “the population studied by Wang et al (i.e., largely urban and minority) has a high risk of preterm birth and also of childhood obesity and later metabolic syndrome.”

“The findings confirm the importance of the developmental origins of health and disease concept to such populations and raise questions about the relative effect size longer-term. However, such populations should not be viewed as special cases; they show a continuum of noncommunicable disease (NCD) risk that is initiated by a range of environmental influences operating across the normal range of early development.”

“Studies such as that by Wang et al reveal just how early the first steps toward prevention of diabetes may be possible and raise the prospect that rigorous studies of early life interventions could form an important aspect of helping to reduce NCD risk.”

(doi:10.1001/jama.2014.2; 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, FEBRUARY 11, 2014

Media Advisory: To contact corresponding author Lisen Arnheim-Dahlström, Ph.D., email lisen.arnheim.dahlstrom@ki.se.

Chicago – Although maximum reduction in the risk of genital warts (condylomata) was seen after 3 doses of human papillomavirus (HPV) vaccine, receipt of 2 vaccine doses was associated with considerable reduction in risk, particularly among women who were younger than 17 years at first vaccination, according to a study in the February 12 issue of JAMA.

HPV infection causes genital warts and cervical cancer, and HPV vaccine prevents both. The typical dose schedule requires 3 doses of vaccine, but small clinical trials have reported measures of vaccine efficacy with fewer than 3 doses. Although the primary goal of HPV vaccination programs is to prevent cervical cancer, genital warts related to HPV types 6 and 11 are prevented with a version of the vaccine and are the earliest measurable preventable disease outcome for the HPV vaccine, according to background information in the study.

Eva Herweijer, M.Sc., of the Karolinska Institutet, Stockholm, Sweden, and colleagues assessed the association between the number of doses of HPV vaccination and genital warts among females 10 to 24 years of age living in Sweden (n = 1,045,165) who were followed up between 2006 and 2010, using the Swedish nationwide population-based health data registers.

Among 20,383 new cases of genital warts, 322 occurred after receipt of at least 1 dose of the vaccine. The researchers found that maximum risk reductions were found after 3 doses, but 2 doses were also protective, although to a lesser extent; there was small difference in the number of cases prevented by 3 doses vs 2 doses.

The authors caution that this study does not account for HPV disease outcomes other than genital warts, and that more studies with longer follow-up are needed to assess if these observed reductions apply for cervical cancer.

(doi:10.1001/jama.2014.95; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the Swedish Foundation for Strategic Research. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, 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, February 11 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 11, 2014

Media Advisory: To contact corresponding author Dorry L. Segev, M.D., Ph.D., call Stephanie Desmon at 410-955-8665 or email sdesmon1@jhmi.edu. To contact editorial co-author John S. Gill, M.D., call Brian Kladko at 604-827-3301 or email brian.kladko@ubc.ca.

Chicago – An analysis of nearly 100,000 kidney donors finds that there is a small increased lifetime risk of developing end-stage renal disease following donation compared with healthy nondonors, although the risk is still much lower than that in the general population, according to a study in the February 12 issue of JAMA.

Every year in the United States, approximately 6,000 healthy adults accept the risks of kidney donation to help family members, friends, or even strangers. “It is imperative that the transplant community, in due diligence to donors, understands the risk of donation to the fullest extent possible and communicates known risks to those considering donation,” according to background information in the article.

Abimereki D. Muzaale, M.D., M.P.H., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues compared the incidence of end-stage renal disease (ESRD) in donors and healthy nondonors to better understand the risk of ESRD. The study included 96,217 kidney donors (donation between 1994-2011) in the United States and a group of 20,024 participants of the Third National Health and Nutrition Examination Survey (NHANES III), who were linked to Centers for Medicare & Medicaid Services data to ascertain development of ESRD (defined as the initiation of maintenance dialysis, placement on the transplant waiting list, or receipt of a living or deceased donor kidney transplant).

The estimated cumulative incidence of ESRD at 15 years after donation was 30.8 per 10,000 in donors and 3.9 per 10,000 in healthy nondonors. This higher incidence among donors was observed in both black and white donors; absolute risk of ESRD was highest among blacks, regardless of their donor status. By age 80 years, the estimated lifetime risk of ESRD was 90 per 10,000 in donors vs 14 per 10,000 in healthy nondonors. Live donors had much lower estimated lifetime risk of ESRD than did the general population (unscreened nondonors; 326 per 10,000).

The authors write that their findings reaffirm the prevailing belief that lifetime risk of ESRD in live donors is no higher than in the general demographics-matched U.S. population.

“Compared with a matched cohort of healthy nondonors, kidney donors had an increased risk of ESRD; however, the magnitude of the absolute risk increase was small. These findings may help inform discussions with persons considering live kidney donation.”

(doi:10.1001/jama.2013.285141; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the Health Resources and Services Administration. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

ama_toc_item id=”16415″]

Editorial: Understanding Rare Adverse Outcomes Following Living Kidney Donation

In an accompanying editorial, John S. Gill, M.D., of the University of British Columbia, Vancouver, and Marcello Tonelli, M.D., of the University of Alberta, Edmonton, discuss the potential limitations of this study and the very low absolute risk of ESRD following live kidney donation.

“It would be easy to misinterpret the findings of Muzaale et al as suggesting that kidney donation is a risky procedure. In reality, the authors have shown that the absolute risk of ESRD among living donors is extremely low; this is their key finding and does not imply the need to alter existing clinical practice.”

“… it would be prudent for clinicians to emphasize the absolute risk of ESRD in discussions with prospective living donors, ideally using a decision aid that will facilitate the process of obtaining informed consent.”

(doi:10.1001/jama.2013.285142; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, FEBRUARY 4, 2014

Media Advisory: To contact Nassir F. Marrouche, M.D., call Phil Sahm at 801-581-2517 or email phil.sahm@hsc.utah.edu.
Chicago – Scarring of tissue in the upper chamber of the heart (atrium) was associated with recurrent rhythm disorder after treatment, according to a study in the February 5 issue of JAMA.

Left atrial fibrosis (formation of scar tissue in the heart) is prominent in patients with atrial fibrillation (AF), according to background information in the article. Extensive atrial tissue fibrosis identified by delayed enhancement magnetic resonance imaging (MRI) has been associated with poor outcomes of AF catheter ablation, a procedure in which electrical energy is used to treat AF.

Nassir F. Marrouche, M.D., of the University of Utah School of Medicine, Salt Lake City, and colleagues conducted a study to characterize the feasibility of measuring atrial scar tissue using delayed enhancement magnetic resonance imaging (MRI), and assessed the association between the amount of scar tissue and response to ablation. The study was conducted between August 2010 and August 2011 at 15 centers in the United States, Europe, and Australia; delayed enhancement MRI images were obtained up to 30 days before ablation.

There were 329 patients enrolled in the study; 57 patients (17.3 percent) were excluded due to poor MRI quality. The researchers found that the incidence of recurrence increased with the amount of scarring, from 15.3 percent recurrence at day 325 with less than 10 percent scarring of the atrial wall to 51.1 percent recurrence for 30 percent or greater scarring.

The authors write that this study demonstrates the feasibility and potential clinical value of using delayed enhancement MRI in the management of patients with AF considered for ablation. “In current practice, criteria for selecting good candidates for AF ablation are limited.”  They add that the amount of left atrial wall fibrosis estimated by delayed enhancement MRI has the potential to offer a noninvasive and effective method for determining which patients with AF are likely to benefit from ablation while avoiding procedures in patients likely to have arrhythmia recurrence.

(doi:10.1001/jama.2014.3; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The Comprehensive Arrhythmia and Research Management Center at the University of Utah provided funding for the study. The George S. and Dolores Dore Eccles Foundation funded part of this study. 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, FEBRUARY 4, 2014

Media Advisory: To contact Barbara Schmidt, M.D., M.Sc., call Alison Fraser at 267-426-6054 or email FraserA1@email.chop.edu.
Chicago – In a group of very low-birth-weight infants, severe retinopathy of prematurity was associated with nonvisual disabilities at age 5 years, according to a study in the February 5 issue of JAMA.

Severe retinopathy (disease of the retina) of prematurity occurs in premature infants treated with excessive concentrations of oxygen and is a serious complication of neonatal intensive care for preterm infants. “Although the incidence of severe retinopathy has increased since the late 1980s, blindness caused by retinopathy has become rare in developed countries. Consequently, clinicians and parents may conclude that severe retinopathy is no longer associated with childhood impairments,” according to background information in the article.

Barbara Schmidt, M.D., M.Sc., of Children’s Hospital of Philadelphia, and colleagues investigated whether infants with severe retinopathy retain an increased risk of nonvisual disabilities compared with those without severe retinopathy. This analysis (using data from a trial, Caffeine for Apnea of Prematurity), included infants with birth weights between 1.1 and 2.8 lbs. who were born between 1999 and 2004 and followed-up at age 5 years (2005-2011).

Of 1,815 eligible infants, 1,582 (87 percent) had complete (n = 1,523) or partial (n = 59) 5-year assessments. Of 95 with severe retinopathy, 40 percent had at least 1 nonvisual disability at 5 years compared with 16 percent of children without it. Fourteen of 94 children (15 percent) with and 36 of 1,487 children (2.4 percent) without severe retinopathy had more than 1 nonvisual disability. Motor impairment, cognitive impairment, and severe hearing loss were 3 to 4 times more common in children with severe retinopathy than those without severe retinopathy.

The authors write that these findings may help improve the ability to counsel parents and to select high-risk infants for long-term follow-up.

“Severe retinopathy of prematurity remains an adverse outcome of neonatal intensive care with poor prognosis for child development, although blindness can mostly be prevented by timely retinal therapy.”

(doi:10.1001/jama.282153; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The Caffeine for Apnea of Prematurity trial was supported by a grant from the Canadian Institutes of Health Research and by the National Health and Medical Research Council of Australia. 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, FEBRUARY 4, 2014

Media Advisory: To contact Norrina B. Allen, Ph.D., M.P.H., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu. To contact editorial co-author George L. Bakris, M.D., call John Easton at 773-795-5225 or email john.easton@uchospitals.edu.
Chicago – In an analysis of blood pressure patterns over a 25-year span from young adulthood to middle age, individuals who exhibited elevated and increasing blood pressure levels throughout this time period had greater odds of having higher measures of coronary artery calcification (a measure of coronary artery atherosclerosis), according to a study in the February 5 issue of JAMA.

“Blood pressure (BP) represents a major modifiable risk factor for cardiovascular disease (CVD). Current risk prediction models take into account BP level only at the time of risk prediction, usually in middle or older age, and do not consider the potential effect of BP levels earlier in life or the changes in BP levels over time,” according to background information in the article.

Norrina B. Allen, Ph.D., M.P.H., of the Feinberg School of Medicine, Northwestern University, Chicago, and colleagues identified common BP trajectories (patterns) throughout early adulthood and sought to determine their association with the presence of coronary artery calcification (CAC) during middle age among 4,681 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. The participants were black and white men and women, 18 to 30 years of age at the beginning of the study in 1985-1986. Data were collected through 25 years of follow-up on systolic BP, diastolic BP, and mid-BP (calculated as [SBP+DBP]/2, an important marker of coronary heart disease risk among younger populations). The primary measured outcome for the study was a higher level of coronary artery calcification detected by computed tomography scan.

The researchers identified 5 distinct trajectories in mid-BP from young adulthood to middle age: 22 percent of participants maintained low BP throughout follow-up (low-stable group); 42 percent had moderate BP levels (moderate-stable group); 12 percent started with moderate BP levels which increased at an average age of 35 years (moderate-increasing group); 19 percent had relatively elevated BP levels throughout (elevated-stable group); and 5 percent started with elevated BP’s which increased during follow-up (elevated-increasing group).

The prevalence of a high CAC score varied from 4 percent in the low-stable BP trajectory group to 25 percent in the elevated-increasing BP trajectory group. Participants who exhibited elevated BP levels throughout the study period and those who had increases in BP levels over this time had larger odds of having a high CAC score.

“Although BP has been a well-known risk factor for CVD for decades, these findings suggest that an individual’s long-term patterns of change in BP starting in early adulthood may provide additional information about his or her risk of development of coronary calcium,” the authors write. “Additional research is needed to examine the utility of specific BP trajectories in risk prediction for clinical CVD events and to explore the effect of lifestyle modification, treatment, and timing of intervention on lifetime trajectories in BP and outcomes.”

(doi:10.1001/jama.2013.285122; 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, February 4 at this link.

Editorial: Early Patterns of Blood Pressure Change and Future Coronary Atherosclerosis

Pantelis A. Sarafidis, M.D., M.Sc., Ph.D., of Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece, and George L. Bakris, M.D., of University of Chicago Medicine, comment on the findings of this study in an accompanying editorial.

“The study by Allen and colleagues presents a novel approach for assessing coronary heart disease and CVD risk, and the data offer an important perspective to support a preventive approach to reduce coronary heart disease risk by demonstrating the existence of widely different BP trajectories ranging from young adulthood through middle age … Further research is warranted to explore the associations of BP trajectories with development of advancing chronic kidney disease and heart failure and to provide novel tools for risk prediction to guide interventions for BP lowering in everyday practice.”

(doi:10.1001/jama.2013.285123; 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 EARLY RELEASE: 8 A.M. (CT) TUESDAY, JANUARY 21, 2014

Media Advisory: To contact Richard Smith, M.B.Ch.B., C.B.E., email richardswsmith@yahoo.co.uk.

Chicago – A video of individuals who gave birth to the evidence-based medicine movement features valuable oral histories of the movement, according to an editorial in the January 22/29 issue of JAMA. Evidence-based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.

In the editorial, Richard Smith, M.B.Ch.B., C.B.E., of the UnitedHealth Chronic Disease Initiative in London, and formerly editor, BMJ, and Drummond Rennie, M.D., of the University of California, San Francisco, and formerly contributing deputy editor, JAMA, discuss evidence-based medicine (EBM) and the important contributions of various individuals.

JAMA and the BMJ invited 6 individuals who helped lead the development of EBM to participate in an oral history event and filming. Videos of this event and of interviews with 3 other EBM leaders have been woven together to create the video, “Evidence-Based Medicine: An Oral History,” (available for free at the embargo time at https://ebm.jamanetwork.com).

The video features EBM leaders’ perspectives on the past, present, and future of EBM, some of the barriers and controversies associated with the EBM movement, and personal reflections of clinical and patient encounters and shared decision making in the context of EBM. “The video makes clear that much has been achieved, but that much remains to be done,” the editorial’s authors write.

(doi:10.1001/jama.2013.286182; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: Funding for the Evidence-Based Medicine Oral History event and filming was provided by JAMA and the BMJ. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding for travel to participate in the Evidence-Based Medicine Oral History event and filming was provided by JAMA and the BMJ.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 21, 2014

Media Advisory: To contact corresponding author Julia S. Johansen, M.D., D.M.Sc., email julia.johansen@post3.tele.dk. To contact editorial co-author Donald J. Buchsbaum, Ph.D., email Beena Thannickal at beenat@uab.edu.

Chicago – Researchers have identified diagnostic microRNA panels in whole blood that had the ability to distinguish, to some degree, patients with and without pancreatic cancer, according to a study in the January 22/29 issue of JAMA. The authors caution that the findings are preliminary, and that further research is necessary to understand whether these microRNAs have clinical implications as a screening test for early detection of pancreatic cancer.

MicroRNAs regulate gene expression and play important roles in the development of tumors and tumor metastasis. MicroRNA panels are a combination of several microRNAs.

Pancreatic cancer is the fourth most common cause of cancer death in the Western world and prognosis is poor, according to background information in the article.  Early diagnosis of pancreatic cancer is difficult partly because it is difficult to get useful biopsies of tissue from patients suspected of having pancreatic cancer, so markers of the disease that could help with early diagnosis are needed to improve prognosis. Several specific microRNA profiles (patterns of microRNAs) have been linked to pancreatic cancer tissue. A diagnostic noninvasive blood test for pancreatic cancer would be very valuable, the authors write.

Nicolai A. Schultz, M.D., Ph.D., of Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, and colleagues examined differences in microRNA in whole blood between patients with pancreatic cancer (n  = 409) and healthy participants (n = 312) and patients with chronic pancreatitis (n = 25) to identify diagnostic panels of microRNAs for use in the diagnosis of pancreatic cancer. Serum cancer antigen 19-9 (CA19-9; an antigen that is elevated in approximately 80 percent of patients with pancreatic cancer) was also measured for comparison.

The researchers identified 2 novel panels with the potential for diagnosing pancreatic cancer.

The authors write that the test could result in referral of more individuals with symptoms to imaging. “The test could thereby diagnose more patients with pancreatic cancer, some of them at an early stage, and thus have a potential to increase the number of patients that can be operated on and possibly cured of pancreatic cancer.”

They add that the harms of a high number of false-positives in screening for pancreatic cancer using an inexpensive, noninvasive blood sample from individuals with or without symptoms should be quantified in the future.

“Although we validated the panels, our findings are preliminary. … Further research is necessary to understand whether these have clinical implications for early detection of pancreatic cancer and how much this information adds to serum CA19-9.”

(doi:10.1001/jama.2013.284664; 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: Will Detection of MicroRNA Biomarkers in Blood Improve the Diagnosis and Survival of Patients With Pancreatic Cancer?

In an accompanying editorial, Donald J. Buchsbaum, Ph.D., of the University of Alabama, Birmingham, and Carlo M. Croce, M.D., of Ohio State University, Columbus, write that additional research is needed regarding the use of microRNAs for the early detection of pancreatic cancer.

“Even though the study was relatively large, well-conducted, and addressed the important topic of development of noninvasive methods to detect pancreatic cancer, the authors appropriately acknowledge the exploratory nature of the investigation. … Given the dismal prognosis for patients with pancreatic cancer, it is important that new diagnostic approaches, such as the one used in this study, are sought. However, additional rigorous investigation will be necessary to support and extend these interesting findings.”

(doi:10.1001/jama.2013.284665; 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, JANUARY 21, 2014

Media Advisory: To contact corresponding author Miguel A. Martinez-Gonzalez, M.D., M.P.H., Ph.D., email mamartinez@unav.es.

Chicago – A multicenter study that previously reported a reduction in heart attack and stroke with a Mediterranean diet supplemented with extra-virgin olive oil or with nuts now also reports a lower risk of peripheral artery disease, according to a study in the January 22/29 issue of JAMA.

The hypothesis that a Mediterranean diet may reduce the risk of peripheral artery disease (PAD) has never been tested in a randomized trial, according to background information in the article.

Miguel Ruiz-Canela, Ph.D., of the University of Navarra, Pamplona, Spain, and colleagues assessed the association of Mediterranean diets with the occurrence of symptomatic PAD in a randomized trial conducted from October 2003 and December 2010. Eligible participants were men 55 to 80 years of age and women 60 to 80 years of age without clinical PAD or baseline cardiovascular disease but with type 2 diabetes mellitus or at least 3 cardiovascular risk factors. Participants were randomized to 1 of 3 groups: a Mediterranean diet supplemented with extra-virgin olive oil; a Mediterranean diet supplemented with nuts; or counseling on a low-fat diet (control group). All participants received a comprehensive dietary educational program on a quarterly basis.

The trial included 7,477 participants, with an average age of 67 years, and 58 percent of whom were women. There were 89 confirmed new cases of clinical PAD after a median (midpoint) follow-up of 4.8 years. Both Mediterranean diet interventions were associated with a lower risk of PAD compared with the control group.

“To our knowledge, this is the first randomized primary prevention trial to suggest an association between a dietary intervention and [reduction in] PAD. These results are consistent with previous observational studies and relevant from a public health perspective,” the authors write.

(doi:10.1001/jama.2013.280618; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Salas-Salvado reported receiving grant funding from the International Nut Council and serving as a consultant to the International Nut Council. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 21, 2014

Media Advisory: To contact corresponding author Aaron S. Kesselheim, M.D., J.D., M.P.H., call Jessica Maki at 617-525-6373 or email jmaki3@partners.org.

Chicago – Many cardiac implantable electronic device models currently in use were approved via a Food and Drug Administration review process in which the models were assumed safe and effective based on approval of prior versions of the device, according to a study in the January 22/29 issue of JAMA.

“In the United States, the Food and Drug Administration (FDA) reviews high-risk medical devices—those that support human life, prevent illness, or present an unreasonable risk—via the premarket approval (PMA) pathway, through which manufacturers collect preclinical and clinical data as necessary to provide ‘reasonable assurance’ of the device’s safety and effectiveness,” according to background information in the article. That process has attracted attention in recent years after recall of device components, like leads from Medtronic Sprint Fidelis and St. Jude Medical Riata implantable cardioverter-defibrillators (ICDs), that were not tested clinically in human trials prior to approval because they were design changes to prior-marketed devices and considered ‘supplements’ to PMA applications submitted almost a decade earlier.

The process of approval by premarket approval supplement “allow[s] patients to benefit from incremental innovation in device technology by providing efficient and inexpensive FDA review pathways for smaller device changes. Supplements may include major or minor design changes as well as routine changes in labeling, materials, or packaging. By statute, the FDA must seek only the ‘least burdensome’ supporting data necessary for review.”

Benjamin N. Rome, B.A., of Harvard Medical School and Brigham and Women’s Hospital, Boston, and colleagues used the FDA’s PMA database to review CIEDs (including pacemakers, ICDs, and cardiac resynchronization therapy [CRT] devices) approved as PMA supplements from 1979 through 2012. They identified the number of supplements to each original PMA and characterized the nature of the changes in each supplement.

Seventy-seven approved PMA applications for CIEDs (46 pacemaker devices, 19 ICDs, and 12 CRT devices) were the basis for 5,829 PMA supplement applications, with a median (midpoint) of 50 supplements per original PMA. In the last decade, the number of approved supplements annually increased to 704. Excluding manufacturing changes that do not alter device design, the number of supplements approved each year averaged 2.6 per PMA per year.

Thirty-seven percent of supplements represented at least minor alterations to the device’s design or materials. Among 180-day supplements (a type of FDA review process) approved between 2010 and 2012, 23 percent included new clinical data to support safety and effectiveness.

“… Our results should not be interpreted to indicate that the FDA is failing to review PMA supplement applications to determine safety and effectiveness,” the authors conclude. However, clinicians and patients should … be aware … that clinical data are rarely collected as part of PMA supplement applications prior to marketing. The recalled Medtronic Sprint Fidelis and St. Jude Riata ICD leads were both PMA supplements — Fidelis a 180-day supplement and Riata a real-time supplement [a type of FDA review process]. Neither lead was studied in human trials prior to FDA approval. The FDA’s approval of many supplements without new human trials, as in the case of these recent ICD changes, highlights the importance of collecting rigorous postapproval performance data,” the authors write.

(doi:10.1001/jama.2013.284986; 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 21, 2014

Media Advisory: To contact Leonard V. Sacks, M.B.B.Ch., call Sandy Walsh at 301-796-4669 or email sandy.walsh@fda.hhs.gov.
Chicago – Several potentially preventable deficiencies, including failure to select optimal drug doses and suitable outcome measures for a study, accounted for significant delays in the approval of new drugs by the Food and Drug Administration (FDA), according to a study in the January 22/29 issue of JAMA.

“The road from medical product discovery to marketing is typically long and costly. The interval between initial clinical testing and product approval has been estimated to average 8 years and only 1 in 6 drugs entering clinical trials ultimately obtains U.S. Food and Drug Administration approval,” according to background information in the article. Many drugs do not receive approval not because they are unsafe or ineffective, but because the information supplied is unsatisfactory to make that determination. Delays and failures that occur late in development affect the availability of innovative new drugs and increase the costs of drug development.

Leonard V. Sacks, M.B.B.Ch., of the U.S. Food and Drug Administration, Silver Spring, Md., and colleagues reviewed marketing applications for all new molecular entities (NMEs; active ingredients never before marketed in the United States in any form) first submitted to the FDA between 2000 and 2012. Using FDA correspondence and reviews, the researchers investigated the scientific and regulatory reasons approval of NMEs were delayed or denied.

Of the 302 identified NME applications, 151 (50 percent) were approved when first submitted and 222 (73.5 percent) eventually achieved marketing approval. Of the 151 first-cycle failures, 71 (47.0 percent) eventually obtained approval in a median (midpoint) of 435 days following the first unsuccessful submission.

Among the reasons for failure to initially receive approval:

• Uncertainty about the optimal dose to maximize efficacy and to minimize safety risks;
• Populations that were studied did not reflect the populations likely to use the drug;
• End points used in clinical trials were unsatisfactory;
• Inconsistent results for multiple predefined end points in clinical studies;
• Inconsistencies in efficacy for portions of the study population.

There were 20 drugs (13.2 percent) that despite showing superiority to placebo were considered to have inadequate efficacy compared with the standard of care.

The frequency of safety deficiencies was similar among never-approved drugs compared with those with delayed approval. However, efficacy deficiencies were significantly more frequent among the never-approved drugs than among those with delayed approvals. Among the 48 drugs with initial efficacy concerns alone, only 31.3 percent were eventually approved compared with 61.5 percent of the 39 drugs with safety concerns alone.

“Failures late in drug development are costly, often involving the commitment of many study participants and personnel. It is advantageous to identify products that fail as early as possible in the development process to avoid these issues. For those drugs that require resubmission before approval is obtained, delays are taxing on the industry and regulators, and patients may have to wait for access to promising, and sometimes lifesaving, new treatments,” the authors write.

“Our findings may be helpful to clinicians and policy makers in interpreting the extensive literature reporting the design and outcome of clinical trials, which in turn may have an effect on practice. For drug developers and clinical investigators, our findings suggest areas of deficiencies in new drug applications in which strategies for drug development could be improved. Early and frequent dialogue between the FDA and drug sponsors addressing critical aspects of study design (including the selection of study populations, study end points, and drug doses) has the potential to reduce delays in the approval of new drugs.”

(doi:10.1001/jama.2013.282542; 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 21, 2014

Media Advisory: To contact corresponding author Joseph S. Ross, M.D., M.H.S., call Karen Peart at 203-432-1326 or email karen.peart@yale.edu. To contact editorial co-author Steven N. Goodman, M.D., M.H.S., Ph.D., call Ruthann Richter at 650-725-8047 or email richter1@stanford.edu.
Chicago – Clinical trials used by the Food and Drug Administration (FDA) to approve new drugs between 2005 and 2012 vary widely in their characteristics, according to a study in the January 22/29 issue of JAMA.

“FDA review of new drug applications is guided by the Federal Food, Drug, and Cosmetic Act, which requires ‘adequate and well controlled investigations’ to determine efficacy,” according to background information in the article. “Many patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the U.S. FDA has not been evaluated.”

Nicholas S. Downing, A.B., of the Yale University School of Medicine, New Haven, Conn., and colleagues evaluated the strength of clinical trial evidence supporting FDA approval decisions for new therapeutic agents by characterizing key features of pivotal efficacy trials (clinical trials that serve as the basis of FDA approval), such as trial size, design, duration, and end points.

The researchers used publicly available FDA documents to identify 188 novel therapeutic agents approved between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials. The vast majority of pivotal trials were randomized (89 percent) and double-blinded (79.5 percent). More than half of the trials used a placebo for comparison (55 percent), and 32 percent used an active (such as another drug) comparator, and 13 percent had no comparator.

The median (midpoint) number of patients enrolled per indication among all pivotal trials was 760. Among 201 indications, 74 (37 percent) were approved on the basis of a single trial, 77 (38 percent) on 2, and 50 (25 percent) on 3 or more. Trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 91 indications (45 percent).

At least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (34 percent). Trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status (drug used to treat rare medical condition), and accelerated approval.

“The variation in the [amount and type] of clinical trial evidence used by the FDA to assess the efficacy of novel therapeutic agents highlights the agency’s flexible standards for approval,” the authors write. “Such regulatory flexibility allows for a customized approach to approval, including the ability to rapidly approve potentially effective therapies for life-threatening diseases, such as certain cancers, or those diseases for which there is no existing effective treatment, such as orphan diseases. These approvals can be made without requiring costly and time-consuming randomized, double-blinded, controlled trials, although these trials are regarded as the gold standard for evaluation.”

The researchers note that understanding the clinical trial evidence underlying newly approved therapeutic agents has important implications for patients and physicians. “When medications become available on the market, decisions must be made about their use, likely informed by how well safety and effectiveness are understood. Comparative effectiveness information, which is not required as part of FDA approval and involves comparison of an intervention with an active control, was available for less than half of indications, consistent with prior research, but leaving uncertainty about the benefits and safety of these medications when compared with other available therapeutic agents.”

The authors write that the wide variation in clinical trial evidence “has the potential to inform current FDA regulatory approval standards and postmarket surveillance initiatives.”

(doi:10.1001/jama.2013.282034; 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, January 21 at this link.

Editorial: Opening the FDA Black Box

In an accompanying editorial, Steven N. Goodman, M.D., M.H.S., Ph.D., of Stanford University, Stanford, Calif., and Rita F. Redberg, M.D., M.Sc., of the University of California, San Francisco, and Editor, JAMA Internal Medicine, comment on the three studies in this issue of JAMA that examine the FDA approval process.

“Although these reports represent important steps in improving understanding of FDA decision making, further commitment to and progress toward ensuring transparency, including reducing report redactions, is needed to help the scientific community and other interested parties answer the questions these studies raise, thereby helping the FDA in its mission to find the right balance between allowing innovation and protecting the public’s health.”

(doi:10.1001/jama.2013.283946; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Redberg reported being a member of the U.S. Food and Drug Administration Circulatory System Devices Panel and a member of the California Technology Assessment Forum. No other conflicts of interest were reported.

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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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