EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 15, 2013

Mega-Trials for Blockbusters

John P. A. Ioannidis, M.D., D.Sc., of the Stanford University School of Medicine, Stanford, Calif., writes that mega-trials (very large, simple trials) should be conducted for licensed interventions with annual sales that exceed $1 billion, i.e., a blockbuster. These blockbusters “should have at least 1 trial performed with at least 10,000 patients randomized to the intervention of interest and as many randomized either to placebo (if deemed to be a reasonable choice) or to another active intervention that is the least expensive effective intervention available.”

“Blockbuster drugs are eventually used by millions of patients. Typically there is evidence from randomized trials suggesting that these drugs are effective—at least for some end points (not necessarily the most serious ones), for some follow-up (not necessarily long enough), and in some specific circumstances (not necessarily representing what happens in real life). The supporting randomized trials typically include only a few hundred participants or, in the best case, a few thousand participants, often with relatively short-term follow-up and are conducted among populations selected to avoid patients with co-morbid conditions and those who take some other drugs.”

“Eventually many blockbusters may prove to be fully worth their cost. Conversely, if some of these widely used products fail to demonstrate benefit in mega-trials, this could mean saving tens of billions of dollars per year and perhaps thousands of lives.”

(JAMA. 2013;309[3]:239-240. Available pre-embargo to the media at https://media.jamanetwork.com)

Prespecified Falsification End Points – Can They Validate True Observational Associations?

Vinay Prasad, M.D., of the National Cancer Institute, Bethesda, Md., and Anupam B. Jena, M.D., Ph.D., of Harvard Medical School and Massachusetts General Hospital, Boston, write that “as observational studies have increased in number—fueled by a boom in electronic recordkeeping and the ease with which observational analyses of large databases can be performed—so too have failures to confirm initial research findings.” The authors suggest that to help identify whether the associations identified in an observational study are true rather than spurious correlations is the use of prespecified falsification hypotheses, which is a claim, distinct from the one being tested, that researchers believe is highly unlikely to be causally related to the intervention in question. “Prespecified falsification hypotheses may provide an intuitive and useful safeguard when observational data are used to find rare harms.”

“Prespecified falsification hypotheses can improve the validity of studies finding rare harms when researchers cannot determine answers to these questions from randomized controlled trials, either because of limited sample sizes or limited follow-up. However, falsification analysis is not a perfect tool for validating the associations in observational studies, nor is it intended to be. The absence of implausible falsification hypotheses does not imply that the primary association of interest is causal, nor does their presence guarantee that real relations do not exist. However, when many false relationships are present, caution is warranted in the interpretation of study findings.”

(JAMA. 2013;309[3]:241-242. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 15, 2013

Media Advisory: To contact Jean Reignier, M.D., Ph.D., email jean.reignier@chd-vendee.fr. To contact editorial author Todd W. Rice, M.D., M.Sc., call Craig Boerner at 615-322-4747 or email craig.boerner@vanderbilt.edu.

CHICAGO – Patients undergoing mechanical ventilation and receiving nutrition via a feeding tube who did not receive monitoring of residual gastric volume (amount of liquid left in the stomach after use of feeding tube) were not at a significantly greater risk of developing ventilator-associated pneumonia, according to a study appearing in the January 16 issue of JAMA. There is concern that monitoring of residual gastric volume leads to unnecessary interruptions of use of the feeding tube and subsequent inadequate feeding.

“Early enteral nutrition [receipt of food via a feeding tube] is the standard of care in critically ill patients receiving invasive mechanical ventilation. However, numerous studies have shown that early enteral nutrition is frequently not used or associated with inadequate calorie delivery,” according to background information in the article. The main reason for non-use is gastrointestinal intolerance to enteral nutrition. “Monitoring of residual gastric volume is recommended to prevent ventilator-associated pneumonia (VAP) in patients receiving early enteral nutrition. However, studies have challenged the reliability and effectiveness of this measure.”

Jean Reignier, M.D., Ph.D., of the District Hospital Center, La Roche-sur-Yon, France and colleagues conducted a study to test the hypothesis that absence of residual gastric volume monitoring was not associated with an increased incidence of VAP compared with routine residual gastric volume monitoring. The randomized, noninferiority (outcome not worse than treatment compared to) trial was conducted from May 2010 through March 2011 in adults requiring invasive mechanical ventilation for more than 2 days and given enteral nutrition within 36 hours after intubation at 9 French intensive care units (ICUs); 452 patients were randomized and 449 included in the intention-to-treat analysis (3 withdrew initial consent).  The intervention for this study was the absence of residual gastric volume monitoring.

The researchers found that in the intention-to-treat population, VAP occurred in 38 of 227 patients (16.7 percent) in the intervention group and in 35 of 222 patients (15.8 percent) in the control group. Patients in the intervention group were 77 percent more likely to receive 100 percent of their calorie goal than patients in the control group. Absence of residual gastric volume monitoring was not inferior to residual gastric volume monitoring regarding new infections, intensive care unit and hospital stay lengths, organ failure scores, or mortality rates.

“In conclusion, the current study supports the hypothesis that a protocol of enteral nutrition management without residual gastric volume monitoring is not inferior to a similar protocol including residual gastric volume monitoring in terms of protection against VAP. Residual gastric volume monitoring leads to unnecessary interruptions of enteral nutrition delivery with subsequent inadequate feeding and should be removed from the standard care of critically ill patients receiving invasive mechanical ventilation and early enteral nutrition,” the authors write.

(JAMA. 2013;309(3):249-256; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The Centre Hospitalier Departemental de la Vendee was the study sponsor. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflict of Interest and none were reported.

Editorial: Gastric Residual Volume – End of an Era

Todd W. Rice, M.D., M.Sc., of the Vanderbilt University School of Medicine, Nashville, Tenn., comments on the findings of this study in an accompanying editorial.

“Despite emerging evidence to the contrary, many enteral feeding protocols continue to interrupt enteral feeding for relatively low gastric residual volumes (GRVs), some with thresholds as low as 150 mL or twice the enteral feeding rate the patient is receiving at the time. The finding from the study by Reignier et al should instill confidence in clinicians to change practice and not routinely check GRVs in all patients mechanically ventilated receiving enteral nutrition.”

(JAMA. 2013;309(3):283-284; 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, JANUARY 15, 2013

Media Advisory: To contact corresponding author William H. Shrank, M.D., M.S.H.S., call Brian Cook or Isabella Leung of the CMS Press Office at 202-690-6145 or email press@cms.hhs.gov. To contact editorial author Jack Hoadley, Ph.D., call Lauren Mullins at 202-687-2269 or email lm973@georgetown.edu.

CHICAGO – In a study that included nearly 1.3 million Medicare beneficiaries who were either first-time enrollees or enrollees switching plans, researchers found a positive association between enrollment and publicly reported Medicare Advantage star ratings reflecting plan quality, according to a study appearing in the January 16 issue of JAMA.

“To inform enrollment decisions and spur improvement in the Medicare Advantage marketplace, the U.S. Centers for Medicare & Medicaid Services (CMS) provides star ratings reflecting Medicare Advantage plan quality. A combined Part C and D overall rating was created in 2011 for Medicare Advantage and prescription drug (MAPD) plans,” according to background information in the article. The star ratings incorporate data from several sources. “In 2011, MAPD star ratings ranged from 2.5 to 5 stars. Only 3 MAPD contracts received 5 stars; some were unrated because they were too new or small,” the authors write. “While star ratings clearly matter to insurers, it is unclear whether they matter to beneficiaries.”

Rachel O. Reid, M.S., of the Centers for Medicare & Medicaid Services, Baltimore, and colleagues conducted a study to assess the association between publicly reported Medicare Advantage plan quality ratings and enrollment. Of the 7.6 million beneficiaries with an eligible 2011 MAPD enrollment, the study population consisted of 952,352 first-time enrollees and 322,699 enrollees switching plans. The analysis controlled for beneficiary and plan characteristics.

Among the key characteristics of included plans by star rating, the highest-rated plans more often had higher premiums, while unrated plans more often had higher out-of-pocket costs or were private fee-for-service or local PPO plans.

The researchers found that among first-time enrollees, higher star ratings were associated with increased likelihood to enroll in a given plan (9.5 percentage points per 1-star increase). The highest rating available to a beneficiary was associated with a 1.9 percentage-point increase in likelihood to enroll. Star ratings were less strongly associated with enrollment for the youngest, black, low-income, rural, and Midwestern enrollees.

Among beneficiaries switching plans, higher star ratings were associated with increased likelihood to enroll in a given plan (4.4 percentage points per 1-star increase). A star rating at least as high as a beneficiary’s prior plan’s rating was associated with a 6.3 percentage-point increase in likelihood to enroll.

“Star ratings were less strongly associated with enrollment among the youngest, low-income, and rural beneficiaries and negatively associated among Midwestern beneficiaries. Compared with other races/ethnicities, star ratings were more strongly associated with enrollment for white beneficiaries,” the authors write.

“We found a positive association between CMS’s 5-star Medicare Advantage quality ratings and enrollment. Bolstering the business case for quality in the Medicare Advantage market, these findings may provide firms with additional incentive to cultivate higher quality, CMS with justification to continue to advance public reporting, and policy makers with a rationale to pursue quality reporting in other health insurance markets,” the authors conclude.

(JAMA. 2013;309(3):267-274; 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. Shrank reported serving as a consultant to United Healthcare; and receiving grant support from CVS Caremark, Aetna, and Express Scripts. The other authors did not report any disclosures.

Please Note: For this study, there will be a digital news release available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, January 15 at this link.

Editorial: Performance Ratings and Plan Selection by Medicare Beneficiaries

“Despite the limitations in this study, it is valuable to see some evidence that Medicare Advantage enrollees may be using ratings as one factor in making choices,” writes Jack Hoadley, Ph.D., of Georgetown University, Washington, D.C., in an accompanying editorial.

“It is critical for the program to keep improving the available plan ratings and to make them increasingly available and relevant to the needs of consumers. Key questions for future study include what tools and what measures do consumers seek when they select plans? How do consumers use ratings as part of a plan selection strategy? How can the plan selection process be simplified and streamlined?”

(JAMA. 2013;309(3):287-288; 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, JANUARY 15, 2013

Media Advisory: To contact Kohei Hasegawa, M.D., M.P.H., call Kristen Stanton at 617-643-3907 or email kstanton3@partners.org. To contact editorial co-author Donald M. Yealy, M.D., call Rick Pietzak at 412-864-4151 or email pietzakr@upmc.edu.

CHICAGO – In patients with out-of-hospital cardiac arrest, cardiopulmonary resuscitation with advanced airway management, such as endotracheal intubation, was a significant predictor of poor neurological outcome compared with conventional bag-valve-mask ventilation, contradicting the assumption that an aggressive airway intervention is associated with improved outcomes, according to a study appearing in the January 16 issue of JAMA.

“Out-of-hospital cardiac arrest (OHCA) is a major public health problem, occurring in 375,000 to 390,000 individuals in the United States each year,” according to background information in the article. The rate of survival after OHCA has increased with advances in care; however, the rate is still low, with recent estimates reporting 8 percent to 10 percent. “Although advanced airway management, such as endotracheal intubation or insertion of supraglottic [above the vocal apparatus of the larynx] airways, has long been the criterion standard for airway management of patients with OHCA, recent studies have challenged the survival benefit of advanced airway management compared with conventional bag-valve-mask ventilation in this clinical setting. However, large-scale studies evaluating the association between advanced airway management and patient-centered outcomes such as neurological status do not exist.”

Kohei Hasegawa, M.D., M.P.H., of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues conducted a study to examine whether cardiopulmonary resuscitation (CPR) with any type of out-of-hospital advanced airway management by emergency medical service (EMS) personnel, compared with CPR with conventional bag-valve-mask ventilation, would be associated with favorable neurological outcome in adult OHCA. The nationwide, population-based study involved 649,654 adult patients in Japan who had an OHCA and in whom resuscitation was attempted by emergency responders with subsequent transport to medical institutions from January 2005 through December 2010. The primary outcome for the study was favorable neurological outcome 1 month after an OHCA.

Of the eligible 649,359 patients with OHCA included in the study, 57 percent underwent bag-valve-mask ventilation and 43 percent advanced airway management, including 6 percent with endotracheal intubation and 37 percent with use of supraglottic airways. Overall, rates of return of spontaneous circulation, 1-month survival, and neurologically favorable survival were 6.5 percent, 4.7 percent, and 2.2 percent, respectively. The rates of neurologically favorable survival were 1.0 percent in the endotracheal intubation group, 1.1 percent in the supraglottic airway group, and 2.9 percent in the bag-valve-mask ventilation group, with patients in the advanced airway group having a 62 percent lower odds of a favorable neurological outcome compared with the bag-valve-mask group. The odds of neurologically favorable survival were significantly lower both for endotracheal intubation and for supraglottic airways.

“Our observations contradict the assumption that aggressive airway intervention is associated with improved outcomes and provide an opportunity to reconsider the approach to prehospital airway management in this population,” the authors write.

“Should clinicians avoid advanced airway management during CPR based on the best available observational evidence? Although one option would be to remove advanced airway management from the skill set of all out-of-hospital rescuers, that approach would disregard situations in which advanced airway management would be expected to be efficacious, especially for long-distance transfers and respiratory failure not yet with cardiac arrest. Future research will need to identify whether there are subsets of patients for whom prehospital advanced airway management is beneficial.”

(JAMA. 2013;309(3):257-266; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant to Dr. Hiraide for emergency management scientific research from the Fire and Disaster Management Agency. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Managing the Airway During Cardiac Arrest

In an accompanying editorial, Henry E. Wang, M.D., M.S., of the University of Alabama School of Medicine, Birmingham, and Donald M. Yealy, M.D., of the University of Pittsburgh, write that the “study by Hasegawa et al sends a clear message.”

“Emergency medical services professionals across the world must engage in the scientific process. A large, well-designed research effort is needed to define the benefit from endotracheal intubation, supraglottic airway insertion, or more simple actions during resuscitation after cardiac arrest. Absent this investment, the emergency medical services community risks turning a blind eye and embracing ineffective or harmful airway interventions. Patients with cardiac arrest and the out-of-hospital rescuers who care for them deserve to know what is best.”

(JAMA. 2013;309(3):285-286; 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. Dr. Yealy reports providing expert testimony for multiple medical malpractice firms and receiving royalties from Wolters Kluwer. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 8, 2013

How to Decide Whether a Clinical Practice Guideline Is Trustworthy

David F. Ransohoff, M.D., of the University of North Carolina School of Medicine, Chapel Hill, and colleagues discuss concerns about the process of developing clinical practice guidelines and the standards for developing practice guidelines created by the Institute of Medicine (IOM).

“Guidelines, especially those that try to set limits, will always raise controversy. Clinicians, patients, and policy makers should insist upon a constructive dialog about the evidence and its translation into recommendations. An explicit, transparent process for evaluating adherence to the IOM committee’s standards should elevate this conversation to a higher plane.”

(JAMA. 2013;309[2]:139-140. Available pre-embargo to the media at https://media.jamanetwork.com)

Changing Physical Activity Participation for the Medical Profession

Antronette K. Yancey, M.D., M.P.H., of the UCLA Fielding School of Public Health, Los Angeles, and colleagues offer suggestions on how health professionals can improve and incorporate physical activity into their lifestyle.

“Simple and quick episodes of moderate to vigorous physical activity can be incorporated into the workplace without disrupting workflow or productivity. Given the value of regular physical activity to health, the medical profession should lead the way in adopting such practices.”

(JAMA. 2013;309[2]:141-142. Available pre-embargo to the media at https://media.jamanetwork.com)

Physical Activity and Structured Exercise for Patients With Stable Ischemic Heart Disease

William E. Boden, M.D., of the Samuel Stratton VA Medical Center and Albany Medical College, Albany, New York, and colleagues examine the gap between scientific evidence and clinical practice regarding structured exercise and increased physical activity for patients with stable ischemic heart disease.

“In an era of spiraling health care expenditures, structured exercise regimens, increased physical activity, or both may be the ultimate low-cost therapy for achieving improved health outcomes. If the ‘exercise is medicine’ adage is to be applied and optimized, the prescription at present remains underfilled for too many patients with stable ischemic heart disease. Thus, the medical community should embrace this clinically effective and cost-effective strategy as a first-line therapy, thereby enabling patients to realize the health benefits from a lifestyle intervention that must become more mainstream in U.S. medical practice.”

(JAMA. 2013;309[2]:143-144. Available pre-embargo to the media at https://media.jamanetwork.com)

Appropriate Use of Non-English-Language Skills in Clinical Care

“An estimated 25 million U.S. residents have limited English proficiency (LEP) and in a 2006 national survey of 2,022 internists, 54 percent reported encountering patients with LEP at least weekly, with many seeing LEP patients every day,” writes Marsha Regenstein, Ph.D., M.C.P., of the George Washington University School of Public Health and Health Services, Washington, D.C., and colleagues. In this Viewpoint, the authors examine the issue of the use of non-English-language skills in clinical care, including clinical encounters potentially needing language interpreters.

“Clinicians should also consider ways to detect when a non-English-language encounter is becoming more likely to cause communication errors. In particular, using teach-back, a National Quality Forum-endorsed practice in which clinicians explicitly state key points of instruction and ask patients to restate them to ensure clarity, is useful in many settings. This can be an especially important means for ongoing communication quality assurance for physicians using their non-English language skills in clinical practice.”

(JAMA. 2013;309[2]:145-146. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 8, 2013

Media Advisory: To contact co-author Dick Tibboel, M.D., Ph.D., email d.tibboel@erasmusmc.nl. To contact editorial author Kanwaljeet J. S. Anand, M.B.B.S., D.Phil., F.R.C.P.C.H., call Sheila Champlin at 901-448-4957 or email schampli@uthsc.edu.

CHICAGO – Among infants undergoing major surgery, postoperative use of intermittent intravenous paracetamol (acetaminophen) for the management of pain resulted in a lower cumulative morphine dose over 48 hours, according to a study appearing in the January 9 issue of JAMA.

Opioid therapy for the treatment of pain is associated with adverse effects.  Researchers are seeking alternative analgesic regimens in neonates and infants, according to background information in the article. Paracetamol has been proposed as an alternative, with one study showing promise.

Ilse Ceelie, M.D., Ph.D., of Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands, and colleagues performed a trial with infants who had undergone major abdominal and thoracic (noncardiac) surgery to determine if intravenous paracetamol would reduce the cumulative morphine dose needed to provide adequate analgesia by at least 30 percent. The randomized study was conducted in a pediatric intensive care unit and included 71 patients (neonates or infants younger than 1 year) undergoing surgery between March 2008 and July 2010, with follow-up of 48 hours. All patients received a dose of morphine 30 minutes before the end of surgery, followed by continuous morphine or intermittent intravenous paracetamol up to 48 hours postsurgery. Infants in both study groups received morphine as rescue medication based on the guidance of the validated pain assessment instruments.

The researchers found that the cumulative morphine dose in the paracetamol group was 66 percent lower than that in the morphine group (median [midpoint], 121 μg/kg per 48 hours vs. 357 μg/kg per 48 hours). “Considering the 2 stratified age groups separately, the cumulative morphine dose in the paracetamol group was 49 percent lower than that in the morphine group for the neonates (age 0 through 10 days) (median, 111 μg/kg per 48 hours vs. 218 μg/kg per 48 hours) and 73 percent lower for the older infants (aged 11 days to 1 year) (median, 152 μg/kg per 48 hours vs. 553 μg/kg per 48 hours).”

The authors also found that neither the total morphine rescue dose, the amount or number of morphine rescue doses or the number of patients requiring rescue doses differed significantly between the paracetamol and morphine groups. Also, there were no significant differences for percentage of adverse effects or pain scores between treatment groups.

“This randomized controlled trial shows that infants who receive intravenous paracetamol as primary analgesic after major surgery require significantly less morphine than those who receive a continuous morphine infusion. Judging from the rescue morphine doses, a similar level of analgesia was obtained in either group. These results suggest that intravenous paracetamol may be an interesting alternative as primary analgesic in neonates and infants,” the authors conclude.

(JAMA. 2013;309(2):149-154; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Pain Panacea for Opiophobia In Infants?

Kanwaljeet J. S. Anand, M.B.B.S., D.Phil., F.R.C.P.C.H., of the University of Tennessee Health Science Center and Children’s Foundation Research Center, Le Bonheur Children’s Hospital, Memphis, comments on the findings of this study in an accompanying editorial.

“Titrating morphine analgesia carefully (based on pain scores) is more labor intensive than the common practice of slightly oversedating infants who require opioid analgesia for painful conditions, such as following operations. However, this approach may avoid the respiratory depression, hypotension, and opioid tolerance observed in many centers. Busy clinical units will have to choose between the nursing resources required to follow such a labor-intensive protocol or to tolerate a relatively low incidence of oversedation and opioid-related adverse effects. Theoretically elegant approaches have little value in clinical practice if they are not practically feasible in the clinical settings for which they were designed. However, research studies such as the report by Ceelie et al are invaluable because they bring methodological rigor and continue to set new standards for future clinical practice.”

(JAMA. 2013;309(2):183-184; 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, JANUARY 8, 2013

Media Advisory: To contact Vanessa G. Allen, M.D., M.P.H., call Nicole Helsberg at 647-260-7466 or email nicole.helsberg@oahpp.ca. To contact editorial author Robert D. Kirkcaldy, M.D., M.P.H., call the NCHHSTP Media Office at 404-639-8895 or email NCHHSTPMediaTeam@cdc.gov.

CHICAGO – In an examination of the effectiveness of cefixime, the only oral cephalosporin antimicrobial recommended for treatment of Neisseria gonorrhoeae (gonorrhea) infections, researchers found a clinical treatment failure rate of nearly 7 percent for patients treated at a clinic in Toronto, according to a preliminary study published in the January 9 issue of JAMA.

“Because of Neisseria gonorrhoeae resistance to all prior first-line antimicrobial agents, cephalosporin [antibiotic] therapy with adjuvant azithromycin or doxycycline is recommended for treatment of gonorrhea,” according to background information in the article. Cefixime is the only oral cephalosporin recommended for gonorrhea treatment. “An increase in the minimum inhibitory concentration [MIC; lowest concentration of an anti-microbial agent that will prevent the growth of an organism] of N gonorrhoeae to cefixime, and to a lesser extent, an intramuscularly administered cephalosporin, ceftriaxone, has been identified in cultured isolates worldwide. The World Health Organization has sounded alarms for the threat of untreatable gonorrhea.”

Vanessa G. Allen, M.D., M.P.H., of Public Health Ontario, Toronto, Canada, and colleagues conducted a study to determine whether N gonorrhoeae strains with reduced susceptibilities to cefixime are associated with clinical failures. The study group consisted of N gonorrhoeae culture-positive individuals identified between May 2010 and April 2011 and treated at a sexual health clinic in Toronto with cefixime as recommended by Public Health Agency of Canada guidelines. The primary outcome measure for the study was cefixime treatment failure, defined as the repeat isolation of N gonorrhoeae at the test-of-cure visit identical to the pretreatment isolate by molecular typing and explicit denial of re-exposure.

There were 291 N gonorrhoeae culture-positive individuals identified. Of 133 who returned for test of cure, 13 were culture positive; 9 patients were determined to have experienced cefixime treatment failure, with an overall rate of clinical treatment failure of 6.77 percent. The rate of clinical failure associated with a cefixime MIC of 0.12 μg/mL or greater was 25 percent compared with 1.90 percent of infections with cefixime MICs less than 0.12 μg/mL.

“This study presents the first series of clinical failures of gonorrhea associated with the use of cefixime in North America, identified by the concurrent strategies of routine test-of-cure and culture-based testing for N gonorrhoeae,” the authors write.

“In light of the increases in cefixime MICs among isolates of N gonorrhoeae across North America, this study offers preliminary clinical data to support the recent CDC recommendations that cefixime is no longer optimal first-line therapy for the successful treatment of gonorrhea. As elevated MICs to ceftriaxone are also emerging, albeit at 1 to 2 MIC dilutions less than the cefixime MIC, proactive strategies for the identification of clinical failures of N gonorrhoeae to this last commercially available agent are required.”

(JAMA. 2013;309(2):163-170; 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.

Editorial: Cephalosporin-Resistant Gonorrhea in North America

In an accompanying editorial, Robert D. Kirkcaldy, M.D., M.P.H., of the Division of STD Prevention, Centers for Disease Control and Prevention, Atlanta, and colleagues write that the findings of this study, of documented cephalosporin treatment failures in North America, although expected, “its arrival is deeply troubling; clinicians now face the emergence of cephalosporin-resistant N gonorrhoeae without any well-studied, effective backup treatment options.”

“New antibiotics for treating gonococcal infections are needed. A clinical trial sponsored by the National Institute of Allergy and Infectious Diseases examining novel combinations of existing drugs just completed enrollment, and a small study of a new oral agent is ongoing. But the antibiotic pipeline is running dry: continued investment in antibiotic development is critical. Meanwhile, the gonococcus has continued to develop the capability to defeat each new antibiotic used. The threat of drug-resistant gonorrhea is increasing and has reached North America. Clinicians, drug developers, and public health professionals must act now.”

(JAMA. 2013;309(2):185-187; 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, JANUARY 8, 2013

Media Advisory: To contact Timothy McAlindon, D.M., M.P.H., call Julie Jette at 617-636-3265 or email jjette@tuftsmedicalcenter.org.

CHICAGO – In a two year randomized trial, patients with symptomatic knee osteoarthritis who received vitamin D supplementation did not have a significant difference in knee pain or cartilage volume loss compared to patients who received placebo, according to a study appearing in the January 9 issue of JAMA.

“Knee osteoarthritis (OA) is a common age-related musculoskeletal disorder that has significant functional impact and has considerable societal costs through work loss, early retirement, and arthroplasty. Despite its impact, there are no medical treatments established to influence the course of the disease,” according to background information in the article. “Some studies have suggested that vitamin D may protect against structural progression.”

Timothy McAlindon, D.M., M.P.H., of Tufts Medical Center, Boston, and colleagues conducted a clinical trial to examine whether vitamin D supplementation is associated with reductions in symptomatic and structural progression of knee OA. The 2-year randomized, placebo-controlled clinical trial included 146 participants with symptomatic knee OA (average age, 62 years; 61 percent women), who were enrolled in the study between March 2006 and June 2009. Participants were randomized to receive either placebo or oral cholecalciferol, 2,000 IU/day, with dose escalation to increase serum levels to more than 36 ng/mL. Eighty-five percent of the participants completed the study.

The primary measured outcomes for the study were knee pain severity (Western Ontario and McMaster Universities [WOMAC] pain scale, 0-20: 0, no pain; 20, extreme pain), and cartilage volume loss measured by magnetic resonance imaging. Secondary outcomes included physical function, knee function (WOMAC function scale, 0-68: 0, no difficulty; 68, extreme difficulty), cartilage thickness, bone marrow lesions, and radiographic joint space width.

Serum 25-hydroxyvitamin D levels increased by an average 16.1 ng/mL in the treatment group and by an average 2.1 ng/mL in the placebo group. Knee pain at the beginning of the study was slightly worse in the treatment group (average, 6.9) than in the placebo group (average, 5.8). Knee function at the beginning of the study was significantly worse in the treatment group (average, 22.7) than in the placebo group (average, 18.5). In the subset analyses for the WOMAC pain outcome, the effects were generally similar, and nonsignificant. The researchers found that knee pain decreased in both groups by an average -2.31 in the treatment group and -1.46 in the placebo group, with no significant differences at any time. The percentage of cartilage volume decreased by the same extent in both groups, by about 4 percent. There were no differences in any of the secondary clinical end points.

There were 31 serious adverse events in the vitamin D group and 23 in the placebo group but the number of participants who experienced an event was 16 in each group.

“… additional results from epidemiologic studies that emerged during the course of this study have been mixed demonstrating positive and negative associations. Two studies appeared to show strong associations of bone density with the development of knee OA, but some of those investigators later published concerns about the possibility of such associations arising as a result of contingent confounding. Therefore, together with the results of this clinical trial, the overall data suggest that vitamin D supplementation at a dose sufficient to elevate 25-hydroxyvitamin D levels to more than 36 ng/mL does not have major effects on clinical or structural outcomes in knee OA, at least in a U.S. sample,” the authors conclude.

(JAMA. 2013;309(2):155-162; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by a grant from the National Institutes of Health, NIAMS, and the Office of Dietary Supplements, a grant from the National Center for Research Resources, and a grant from the Houston Veterans Affairs Health Services Research and Development Service. 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 1, 2013

How and Why U.S. Health Care Differs From That in Other OECD Countries

Victor R. Fuchs, Ph.D., of Stanford University, Stanford, Calif., compares U.S. health care to that in other countries of the Organization for Economic Co-operation and Development (OECD), and “reaches one inescapable conclusion—U.S. health care is very different from health care in other countries.” In this Viewpoint, the author examines the differences, and suggests a strategy for obtaining further health care reform.

“Comprehensive health care reform in the United States is necessary to avoid a financial disaster, but enactment of such reform will require attention to U.S. history, values, and politics.”

(JAMA. 2013;309[1]:33-34. Available pre-embargo to the media at https://media.jamanetwork.com)

Please Note: An author podcast on this article will be available post-embargo on the JAMA website.

The Era of Delivery System Reform Begins

Zirui Song, Ph.D., of the Harvard Medical School, Boston, and Thomas H. Lee, M.D., of Brigham and Women’s Hospital and Partners Healthcare, Boston, discuss delivery system reform for the modern physician organization.

“Physician organizations will need help, not just from patients, but also from payers at the bargaining table, drug companies at the checkout line, and a legal system that protects physicians when choosing against unnecessary care. But if these organizations can begin to shift the culture of medicine—if they can find ways to deliver better care at lower cost—they can begin to navigate health care through the era of delivery system reform.”

(JAMA. 2013;309[1]:35-36. Available pre-embargo to the media at https://media.jamanetwork.com)

Rebooting Cancer Tissue Handling in the Sequencing Era – Toward Routine Use of Frozen Tumor Tissue

Laura Goetz, M.D., M.P.H., of the Scripps Translational Science Institute, La Jolla, Calif., and colleagues examine the relevant issues behind the incorporation of optimal tissue sampling techniques into routine pathologic practice and make recommendations for the cancer genomic medicine of the future.

“Moving the pathology and oncology communities toward a new practice incorporating larger tissue samples and the routine use of frozen tissue represents a formidable but attainable change, one that will undoubtedly involve patients’ preferences and consent. How quickly a new practice should emerge depends on clinical studies indicating improved patient outcomes associated with detailed genetic evaluation. As genomic testing becomes part of routine care and patients become increasingly informed, medicine will have to adapt to meet the demands of the next generation of patients with cancer, now informed about sequencing options for their particular malignancy.”

(JAMA. 2013;309[1]:37-38. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 1, 2013

Media Advisory: To contact Carolien Roos, M.D., email c.roos@obgyn.umcn.nl.

CHICAGO – In women with threatened (symptoms of) preterm labor, maintenance therapy to suppress labor with the calcium-channel blocker nifedipine for 12 days did not result in a significant reduction in adverse perinatal (just before and after birth) outcomes, such as perinatal death, chronic lung disease or neonatal sepsis, when compared with placebo, according to a study in the January 2 issue of JAMA.

Preterm birth is the most common cause of neonatal illness and death worldwide. “Almost 75 percent of perinatal deaths occur in infants born before 37 weeks’ gestation. Consequently, preterm birth is associated with a large burden of disease, high costs for medical care, special education, and institutionalized care for disabled infants. In threatened preterm labor before 34 weeks, delay of delivery for 48 hours allows antenatal corticosteroid treatment to improve fetal maturity and transfer of the pregnant woman to a center with a neonatal intensive care unit,” according to background information in the article. Delay of delivery for more than 48 hours may improve perinatal outcome. “However, the effectiveness of maintenance tocolysis [medication to suppress labor], after an initial course of tocolysis and corticosteroids for 48 hours, on pregnancy and perinatal outcome has not been demonstrated.”

Carolien Roos, M.D., of Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands, and colleagues evaluated the effect of maintenance tocolysis with nifedipine on perinatal outcome. Maintenance tocolysis with nifedipine has been assessed in 3 small trials that showed contradictory results. This randomized controlled trial was conducted in 11 perinatal units including all tertiary centers in the Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010).

A total of 406 women were randomly assigned to maintenance tocolysis with nifedipine orally (n = 201) or placebo (n = 205) for 12 days. Average gestational age at randomization was 29.2 weeks for both groups. The primary outcome measure for the study was a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis).

The researchers found that adverse perinatal outcome was not significantly different between the groups, with 24 (11.9 percent) cases in the nifedipine group and 28 (13.7 percent) in the placebo group (risk difference 1.8 percent). Perinatal death occurred in 5 (2.5 percent) in the nifedipine group and in 4 (2.0 percent) in the placebo group. Average gestational age at delivery was comparable for both groups: 34.1 weeks for the nifedipine group and 34.2 weeks for the placebo group.

Birth weight was not significantly different between the 2 groups. Neonatal intensive care unit admission occurred in 40.8 percent of neonates in the nifedipine group and in 39.7 percent in the placebo group. The length of neonatal intensive care unit admission was 10 days for both groups.

“Although the lower than anticipated rate of adverse perinatal outcomes in the control group indicates that a benefit of nifedipine cannot completely be excluded, its use for maintenance tocolysis does not appear beneficial at this time,” the authors write. “Future research should be directed toward therapies tailored to the specific underlying causes of preterm labor.”

(JAMA. 2013;309(1):41-47; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This trial was funded by ZonMw, the Netherlands Organization for Health Research and a grant from the Development Healthcare Efficiency Program. 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 1, 2013

Media Advisory: To contact Sana M. Al-Khatib, M.D., M.H.S., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

CHICAGO – Comparing the largest registry of implantable cardioverter-defibrillator (ICD) implants in the United States with 2 primary prevention randomized clinical trials, researchers found that patients who met certain criteria and who received a primary prevention ICD in clinical practice had survival that was not significantly different from patients who received an ICD in the clinical trials, findings that support the continued use of primary prevention ICDs in similar patients seen in clinical practice, according to a study in the January 2 issue of JAMA.

“The implantable cardioverter-defibrillator is a highly effective therapy for preventing sudden cardiac death in patients with heart failure. However, the outcomes of this therapy in routine clinical practice are largely uncertain. Because randomized clinical trials generally enroll patients with fewer comorbidities [other illnesses] and are usually conducted in highly controlled and monitored settings, the results of the primary prevention ICD trials may not be generalizable to routine clinical practice,” according to background information in the article. The authors add that whether these findings “are generalizable to clinical practice needs to be investigated, especially given the cost and potential complications associated with this device, such as infection and lead and device failure.”

Sana M. Al-Khatib, M.D., M.H.S., of the Duke Clinical Research Institute, Durham, N.C., and colleagues conducted a study to determine whether a difference in survival exists between trial-eligible patients who receive a primary prevention ICD as documented in a large national registry and similar patients who received an ICD in the 2 largest primary prevention clinical trials, MADIT-II (n = 742) and SCD-HeFT (n = 829). The study consisted of a retrospective analysis of data for patients enrolled in the National Cardiovascular Data Registry ICD Registry between January 1, 2006, and December 31, 2007, meeting the MADIT-II criteria (2,464 propensity score-matched patients) or the SCD-HeFT criteria (3,352 propensity score-matched patients). Mortality data for the registry patients were collected through December 31, 2009. The median (midpoint) follow-up time in MADIT-II, SCD-HeFT, and the ICD Registry was 19.5, 46.1, and 35.2 months, respectively. Patients receiving ICDs in clinical practice were significantly older and had more comorbidities than patients enrolled in the clinical trials.

After analysis of the data, the authors found no significant difference in survival between MADIT-II-like patients in the ICD Registry and MADIT-II patients randomized to receive an ICD (2-year mortality rates: 13.9 percent vs. 15.6 percent). Also, the survival of MADIT-II-like patients in the ICD Registry was significantly better than the survival of MADIT-II patients randomized to receive medical therapy (2-year mortality rates: 13.9 percent vs. 22 percent).

There was also no significant survival difference between SCD-HeFT-like patients in the ICD Registry and patients randomized to receive ICD therapy in SCD-HeFT (3-year mortality rates: 17.3 percent vs. 17.4 percent). The survival of SCD-HeFT-like patients in the ICD Registry was significantly better than the survival of SCD-HeFT patients randomized to placebo (3-year mortality rates: 17.3 percent vs. 22.4 percent).

“Importantly, the generalizability of these results held even after limiting the analyses to patients 65 years and older,” the researchers write.

The authors note that prior work in other fields has demonstrated that it is often challenging to generalize the findings from randomized clinical trials to clinical practice. “Patients enrolled in randomized clinical trials of primary prevention ICD therapy were monitored carefully over the course of the trials, and physicians who implanted and followed those devices were highly experienced. This level of care may not occur in real-world, practice.”

“… it is reasonable to question whether the results of the trials can be expected in clinical practice. Through propensity score matching and adjustment for differences between registry patients and patients enrolled in the clinical trials, our matched sample became similar to patients enrolled in the clinical trials. This enabled us to address the concern that the care of patients in the highly controlled and monitored setting of clinical trials compromises the external validity of the results.”

(JAMA. 2013;309(1):55-62; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This analysis was funded by a grant from the National Heart, Lung, and Blood Institute. 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 1, 2013

Media Advisory: To contact Olof Stephansson, M.D., Ph.D., email olof.stephansson@ki.se.

CHICAGO – In a study that included nearly 30,000 women from Nordic countries who had filled a selective serotonin reuptake inhibitor (SSRI) prescription during pregnancy, researchers found no significant association between use of these medications during pregnancy and risk of stillbirth, neonatal death, or postneonatal death, after accounting for factors including maternal psychiatric disease, according to a study in the January 2 issue of JAMA.

“Depression during pregnancy is common with prevalences ranging between 7 percent and 19 percent in economically developed countries. Maternal depression is associated with poorer pregnancy outcomes, including increased risk of preterm delivery, which in turn may cause neonatal morbidity and mortality,” according to background information in the article. “Use of selective serotonin reuptake inhibitors during pregnancy has been associated with congenital anomalies, neonatal withdrawal syndrome, and persistent pulmonary hypertension of the newborn. However, the risk of stillbirth and infant mortality when accounting for previous maternal psychiatric disease remains unknown.”

Olof Stephansson, M.D., Ph.D., of the Karolinska Institutet, Stockholm, Sweden and colleagues conducted a study to examine whether SSRI exposure during pregnancy was associated with increased risks of stillbirth, neonatal death, and postneonatal death. The study included women with single births  from all Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) at different periods from 1996 through 2007. The researchers obtained information on maternal use of SSRIs from prescription registries; maternal characteristics, pregnancy, and neonatal outcomes were obtained from patient and medical birth registries. The authors estimated relative risks of stillbirth, neonatal death, and postneonatal death associated with SSRI use during pregnancy taking into account maternal characteristics and previous psychiatric hospitalization.

Among 1,633,877 singleton births in the study, there were 6,054 stillbirths; 3,609 neonatal deaths; and 1,578 postneonatal deaths. A total of 29,228 (1.79 percent) of mothers had filled a prescription for an SSRI during pregnancy. The researchers found that women exposed to an SSRI had higher rates of stillbirth (4.62 vs. 3.69 per 1000) and postneonatal death (1.38 vs. 0.96 per 1000) than those who did not. The rate of neonatal death was similar between groups (2.54 vs. 2.21 per 1000). “Yet in multivariate models, SSRI use was not associated with stillbirth, neonatal death, or postneonatal death. Estimates were further attenuated when stratified by previous hospitalization for psychiatric disease,” the authors write.

“The present study of more than 1.6 million births suggests that SSRI use during pregnancy was not associated with increased risks of stillbirth, neonatal death, or postneonatal death. The increased rates of stillbirth and postneonatal mortality among infants exposed to an SSRI during pregnancy were explained by the severity of the underlying maternal psychiatric disease and unfavorable distribution of maternal characteristics such as cigarette smoking and advanced maternal age.”

“However, decisions regarding use of SSRIs during pregnancy must take into account other perinatal outcomes and the risks associated with maternal mental illness,” the researchers conclude.

(JAMA. 2013;309(1):48-54; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by the Swedish Pharmacy Company and by the authors’ affiliations. Olof Stephansson was supported by a postdoctorate scholarship from the Swedish Society of Medicine. 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 1, 2013

Media Advisory: To contact corresponding author Robert S. Sherwin, M.D., call Helen Dodson at 303-436-3984 or email helen.dodson@yale.edu. To contact editorial co-author Jonathan Q. Purnell, M.D., call Mirabai Vogt at 503-494-7986 or email vogtmi@ohsu.edu.

CHICAGO – In a study examining possible factors regarding the associations between fructose consumption and weight gain, brain magnetic resonance imaging of study participants indicated that ingestion of glucose but not fructose reduced cerebral blood flow and activity in brain regions that regulate appetite, and ingestion of glucose but not fructose produced increased ratings of satiety and fullness, according to a preliminary study published in the January 2 issue of JAMA.

“Increases in fructose consumption have paralleled the increasing prevalence of obesity, and high-fructose diets are thought to promote weight gain and insulin resistance. Fructose ingestion produces smaller increases in circulating satiety hormones compared with glucose ingestion, and central administration of fructose provokes feeding in rodents, whereas centrally administered glucose promotes satiety,” according to background information in the article. “Thus, fructose possibly increases food-seeking behavior and increases food intake.” How brain regions associated with fructose- and glucose-mediated changes in animal feeding behaviors translates to humans is not completely understood.

Kathleen A. Page, M.D., of Yale University School of Medicine, New Haven, Conn., and colleagues conducted a study to examine neurophysiological factors that might underlie associations between fructose consumption and weight gain. The study included 20 healthy adult volunteers who underwent two magnetic resonance imaging sessions in conjunction with fructose or glucose drink ingestion. The primary outcome measure for the study was the relative changes in hypothalamic (a region of the brain) regional cerebral blood flow (CBF) after glucose or fructose ingestion.

The researchers found that there was a significantly greater reduction in hypothalamic CBF after glucose vs. fructose ingestion. “Glucose but not fructose ingestion reduced the activation of the hypothalamus, insula, and striatum—brain regions that regulate appetite, motivation, and reward processing; glucose ingestion also increased functional connections between the hypothalamic-striatal network and increased satiety.”

“The disparate responses to fructose were associated with reduced systemic levels of the satiety-signaling hormone insulin and were not likely attributable to an inability of fructose to cross the blood-brain barrier into the hypothalamus or to a lack of hypothalamic expression of genes necessary for fructose metabolism.”

(JAMA. 2013;309(1):63-70; 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: Fructose Ingestion and Cerebral, Metabolic, and Satiety Responses

Jonathan Q. Purnell, M.D., and Damien A. Fair, PA-C, Ph.D., of Oregon Health & Science University, Portland, write in an accompanying editorial that “these findings support the conceptual framework that when the human brain is exposed to fructose, neurobiological pathways involved in appetite regulation are modulated, thereby promoting increased food intake.”

“… the implications of the study by Page et al as well as the mounting evidence from epidemiologic, metabolic feeding, and animal studies, are that the advances in food processing and economic forces leading to increased intake of added sugar and accompanying fructose in U.S. society are indeed extending the supersizing concept to the population’s collective waistlines.”

(JAMA. 2013;309(1):85-86; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JANUARY 1, 2013

Media Advisory: To contact Katherine M. Flegal, Ph.D., call Karen Hunter at 404-639-3286 or email ksh7@cdc.gov. To contact editorial co-author Steven B. Heymsfield, M.D., email Steven.heymsfield@pbrc.edu.

CHICAGO – In an analysis of nearly 100 studies that included approximately 3 million adults, relative to normal weight, overall obesity (combining all grades) and higher levels of obesity were both associated with a significantly higher all-cause risk of death, while overweight was associated with significantly lower all-cause mortality, according to a study in the January 2 issue of JAMA.

“Estimates of the relative mortality risks associated with normal weight, overweight, and obesity may help to inform decision making in the clinical setting,” according to background information in the article.

Katherine M. Flegal, Ph.D., of the National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Md., and colleagues conducted a study to compile and summarize published analyses of body mass index (BMI) and all-cause mortality that provide hazard ratios (HRs) for standard BMI categories. For the review and meta-analysis, the researchers identified 97 studies that met inclusion criteria, which provided a combined sample size of more than 2.88 million individuals and more than 270,000 deaths. Regions of origin of participants included the United States or Canada (n = 41 studies), Europe (n = 37), Australia (n = 7), China or Taiwan (n = 4), Japan (n = 2), Brazil (n = 2), Israel (n = 2), India (n = l), and Mexico (n = l).

All-cause mortality HRs for overweight (BMI of 25-<30), obesity (BMI of ≥30), grade 1 obesity (BMI of 30-<35), and grades 2 and 3 obesity (BMI of ≥35) were calculated relative to normal weight (BMI of 18.5-<25).

The researchers found that the summary HRs indicated a 6 percent lower risk of death for overweight; a 18 percent higher risk of death for obesity (all grades); a 5 percent lower risk of death for grade 1 obesity; and a 29 percent increased risk of death for grades 2 and 3 obesity.

The authors note that the finding that grade 1 obesity was not associated with higher mortality suggests that that the excess mortality in obesity may predominantly be due to elevated mortality at higher BMI levels.

The researchers add that their findings are consistent with observations of lower mortality among overweight and moderately obese patients. “Possible explanations have included earlier presentation of heavier patients, greater likelihood of receiving optimal medical treatment, cardioprotective metabolic effects of increased body fat, and benefits of higher metabolic reserves.”

The use of predefined standard BMI groupings can facilitate between-study comparisons, the authors conclude.

(JAMA. 2013;309(1):71-82; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: There was no external funding for this work. The Centers for Disease Control and Prevention and the National Cancer Institute reviewed and approved the manuscript before submission. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, January 1 at this link.

Editorial: Does Body Mass Index Adequately Convey a Patient’s Mortality Risk?

“Can overweight as defined by BMI actually have a protective association with mortality?” write Steven B. Heymsfield, M.D., and William T. Cefalu, M.D., of the Pennington Biomedical Research Center, Baton Rouge, La., in an accompanying editorial

“The presence of a wasting disease, heart disease, diabetes, renal dialysis, or older age are all associated with an inverse relationship between BMI and mortality rate, an observation termed the obesity paradox or reverse epidemiology. The optimal BMI linked with lowest mortality in patients with chronic disease may be within the overweight and obesity range. Even in the absence of chronic disease, small excess amounts of adipose tissue may provide needed energy reserves during acute catabolic illnesses, have beneficial mechanical effects with some types of traumatic injuries, and convey other salutary effects that need to be investigated in light of the studies by Flegal et al and others.”

“Not all patients classified as being overweight or having grade 1 obesity, particularly those with chronic diseases, can be assumed to require weight loss treatment. Establishing BMI is only the first step toward a more comprehensive risk evaluation.”

(JAMA. 2013;309(1):87-88; 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 25, 2012

Obesity May Be Declining Among Preschool-Aged Children Living in Low-Income Families

“Obesity and extreme obesity in childhood, which are more prevalent among minority and low-income families, have been associated with other cardiovascular risk factors, increased health care costs, and premature death. Obesity and extreme obesity during early childhood are likely to continue into adulthood. Understanding trends in extreme obesity is important because the prevalence of cardiovascular risk factors increases with severity of childhood obesity,” writes Liping Pan, M.D., M.P.H., of the Centers for Disease Control and Prevention, Atlanta, and colleagues. National trends in extreme obesity among young children living in low-income families have not been known.

As reported in a Research Letter, the authors analyzed data from the Pediatric Nutrition Surveillance System (PedNSS), which includes almost 50 percent of children eligible for federally funded maternal and child health and nutrition programs. The analysis for this study included 26.7 million children ages 2 through 4 years from 30 states and the District of Columbia that consistently reported data to PedNSS from 1998 through 2010. One routine clinic visit with demographic information and measured height and weight was randomly selected for each child. Obesity (body mass index [BMI] 95th percentile or greater for age and sex) and extreme obesity (BMI 120 percent or greater of the 95th percentile) were defined according to the 2000 CDC growth charts.

The 2010 study population was slightly younger and had proportionally more Hispanics and fewer non-Hispanic whites and blacks compared with the 1998 population.  The researchers found that the prevalence of obesity increased from 13.05 percent in 1998 to 15.21 percent in 2003. The prevalence of extreme obesity increased from 1.75 percent in 1998 to 2.22 percent in 2003. However, the prevalence of obesity decreased slightly to 14.94 percent in 2010; and the prevalence of extreme obesity decreased to 2.07 percent in 2010.

“To our knowledge, this is the first national study to show that the prevalence of obesity and extreme obesity among young U.S. children may have begun to decline,” the authors write. “The results of this study indicate modest recent progress of obesity prevention among young children. These findings may have important health implications because of the lifelong health risks of obesity and extreme obesity in early childhood.”

(JAMA. 2012;308[24]:2563-2565. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Opportunities to Reduce Childhood Hunger and Obesity

David S. Ludwig, M.D., Ph.D., of Boston Children’s Hospital, and colleagues discuss the Supplemental Nutrition Assistance Program (SNAP, formerly known as the Food Stamp Program), and provide recommendations for improving nutritional quality for children in the U.S.

“SNAP is essential for hunger prevention in the United States, but its exclusive focus on food quantity contributes to malnutrition and obesity, and is misaligned with the goal of helping beneficiaries lead healthier lives. The nation’s $75 billion investment in SNAP could provide a major opportunity to reduce the burden of diet-related disease among low-income children and families if policies that promote nutritional quality are instituted.”

(JAMA. 2012;308[24]:2567-2568. Available pre-embargo to the media at https://media.jamanetwork.com)

Measure, Promote, and Reward Mobility to Prevent Falls in Older Patients

Samir K. Sinha, M.D., D.Phil., and Allan S. Detsky, M.D., Ph.D., of the University of Toronto, Ontario, Canada, examine the importance of maintaining and improving mobility among older patients to reduce the risk of a fall.

“A focus on maintaining and improving mobility should be encouraged when an older adult becomes acutely ill and particularly vulnerable to permanently losing functional capacity during a hospitalization. More importantly, encouraging routine strength and balance training in community-dwelling older adults should be a priority. This strategy not only could lower the risk of hospitalization due to falls and fractures but also, more importantly and even at advanced ages, could enhance quality and length of life.”

(JAMA. 2012;308[24]:2573-2574. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 25, 2012

Media Advisory: To contact Bryant J. Webber, M.D., call Sharon Willis at 301-295-3578 or email sharon.willis@usuhs.edu. To contact editorial author Daniel Levy, M.D., call the NHLBI press office at 301-496-4236 or email nhlbi_news@nhlbi.nih.gov.

CHICAGO – Among deployed U.S. service members who died of combat or unintentional injuries between 2001-2011 and underwent autopsies, the prevalence of coronary atherosclerosis was 8.5 percent, with factors associated with a higher prevalence of the disease including older age, lower educational level and prior diagnoses of dyslipidemia, hypertension, and obesity, according to a study in the December 26 issue of JAMA.

“An early breakthrough in the understanding of the natural history of atherosclerotic heart disease was achieved in 1953, when Enos and colleagues at the Armed Forces Institute of Pathology reported a 77 percent prevalence of coronary atherosclerosis among U.S. soldiers killed in the Korean War. By demonstrating anatomically that atherosclerosis affected a large proportion of young individuals without clinical evidence of heart disease, their study revolutionized the understanding of the onset and progression of cardiovascular disease. A follow-up report in the Vietnam War era, along with a number of autopsy studies in the civilian population provided additional evidence that the onset of atherosclerosis may occur at an early age,” according to background information in the article. Since the publication of these studies, health policies have been implemented to reduce the risk of cardiovascular disease associated with risk factors such as hypertension, diabetes, cholesterol, and smoking.

Bryant J. Webber, M.D., of the Uniformed Services University of the Health Sciences, Bethesda, Md., and colleagues conducted a study to assess the prevalence of atherosclerosis in the U.S. armed forces. The study included all U.S. service members who died of combat or unintentional injuries in support of Operations Enduring Freedom and Iraqi Freedom/New Dawn between October 2001 and August 2011 and whose cardiovascular autopsy reports were available at the time of data collection in January 2012. Prevalence of atherosclerosis was analyzed by various demographic characteristics and medical history. Classifications of coronary atherosclerosis severity were determined prior to data analysis and designed to provide consistency with previous military studies: minimal (fatty streaking only), moderate (10 percent – 49 percent luminal [interior of the vessel] narrowing of one or more vessels), and severe (50 percent or more narrowing of one or more vessels). Of the 3,832 service members included in the analysis, the average age was 26 years.

The overall prevalence of coronary or aortic atherosclerosis was 12.1 percent. The prevalence of any coronary atherosclerosis was 8.5 percent; severe coronary atherosclerosis was present in 2.3 percent, moderate in 4.7 percent, and minimal in 1.5 percent. The researchers found that age consistently produced the strongest association with prevalent atherosclerosis. Service members with atherosclerosis (average age, 30.5) were approximately 5 years older than those without; those 40 years of age and older had about 7 times the prevalence of disease as compared with those 24 years of age and younger (45.9 percent vs. 6.6 percent)

Lower education level and higher military entrance body mass index (BMI) were significantly associated with prevalent atherosclerosis, after adjusting for age. As compared with those who completed high school or less, those who completed at least some college had lower prevalence of disease. As compared with those with a normal BMI on military entrance, those with a BMI in the overweight or obese range had a significantly higher prevalence of atherosclerosis

The authors also found that age-adjusted atherosclerosis prevalence was associated with several diagnoses. As compared with those with no major cardiovascular risk factor diagnoses, those with a diagnosis of dyslipidemia (50.0 percent vs. 11.1 percent), hypertension (43.6 percent vs. 11.1 percent), or obesity (22.3 percent vs. 11.1 percent) had a significantly higher prevalence of atherosclerosis.

The researchers note that the prevalence rates found in this study demonstrate a decline from the rates of 77 percent noted in the Korean War and 45 percent in the Vietnam War, but add that targets for further improvement remain.

“Military and civilian health care systems should continue to help patients reduce their cardiovascular risk factors, beginning in childhood and continuing throughout adult life. Despite remarkable progress in prevention and treatment, cardiovascular disease remains the leading cause of death in the United States and other developed nations, and even small improvements in the prevalence of smoking and other risk factors may reduce death rates further and prolong healthy lives.”

(JAMA. 2012;308(24):2577-2583; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by the Uniformed Services University of the Health Sciences, Armed Forces Medical Examiner System, and Armed Forces Health Surveillance Center. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, December 25 at this link.

Editorial: Combating the Epidemic of Heart Disease

Daniel Levy, M.D., of the National Heart, Lung, and Blood Institute, Bethesda, Md., comments on the findings of this study in an accompanying editorial.

“Autopsy studies have demonstrated that coronary disease begins at a young age. Consequently, primary prevention campaigns to address obesity and related risks should begin in childhood. Declines in cardiovascular disease risk factors have almost certainly contributed to the observed reductions in prevalence of subclinical atherosclerosis, incidence of clinical atherosclerotic disease, and deaths from heart disease. Although age-adjusted heart disease death rates have declined by 72 percent since their peak during the Vietnam War years, cardiovascular disease remains the leading cause of death in the United States. The national battle against heart disease is not over; increasing rates of obesity and diabetes signal a need to engage earlier and with greater intensity in a campaign of pre-emption and prevention.

(JAMA. 2012;308(24):2624-2625; 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 25, 2012

Media Advisory: To contact corresponding author Harry L. A. Janssen, M.D., Ph.D., email h.janssen@erasmusmc.nl.

CHICAGO – Among patients with chronic hepatitis C virus infection and advanced hepatic fibrosis (development of excess fibrous connective tissue), sustained virological response (SVR) to interferon-based treatment was associated with a lower risk of all-cause mortality compared with patients without SVR, according to a study in the December 26 issue of JAMA.

“Chronic hepatitis C virus (HCV) infection is a major cause of cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease. The incidence of HCV-related cirrhosis and its complications is expected to increase in upcoming years. Davis et al estimated that currently 25 percent of the approximately 3.5 million U.S. patients with chronic HCV infection have cirrhosis and that the proportion of patients with cirrhosis is likely to increase up to 45 percent by 2030,” according to background information in the article.

“Sustained virological response is defined as absence of viremia [the presence of a virus in the blood] 24 weeks after cessation of all antiviral medication. Although SVR has long-term durability, data on the relationship with improved survival to support its use as a surrogate end point of antiviral therapy is scarce. Demonstrating direct clinical benefits would better justify the use of intensive and costly antiviral therapy …” the authors write.

Adriaan J. van der Meer, M.D., of Erasmus MC University Medical Center, Rotterdam, the Netherlands and colleagues conducted a study to examine whether achievement of SVR vs. without SVR is associated with a prolonged overall survival in patients with chronic HCV infection and advanced hepatic fibrosis. The study, conducted at five tertiary care hospitals in Europe and Canada, included 530 patients with chronic HCV infection who started an interferon-based treatment regimen between 1990 and 2003, following histological proof of advanced hepatic fibrosis or cirrhosis. Complete follow-up ranged between January 2010 and October 2011. The patients were followed up for a median (midpoint) of 8.4 years. The baseline median age was 48 years and 369 patients (70 percent) were men.

There were 192 patients (36 percent) who achieved SVR; 13 patients with SVR and 100 without SVR died (10-year cumulative all-cause mortality rate, 8.9 percent with SVR and 26.0 percent without SVR). In further analysis, the researchers found that SVR was associated with a reduced risk of all-cause mortality and liver-related mortality or transplantation. Other baseline factors significantly associated with all-cause mortality included older age, HCV genotype 3 infection, presence of diabetes, and a history of severe alcohol use. Of the 100 deaths in patients without SVR, the cause was liver-related in 70 patients (70 percent), not liver-related in 15 percent of patients, and unknown in another 15 percent.

The 10-year cumulative incidence rate of liver-related mortality or transplantation was 1.9 percent with SVR and 27.4 percent without SVR. After 10 years, the cumulative occurrence of HCC was 5.1 percent in patients with SVR and 21.8 percent in patients without SVR. The 10-year cumulative liver failure rate was 2.1 percent in patients with SVR vs. 29.9 percent in patients without SVR.

“In our international, multicenter, long-term follow-up study, SVR was associated with prolonged overall survival. The risk of all-cause mortality was almost 4-fold lower in patients with SVR compared with patients without SVR. Our study with a long follow-up duration demonstrated a lower risk for all-cause mortality in patients with chronic HCV infection and advanced hepatic fibrosis who achieved SVR. In addition, we were able to further establish and quantify the risk reduction of HCC, liver failure, and liver-related mortality or liver transplantation in patients with SVR,” the authors conclude.

(JAMA. 2012;308(24):2584-2593; 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 18, 2012

Iodine Supplementation During Pregnancy and Lactation

Alex Stagnaro-Green, M.D., M.H.P.E., of the George Washington University School of Medicine and Health Sciences, Washington, D.C., and colleagues discuss the possible adverse effects of iodine deficiency and the importance of supplementation during pregnancy and while breastfeeding.

“The status quo can be maintained in which iodine supplementation is recommended, but provided in only 50 percent of prenatal vitamins. The alternative is for relevant medical organizations to work collaboratively with pharmaceutical and vitamin manufacturers to ensure that all prenatal multivitamins contain 150 μg of potassium iodine. In the interim, clinicians should recommend only those prenatal vitamins that contain iodine. The path seems clear. It is time for all prenatal vitamins to contain iodine.”

(JAMA. 2012;308[22]:2463-2464. Available pre-embargo to the media at https://media.jamanetwork.com)

Making Health Care Reform Work – Where Physician and Employer Interests Converge

Harris Allen, Ph.D., of the Harris Allen Group, Brookline, Mass., and colleagues write that physicians and businesses share a common goal—to advance better health; yet the business community maintains a low profile in health care reform under the Affordable Care Act (ACA). In this Viewpoint, the authors examine missed opportunities for strengthening employer linkages with the ACA, and what can be done for improvement.

“Employers need to reprise their role in health care reform efforts in a manner that will help advance their shared goal of better health with physicians. Building on the ACA’s legislative authority, businesses can reach out to their commercial carriers to coordinate, unify, and standardize performance payment metrics and insist that they include not only direct but also indirect health care costs. Extending the process of standardization to both types of measures holds much promise for minimizing reporting complexity and clinical care redundancy in ways that will materially enhance physician capacity to deliver care in the unfolding reform environment.”

(JAMA. 2012;308[22]:2465-2466. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 18, 2012

Media Advisory: To contact Edward W. Gregg, Ph.D., call Karen Hunter at 404-639-3286 or email ksh7@cdc.gov. To contact editorial co-author David E. Arterburn, M.D., M.P.H., call Joan DeClaire at 206-287-2653 or email declaire.j@ghc.org.

CHICAGO – Among overweight adults, participation in an intensive lifestyle intervention (that included counseling sessions and targets to reduce caloric intake and increase physical activity) was associated with a greater likelihood of partial remission of type 2 diabetes, however the absolute remission rates were modest, according to a study in the December 19 issue of JAMA.

“Diabetes traditionally has been considered a progressive, incurable condition wherein the best case scenario after diagnosis is tight metabolic and risk factor management to forestall vascular and neuropathic complications,” according to background information in the article. Some bariatric surgery studies have suggested that many diabetes cases among obese patients can be resolved. “Patients diagnosed as having type 2 diabetes frequently ask their physicians whether their condition is reversible, and some physicians may provide hopeful advice that lifestyle change can normalize glucose levels,” the authors write. “However, the rate of remission of type 2 diabetes that may be achieved using non-surgical approaches has not been reported.”

Edward W. Gregg, Ph.D., of the Centers for Disease Control and Prevention, Atlanta, and colleagues conducted a study to examine the association of an intensive lifestyle intervention with frequency of partial and complete remission of type 2 diabetes. The study consisted of an ancillary observational analysis of a 4-year randomized controlled trial (baseline visit, August 2001-April 2004; last follow-up, April 2008) comparing an intensive lifestyle intervention (ILI) with a diabetes support and education control condition (DSE). The study included 4,503 U.S. adults with body mass index of 25 or higher and type 2 diabetes.

Participants were randomly assigned to receive the ILI, which included weekly group and individual counseling in the first 6 months followed by 3 sessions per month for the second 6 months and twice-monthly contact and regular refresher group series and campaigns in years 2 to 4 (n = 2,241); or the DSE, which was an offer of 3 group sessions per year on diet, physical activity, and social support (n = 2,262). The ILI aimed to reduce total caloric intake to 1,200 to 1,800 calories a day through reductions in total and saturated fat intake and by increasing physical activity levels to a goal of 175 minutes/week. Liquid meal replacements were provided to assist dietary goals.

Participants in the ILI group lost significantly more weight than DSE participants at year 1 (-8.6 percent vs. -0.7 percent) and at year 4 (-4.7 percent vs. -0.8 percent) and had greater increases in fitness at both year 1 (20.6 percent vs. 5.3 percent) and year 4 (4.9 percent vs. -1.5 percent). The researchers found that the prevalence of complete remission (i.e., glucose normalization without medication) was more common in the ILI group than in the DSE group across all years of the study. However, the absolute prevalence was low, ranging from 1.3 percent for ILI vs. 0.1 percent for DSE in year 1; to 0.7 percent for ILI vs. 0.2 percent for DSE in year 4.

Additional analyses indicated that ILI participants were significantly more likely to experience any remission (partial or complete), with a prevalence of 11.5 percent during the first year, decreasing to 7.3 percent during year 4, compared with 2.0 percent in the DSE group at both time points. Rates of any remission were notably higher (15 percent – 21 percent) among persons with substantial weight loss or fitness change, shorter duration of extant diabetes, or a lower HbA_1c level (a measure of blood glucose) at entry and those not using insulin.

“The ILI group was significantly more likely to have continuous, sustained remission, as 9.2 percent experienced at least a 2-year remission (vs. for DSE, 1.7 percent) at some point during follow-up, 6.4 percent had at least a 3-year remission (vs. DSE, 1.3 percent), and 3.5 percent had a continuous 4-year remission (vs. DSE, 0.5 percent). The results from the complete case analyses were similar,” the authors write.

“The increasing worldwide prevalence of type 2 diabetes, along with its wide-ranging complications, has led to hopes that the disease can be reversed or prevented. These analyses of more than 4,500 overweight adults with type 2 diabetes confirm that complete remission associated with an intensive life-style intervention, when defined by glucose normalization without need for drugs, is rare. However, partial remission, defined as a transition to prediabetic or normal glucose levels without drug treatment for a specific period, is an obtainable goal for some patients with type 2 diabetes.”

(JAMA. 2012;308(23):2489-2496; 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: A Look Ahead at the Future of Diabetes Prevention and Treatment

David E. Arterburn, M.D., M.P.H., of the Group Health Research Institute, Seattle, and Patrick J. O’Connor, M.D., M.A., M.P.H., of the HealthPartners Institute for Education and Research, Minneapolis, write in an accompanying editorial that “evidence-based and cost-effective diabetes prevention strategies should be more broadly applied using the full range of available technologies and incentives.”

“But that is not enough. Research, education, and policy efforts need to be focused further upstream, toward primary prevention: reducing incident obesity in children, adolescents, and adults, especially among those with a family history of obesity or diabetes. Prevention of diabetes and obesity should be a rallying cry for all clinicians who care about the health of the nation.”

(JAMA. 2012;308(23):2517-2518; 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 18, 2012

Media Advisory: To contact corresponding author Gilles Montalescot, M.D., Ph.D., email gilles.montalescot@psl.aphp.fr.

CHICAGO – Among patients scheduled for a percutaneous coronary intervention (PCI; procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries), pretreatment with the antiplatelet agent clopidogrel was not associated with a lower risk of overall mortality but was associated with a significantly lower risk of major coronary events, according to a review and meta-analysis of previous studies published in the December 19 issue of JAMA.

“In addition to aspirin, clopidogrel has been shown to improve ischemic outcomes of patients with stable coronary artery disease following PCI and of patients with acute coronary syndromes (ACS; such as heart attack or unstable angina) who were either medically treated or who had undergone either revascularization by fibrinolysis or PCI,” according to background information on the article. “Clopidogrel pretreatment is recommended for patients with ACS and stable coronary artery disease who are scheduled for PCI, but whether using clopidogrel as a pretreatment for PCI is associated with positive clinical outcomes has not been established.”

Anne Bellemain-Appaix, M.D., of the Service de Cardiologie-La Fontonne Hospital, Antibes, France, and colleagues conducted a review and meta-analysis of data from randomized trials and registries involving patients with coronary artery disease (stable or with ACS) undergoing catheterization for potential revascularization to evaluate the association between clopidogrel pretreatment with mortality and major bleeding after PCI. After a search of the medical literature, the researchers identified 15 articles published between August 2001 and September 2012 that met the study inclusion criteria: 6 randomized controlled trials (RCTs), 2 observational analyses of RCTs, and 7 observational studies. Pretreatment was defined as the administration of clopidogrel before PCI or catheterization. The primary efficacy and safety end points were all-cause mortality and major bleeding. Secondary end points included major cardiac events.

Of the 37,814 patients included in the meta-analysis, 8,608 patients had participated in RCTs; 10,945 in observational analyses of RCTs; and 18,261 in observational studies. In the RCT cohort of patients, clopidogrel pretreatment was not significantly associated with a reduction of all-cause mortality (absolute risk, 1.54 percent vs. 1.97 percent). These results were consistent across the observational analyses of RCTs and the observational studies analyses. Clopidogrel pretreatment was also not associated with a significantly increased risk of major bleeding in the main analysis of RCTs (absolute risk, 3.57 percent vs. 3.08 percent).

In the main analysis, clopidogrel pretreatment was significantly associated with a reduction of major coronary events (absolute risk, 9.83 percent vs. 12.35 percent) and heart attack (absolute risk, 4.53 percent vs. 5.90 percent).

The authors note that although no significant heterogeneity existed for clinical presentation, the higher-risk ST-segment elevation myocardial infarction (STEMI; a certain pattern on an electrocardiogram following a heart attack) population appeared to gain the most benefit from pretreatment. “In contrast, patients undergoing elective PCI had no apparent benefit from clopidogrel pretreatment, questioning the need of such a systematic strategy at least in low-risk patients.”

“Although a pretreatment strategy has been recommended for years in patients undergoing PCI, this study shows the limits of the available evidence, with no significant benefit on hard outcomes. The value of pretreatment, including with new antiplatelet agents, needs to be assessed in large prospective studies.”

(JAMA. 2012;308(23):2507-2517; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Please Note: An author podcast on this study will be available post-embargo on the JAMA website.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 18, 2012

Media Advisory: To contact Barbara E. K. Klein, M.D., M.P.H., call Susan Lampert Smith at 608-262-7335 or email slsmith2@wisc.edu.

CHICAGO – Among nearly 5,000 study participants, regular aspirin use reported ten years prior was associated with a small but statistically significant increase in the risk of neovascular age-related macular degeneration, according to a study in the December 19 issue of JAMA.

“Aspirin use in the United States is widespread, with an estimated 19.3 percent of adults reporting regular consumption, and reported use increases with age,” according to background information in the study. “The results of cross-sectional studies of aspirin use and its relation to age-related macular degeneration (AMD) have been inconsistent. AMD is a potentially blinding condition for which prevalence and incidence are increasing with the increased survival of the population, and regular use of aspirin is common and becoming more widespread in persons in the age range at highest risk for this disease. Therefore, it is imperative to further examine this potential association.”

Barbara E. K. Klein, M.D., M.P.H., of the University of Wisconsin School of Medicine and Public Health, Madison, and colleagues conducted a study to examine the association between aspirin use and AMD. The researchers used data from the Beaver Dam Eye Study, a longitudinal population-based study of age-related eye diseases conducted in Wisconsin. Examinations were performed every 5 years over a 20-year period (1988-1990 through 2008-2010). Study participants (n = 4,926) were 43 to 86 years of age at entry in the study. At subsequent examinations, participants were asked if they had regularly used aspirin at least twice a week for more than 3 months. The average duration of follow-up was 14.8 years.

For the study, the researchers measured the incidences of different types of AMD (early, late, and 2 subtypes of late AMD [neovascular AMD and pure geographic atrophy]).

There were 512 incident cases of early AMD and 117 incident cases of late AMD over the course of the study. The researchers found that regular use of aspirin use 10 years prior to the retinal examination was associated with late AMD (age- and sex-adjusted incidence, 1.8 percent for users vs. 1.0 percent for nonusers). When examining the relationships by late AMD subtype, neovascular AMD was significantly associated with such use (age-and sex-adjusted incidence, 1.4 percent for users vs. 0.6 percent for nonusers), but not for pure geographic atrophy. Aspirin use 5 years or 10 years prior to retinal examination was not associated with incident early AMD.

“Our findings are consistent with a small but statistically significant association between regular aspirin use and incidence of neovascular AMD. Additional replication is required to confirm our observations. If confirmed, defining the causal mechanisms may be important in developing methods to block this effect to prevent or retard the development of neovascular AMD in persons who use aspirin, especially to prevent CVD,” the authors conclude.

(JAMA. 2012;308(23):2469-2478; 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 18, 2012

Media Advisory: To contact co-author Steven D. Stellman, Ph.D., M.P.H., call Jean Weinberg at 347-396-4177 or email jweinberg@health.nyc.gov; or Marcus Liem at 347-396-2919 or email mliem@health.nyc.gov.

CHICAGO – Among rescue and recovery workers exposed to the dust, debris, and fumes following the World Trade Center terrorist attack, there was an increased incidence of prostate and thyroid cancers and multiple myeloma, although it is not clear how big a factor medical screening and non-WTC risk factors contributed to these increases, according to a study in the December 19 issue of JAMA. The authors did not find a statistically significant increased incidence for all cancer sites combined, and note that the findings on the three cancers that did increase should be viewed with caution for several reasons, including that they were based on a small number of cancers, multiple comparisons, and a relatively short follow-up time.

“The terrorist attacks on the World Trade Center (WTC) on September 11, 2001, claimed more than 2,700 lives and exposed hundreds of thousands of people to dust, debris, pulverized building materials, and potentially toxic emissions, resulting in short- and medium-term health effects,” according to background information in the article. The dust, smoke, and aerosols were complex mixtures of volatile chemicals and respirable particulate matter and contained known and suspected carcinogens. “The presence of carcinogenic agents raises the possibility that exposure to the WTC environment could eventually lead to cancers.”

Jiehui Li, M.B.B.S., M.Sc., of the New York City Department of Health and Mental Hygiene, Long Island City, New York, and colleagues conducted a study to evaluate cancer incidence among WTC rescue/recovery workers and volunteers and those not involved with rescue/recovery work. The observational study included 55,778 New York State residents enrolled in the World Trade Center Health Registry in 2003-2004, including rescue/recovery workers (n = 21,850) and those not involved in rescue/recovery (n = 33,928), who were followed-up from enrollment through December 2008. Within-group comparisons using various models also assessed the relationship between intensity of World Trade Center exposure and selected cancers.

Cancer cases were identified through linkage with 11 state cancer registries. Standardized incidence ratios (SIRs) adjusted for age, race/ethnicity, and sex were computed with 2003-2008 New York State rates as the reference, focusing on cancers diagnosed in 2007-2008 as being most likely to be related to exposure during September 11 and its aftermath. The total and site-specific incidence rate differences between the study population and the New York State population in 2007-2008 also were calculated.

Through December 31, 2008, 1,187 incident cancers were reported among the 55,778 eligible enrollees. Of these 1,187 cancers, 439 (37 percent) were diagnosed among rescue/recovery workers and 748 (63 percent) were among participants not involved in rescue/recovery. The median (midpoint) age at diagnosis across all cancer sites was 57 years. For all sites combined, cancer incidence was not significantly different from that in the reference population during either the early period (enrollment through 2006) or the later period (2007-2008). The researchers found that of the 23 cancer sites investigated, 3 had significantly elevated incidence during the later period: prostate, thyroid, and multiple myeloma. Of these 3, thyroid cancer also was significantly elevated during the early period.

“No increased incidence was observed in 2007-2008 among those not involved in rescue/recovery. Using within-cohort comparisons, the intensity of World Trade Center exposure was not significantly associated with cancer of the lung, prostate, thyroid, non-Hodgkin lymphoma, or hematological cancer in either group,” the authors write.

“Given the relatively short follow-up time and lack of data on medical screening and other risk factors, the increase in prostate and thyroid cancers and multiple myeloma should be interpreted with caution. The etiological role of WTC exposures in these 3 cancers is unclear. Longer follow-up of rescue/recovery workers and participants not involved in rescue/recovery is needed with attention to selected cancer sites and to examine risk for cancers with typically long latency periods.”

(JAMA. 2012;308(23):2479-2488; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, December 18 at this link.

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

Study Finds Association Between Weight of Pancreas and Potential Diabetes Biomarker

Autopsy and imaging studies suggest that among adults with type 1 diabetes (T1D), their pancreas is smaller and weighs less than the pancreas of adults without the disease. However, it is unknown when pancreatic atrophy begins in T1D. Martha Campbell-Thompson, D.V.M., Ph.D., of the University of Florida, Gainesville, and colleagues conducted a study to examine pancreas weight early in the natural history of T1D from at-risk individuals without diabetes but with disease-associated autoantibodies, obtained through the Network for Pancreatic Organ Donors with Diabetes program. All donors were identified by organ procurement organizations that coordinate organ and tissue donations for clinical transplantation or research.

As reported in a Research Letter, the final analysis included 51 donors (no diabetes, n = 23; positive for autoantibody only, n = 8; type 1 diabetes, n = 20). The authors found that the average weight of pancreata (plural form of pancreas) from those without diabetes (controls) was 81.4 g compared with 61.3 g from the group positive for a single autoantibody only and 44.9 g from the T1D group.

“In this study, the weight of pancreata in individuals without T1D, but with serum markers that potentially precede the clinical manifestations, as well as in individuals with T1D, was less than in controls. This suggests that early atrophy of the organ may be an important subclinical feature of T1D pathogenesis,” the authors write. “Future studies should include validation and analysis of the potential mechanisms underlying this observation to understand whether early pancreatic atrophy contributes to the pathogenesis of T1D.”

(JAMA. 2012;308[22]:2337-2339. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Lixivaptan for Hyponatremia – The Numbers Game

Ryan T. Borne, M.D., and Mori J. Krantz, M.D., of the Denver Health Hospital and Authority, examine the approval of the drug lixivaptan for the treatment of hyponatremia (abnormally low level of sodium in the blood) and the questions regarding the benefit of this class of drugs (vasopressin receptor antagonist).

“Sole reliance on laboratory surrogates can lead to widespread adoption of ineffective or harmful treatments. Regulators should create a landscape that supports evaluation of safety and efficacy across all phases of development and exhibit caution when making inferences based on predictive data from epidemiologic studies. Therapeutically modifying a given surrogate marker tightly linked in epidemiologic studies with improved outcomes cannot guarantee clinical efficacy,” they write. “… in the case of the vasopressin receptor antagonist class, it remains dubious that an increase in serum sodium levels will ultimately be demonstrated to improve outcomes in clinical trials given the myriad etiologies for hyponatremia. The manufacturers of lixivaptan sought approval for use in less severe hyponatremia and even among outpatients. The potential risks and benefits of lixivaptan and this expanded label are being carefully considered by the FDA.”

(JAMA. 2012;308[22]:2345-2346. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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For More Information: contact The JAMA Network^® Media Relations Department at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

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

Media Advisory: To contact corresponding author David S. Friedman, M.D., M.P.H., Ph.D., call John Lazarou at 410-502-8902 or email jlazaro1@jhmi.edu. To contact editorial co-author David C. Musch, Ph.D., M.P.H., call Betsy Nisbet at 734-647-5586 or email bsnisbet@umich.edu.

CHICAGO – The prevalence of nonrefractive visual impairment (not due to need for glasses) in the U.S. has increased significantly in recent years, which may be partly related to a higher prevalence of diabetes, an associated risk factor, according to a study in the December 12 issue of JAMA.

“It is estimated that more than 14 million individuals in the United States aged 12 years and older are visually impaired (<20/40). Of these cases, 11 million are attributable to refractive error. In the United States, the most common causes of nonrefractive visual impairment are age-related macular degeneration, cataract, diabetic retinopathy, glaucoma, and other retinal disorders,” according to background information in the article. Previous studies have shown that visual impairment is common in persons with diabetes. “The prevalence of diagnosed diabetes has increased among adults in recent years, rising from 4.9 percent in 1990 to 6.5 percent in 1998, 7.9 percent in 2001, 10.7 percent in 2007, and 11.3 percent in 2010.”

Fang Ko, M.D., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues conducted a study to assess the prevalence of nonrefractive visual impairment and factors associated with risk of visual impairment. The study included data from the National Health and Nutrition Examination Survey (NHANES), a representative sample of the U.S. population. In 1999-2002 and 2005-2008, 9,471 and 10,480 participants 20 years of age or older received questionnaires, laboratory tests, and physical examinations. Visual acuity of less than 20/40 aided by autorefractor (a device for measuring a person’s refractive error) was classified as nonrefractive visual impairment.

The researchers found that prevalence of nonrefractive visual impairment increased 21 percent, from 1.4 percent in 1999-2002 to 1.7 percent in 2005-2008; and increased 40 percent among non-Hispanic whites 20-39 years of age, from 0.5 percent to 0.7 percent. In analysis among all participants, factors associated with nonrefractive visual impairment included older age, poverty, lower education level, and diabetes diagnosed 10 or more years ago. Among these risk factors, only the latter has increased in prevalence between the 2 time periods considered. Prevalence of diabetes with 10 or more years since diagnosis increased 22 percent overall from 2.8 percent to 3.6 percent; and 133 percent among non-Hispanic whites 20-39 years of age, from 0.3 percent to 0.7 percent.

“We report a previously unrecognized increase of visual impairment among U.S. adults that cannot be attributed to refractive error,” the authors write. “If the current finding becomes a persisting trend, it could result in increasing rates of disability in the U.S. population, including greater numbers of patients with end-organ diabetic damage who would require ophthalmic care. These results have important implications for resource allocation in the debate of distribution of limited medical services and funding. Continued monitoring of visual disability and diabetes, as well as additional research addressing causes, prevention, and treatment, is warranted.”

(JAMA. 2012;308(22):2361-2368; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, December 11 at this link.

Editorial: Diabetes and Nonrefractive Visual Impairment – The Young Have It

David C. Musch, Ph.D., M.P.H., and Thomas W. Gardner, M.D., M.S., of the University of Michigan, Ann Arbor, write in an accompanying editorial that the results of this study “are indeed meaningful, considering the cohort of young people for whom a milieu of sociodemographic and lifestyle factors have led to increased risk of type 2 diabetes and its consequences, which include nonrefractive visual impairment.”

“… this report should send an important message to pediatricians, family practitioners, internists, and ophthalmologists who already are seeing an increase of type 2 diabetes among their younger patients, and should alert public health planners, who need to prepare for the effects on the health care system. The findings of Ko et al should also stimulate funding for new and ongoing efforts to prevent the underlying causes that lead to diabetes and its complications such as obesity-prevention programs aimed at children and adolescents.”

(JAMA. 2012;308(22):2403-2404; 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 11, 2012

Media Advisory: To contact corresponding author Konrad E. Bloch, M.D., email konrad.bloch@usz.ch.

CHICAGO – For individuals with obstructive sleep apnea traveling to higher altitudes (which may exacerbate symptoms), use of a combination therapy resulted in improvement in symptoms including  reduced insomnia and better control of sleep apnea, according to a preliminary study published in the December 12 issue of JAMA.

As travel to the mountains for professional and recreational activities is increasingly popular, involving millions of persons worldwide, the estimated number of patients with obstructive sleep apnea (OSA) among mountain tourists is also high, and may involve several hundred thousand persons each year, which may expose them to hypoxemia (abnormally low levels of oxygen in the blood) and exacerbation of sleep apnea. “The treatment in this setting is not established,” according to background information in the article.

Tsogyal D. Latshang, M.D., of the University of Zurich, Switzerland, and colleagues conducted a study to evaluate whether taking of the drug acetazolamide (a respiratory stimulant used to treat acute mountain sickness and high-altitude periodic breathing) combined with auto-adjusted continuous positive airway pressure (autoCPAP, computer-controlled continuous mask pressure adjustment) would provide better oxygenation and control of sleep-related breathing disturbances than autoCPAP alone in patients with OSA spending a few days at moderate altitude. The randomized trial included 51 patients with OSA living below an altitude of 800 meters (2,625 feet) and receiving CPAP therapy who underwent studies at a university hospital at 490 meters (1,608 feet) and resorts in Swiss mountain villages at 1,630 meters (5,348 feet) and 2,590 meters (8,497 feet) in the summer of 2009. Patients were studied during 2 stays of 3 days each in the mountain villages. At altitude, patients either took acetazolamide (750 mg/d) or placebo in addition to autoCPAP.

The researchers found that at 1,630 meters and 2,590 meters, combined acetazolamide and autoCPAP treatment was associated with higher oxygen saturation and a lower apnea/hypopnea index (AHI) compared with placebo and autoCPAP. AutoCPAP and acetazolamide increased the median [midpoint] nocturnal oxygen saturation by 1.0 percent at 1,630 meters and by 2.0 percent at 2,590 meters. Also, acetazolamide and autoCPAP resulted in better control of sleep apnea at these altitudes than placebo and autoCPAP: median apnea/ hypopnea index was 5.8 events per hour (5.8/h) and 6.8/h vs. 10.7/h and 19.3/h, respectively; median reduction was 3.2/h and 9.2/h. Median night-time spent with oxygen saturation less than 90 percent at 2,590 meters was 13 percent vs. 57 percent.

“The current randomized, placebo-controlled, double-blind trial provides several novel findings that are clinically relevant for patients with OSA traveling to altitude. First, the data show that combined therapy with acetazolamide and autoCPAP provides a better oxygenation during sleep and wakefulness, prevents an exacerbation of sleep apnea at altitude, and reduces the time spent awake during nights compared with autoCPAP alone. Second, the results demonstrate that autoCPAP alone is an effective therapy for obstructive apneas/hypopneas even at altitude where central apneas/hypopneas emerge,” the authors write.

“Our study provides important information for patients with OSA planning a stay at altitude because they can continue using their CPAP in autoadjusting mode during altitude travel and enhance this treatment with acetazolamide if they want to spend less time awake at night, to achieve a higher arterial oxygen saturation and an optimal control of sleep apnea.”

(JAMA. 2012;308(22):2390-2398; 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 4, 2012

Overcoming the Obstacles to Research During Residency – What Does It Take?

Michael B. Rothberg, M.D., M.P.H., of the Cleveland Clinic, writes that “although most physicians work as clinicians and never perform research, the Accreditation Council for Graduate Medical Education requires that residents ‘participate in scholarly activity’ and that programs ‘allocate adequate educational resources to facilitate resident involvement in scholarly activities.’” Dr. Rothberg notes that conducting research in residency is challenging, and insufficient scholarly activity remains a common reason for residency program citation.  In this Viewpoint, the author provides suggestions for overcoming the challenges presented.

“In conclusion, the requirement for resident research holds substantial promise for improving the practice of medicine, enhancing quality, and decreasing cost, but for research to become widespread, residency training programs must overcome a number of substantial obstacles. Successful implementation requires an intentional approach that addresses specific barriers, beginning with a commitment to change the underlying culture of the institution to create an atmosphere of inquiry and the financial investment to build the necessary infrastructure to facilitate rapid turnaround of small projects.”

(JAMA. 2012;308[21]:2191-2192. Available pre-embargo to the media at https://media.jamanetwork.com)

Residency Training and International Medical Graduates – Coming to America No More

Giovanni Traverso, M.B., B.Chir., Ph.D., of Massachusetts General Hospital, and Graham T. McMahon, M.D., M.M.Sc., of Brigham and Women’s Hospital, Boston, discuss the expected decrease in the number of international medical graduates (IMGs) who train in the United States, and the possible adverse effects.

“The rapidly increasing number of medical school graduates coupled with a constrained graduate medical education system is likely to have a substantial effect on the number of IMG recruits to U.S. programs. These trends threaten to reduce the diversity of the physician community and could meaningfully affect primary care delivery in the United States and even health care quality abroad. Despite the proven value of IMGs to the U.S. health care system, coming to America is likely to prove increasingly challenging for future IMGs.”

(JAMA. 2012;308[21]:2193-2194. Available pre-embargo to the media at https://media.jamanetwork.com)

Professionalism in the Era of Duty Hours – Time for a Shift Change?

Vineet M. Arora, M.D., M.A.P.P., of the University of Chicago, and colleagues write that “concerns have been raised that the implementation of shorter duty hours for residents may erode the professional allegiance of these physicians to their patients. Those who trained before duty hour regulations often dismiss current physicians in training as lifestyle oriented and not committed to the profession.”

In this Viewpoint, the authors examine how the conflict between nostalgic definitions of professionalism and the new model of medical training can be reconciled.

“To make the transition from a nostalgic to a new type of professionalism, the system of residency training must fully adopt a team-based care model in which patient ownership is not relegated to an individual, but shared among a group of team members. As shift work is adopted, such a structure can promote professionalism by preventing a ‘that’s not my patient’ sentiment by covering physicians,” they write. “It is the responsibility of educators and leaders to search for creative solutions to facilitate adoption of new professionalism. After all, now is the time for a shift change.”

(JAMA. 2012;308[21]:2195-2196. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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For More Information: contact The JAMA Network® Media Relations Department at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact corresponding author Deborah Korenstein, M.D., call Kevin Orozovich at 212-241-9200 or email newsmedia@mssm.edu.

Azalea Kim, M.P.A., of the Mount Sinai School of Medicine, New York, and colleagues studied the association between routine conflicts of interest (COI) disclosure with preclinical medical students and students’ attitudes toward disclosure and industry interactions. In September 2010, the Mount Sinai School of Medicine began mandating COI disclosure by lecturers to preclinical medical students.

“Disclosure of potential COI from relationships with the pharmaceutical and device industries is recommended in publishing, research, and education of residents, faculty, and students. Disclosure in education may foster critical evaluation of information and assessment for potential bias, but its effect is unclear.”

As reported in a Research Letter, the authors adapted a published survey to assess student attitudes toward COI disclosure and the appropriateness of industry gifts to physicians, industry-sponsored education, and industry-faculty relationships. All year 1 (n = 143) and year 2 (n = 141) students were eligible to participate; results from the two classes were pooled. Participants were surveyed during class meetings at the beginning and end of the 2010-2011 academic year, comparing attitudes before and after policy implementation.

The researchers found that nearly all students (>97.0 percent) favored disclosure in both surveys. “Attitudes toward academic-industry relationships changed after policy implementation. Agreement increased over whether schools should limit industry meetings with students. Agreement decreased over whether industry should fund medical school programs. Attitudes did not change regarding the influence of COI on educators or educational content. Few students believed that educational content or quality were influenced by educator relationships with industry.”

“Our findings suggest that a COI disclosure policy to students is feasible and may influence student attitudes toward industry prescribing but not education.”

(JAMA. 2012;308[21]:2187-2189. Available pre-embargo to the media at https://media.jamanetwork.com)

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Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact Peter Yeates, M.B.B.S., M.Clin.Ed., email peter.yeates@manchester.ac.uk.

Peter Yeates, M.B.B.S., M.Clin.Ed., of the University of Manchester, United Kingdom, and colleagues conducted a study to examine whether observations of the performance of postgraduate year 1 physicians influence raters’ scores of subsequent performances.

“The usefulness of performance assessments within medical education is limited by high interrater score variability, which neither rater training nor changes in scale format have successfully ameliorated. Several factors may explain raters’ score variability, including a tendency of raters to make assessments by comparing against other recently viewed learners, rather than by using an absolute standard of competence. This has the potential to result in biased judgments,” according to background information in the article.

The study consisted of an internet-based randomized experiment using videos of Mini Clinical Evaluation Exercise (Mini-CEX) assessments of postgraduate year 1 trainees interviewing new internal medicine patients. Participants were 41 attending physicians from England and Wales experienced with the Mini-CEX, with 20 watching and scoring 3 good trainee performances and 21 watching and scoring 3 poor performances. All then watched and scored the same 3 borderline video performances. The study was completed between July and November 2011.

The researchers found that attending physicians exposed to videos of good medical trainee performances rated subsequent borderline performances lower than those who had been exposed to poor performances, consistent with a contrast bias. The implication is that a rater of a trainee’s performance may be unconsciously influenced by the previous trainee, rather than objectively assessing the individual in isolation.

“With the movement toward competency-based models of education, assessment has largely shifted to a system that relies on judgments of performance compared with a fixed standard at which competence is achieved (criterion referencing). Although this makes conceptual sense (with its inherent ability to reassure both the profession and the public that an acceptable standard has been reached), the findings in this study, which are consistent with contrast bias, suggest that raters may not be capable of reliably judging in this way.”

(JAMA. 2012;308[21]:2226-2232. Available pre-embargo to the media at https://media.jamanetwork.com)

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Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact Kevin W. Eva, Ph.D., call Brian Kladko at 604-827-3301 or email brian.kladko@ubc.ca.

Kevin W. Eva, Ph.D., of the University of British Columbia, Vancouver, and colleagues conducted a study to determine whether students deemed acceptable through a revised admissions protocol using a 12-station multiple mini-interview (MMI) would outperform rejected medical students when they later took the Canadian national licensing examinations after completing medical school. The MMI process requires candidates to rotate through brief sequential interviews with structured tasks and independent assessment within each interview.

“Modern conceptions of medical practice demand more of practitioners than a strong knowledge base. By emphasizing compassionate care, professionalism, and interpersonal skill, the Accreditation Council for Graduate Medical Education core competencies indicate that physicians are expected to possess strong personal qualities distinct from academic achievement. There is evidence of a link between these aspects of practice and quality of care,” according to background information in the article. “There has been difficulty designing medical school admissions processes that provide valid measurement of candidates’ nonacademic qualities.”

The study included potential medical students who were interviewed at McMaster University in Hamilton, Canada, using an MMI in 2004 or 2005 and accepted (whether or not they matriculated [enrolled] at McMaster) with those who were interviewed and rejected but gained entry elsewhere.

The computer-based Medical Council of Canada Qualifying Examination (MCCQE) part I (aimed at assessing medical knowledge and clinical decision making) can be taken on graduation from medical school; MCCQE part II (involving simulated patient interactions testing various aspects of practice) is based on the objective structured clinical examination and typically completed 16 months into postgraduate training. Interviews were granted to 1,071 candidates, and those who gained entry could feasibly complete both parts of their licensure examination between May 2007 and March 2011. Scores could be matched on the examinations for 751 (part I) and 623 (part II) interviewees. Admissions decisions were made with use of scores assigned to autobiographical essays, grade point average (GPA), and MMI performance. Academic and nonacademic measures contributed equally to the final ranking.

The researchers found that compared with students who were rejected by an admission process that used MMI assessment, students who were accepted scored higher on Canadian national licensing examinations, whether they had attended McMaster or another school.

“In conclusion, there appears to be a complementary relationship between GPA and the MMI process, with the former related to more knowledge-oriented outcome measures and the latter to more clinical/ethical/interpersonal skill-oriented outcomes. Our study demonstrates that at McMaster, a GPA plus MMI approach has yielded better outcomes than were achieved by the historical use of GPA plus panel-style interview/simulated tutorial.”

(JAMA. 2012;308[21]:2233-2240. Available pre-embargo to the media at https://media.jamanetwork.com)

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Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact corresponding author Khalid S. Khan, M.B.B.S., M.Sc., email k.s.khan@qmul.ac.uk.

Regina Kulier, M.D., of the World Health Organization, Geneva, Switzerland, and colleagues conducted a study to evaluate the effects of a clinically integrated e-learning evidence-based medicine (EBM) course on knowledge, skills, and educational environment in comparison with traditional EBM teaching in a group of low-middle-income countries.

“Evidence-based medicine encourages assimilation and implementation of new, valid, and relevant scientific knowledge by health care professionals as part of their daily clinical work. To be effective at achieving this, EBM curricula need to be clinically integrated,” according to background information in the article. “In low-middle-income countries (LMICs) there is a scarcity of EBM-trained clinical tutors, lack of protected time for teaching EBM, and poor access to relevant databases in languages other than English.”

The randomized trial was conducted between April 2009 and November 2010 among postgraduate trainees in obstetrics-gynecology in 7 LMICs (Argentina, Brazil, Democratic Republic of the Congo, India, Philippines, South Africa, Thailand). Each training unit was randomized to an experimental clinically integrated course consisting of e-modules using the World Health Organization Reproductive Health Library (RHL) for learning activities and trainee assessments (31 clusters, 123 participants) or to a control self-directed EBM course incorporating the RHL (29 clusters, 81 participants). A facilitator with EBM teaching experience was available at all teaching units. Courses were administered for 8 weeks, with assessments at baseline and 4 weeks after course completion. The study was completed in 24 experimental clusters (98 participants) and 22 control clusters (68 participants).

After the trial, the experimental group had higher average scores in knowledge and skills. Although there was no difference in improvement for the overall score for educational environment, there was an associated average improvement in the domains of general relationships and support and EBM application opportunities.

“The associated improvements in educational environment suggest that EBM principles that are learned may become culturally embedded in the workplace,” the authors write.

(JAMA. 2012;308[21]:2218-2225. Available pre-embargo to the media at https://media.jamanetwork.com)

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Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact Kevin G. Volpp, M.D., Ph.D., call Jessica Mikulski at 215-349-8369 or email jessica.mikulski@uphs.upenn.edu

Kevin G. Volpp, M.D., Ph.D., of the Philadelphia Veterans Affairs Medical Center and University of Pennsylvania, Philadelphia, and colleagues conducted a study to determine whether a protected sleep period of 5 hours is feasible and effective in increasing the time slept by interns on extended duty overnight shifts.

In 2009, the Institute of Medicine (IOM) published a report on resident work hours and work schedules to improve patient safety that recommended a protected sleep period of 5 hours during any work shift longer than 16 hours to reduce the risk of fatigue-related errors when residents are in the hospital for prolonged duty periods of up to 30 hours. “The IOM report acknowledged that there was a paucity of data on optimizing duty hours for physicians in training but argued that the evidence on the hazards of fatigue-related performance errors in other professions likely extended to medicine,” according to background information in the article.

For the study, two randomized controlled trials were conducted in parallel: one at the Philadelphia Veterans Affairs Medical Center, the other at the Hospital of the University of Pennsylvania (2009-2010). Of the 106 interns and senior medical students who consented, 3 were not scheduled on any study rotations. Among the others, 44 worked at the VA center, 16 at the university hospital, and 43 at both. Twelve 4-week blocks were randomly assigned to either a standard intern schedule (extended duty overnight shifts of up to 30 hours; equivalent to 1,200 overnight intern shifts at each site), or a protected sleep period (protected time from 12:30 a.m. to 5:30 a.m. with handover of work cell phone; equivalent to 1,200 overnight intern shifts at each site). Participants were asked to wear wrist actigraphs (monitors changes in physical activity) and complete sleep diaries.

The researchers found that at the VA center, participants with protected sleep had an average 2.86 hours of sleep vs. 1.98 hours among those who did not have protected hours of sleep. At the university hospital, participants with protected sleep had an average 3.04 hours of sleep compared to 2.04 hours among those who did not have protected sleep. Participants with protected sleep were significantly less likely to have call nights with no sleep: 5.8 percent vs. 18.6 percent at the VA center and 5.9 percent vs. 14.2 percent at the university hospital. As gauged by a sleepiness scale, participants felt less sleepy after on-call nights in the intervention group.

“Although there is evidence that obtaining sleep (relative to no sleep) during prolonged duty helps reduce fatigue and that the amount of fatigue reduction increases with the amount of sleep, from this study we do not have evidence that this is also associated with improvements in patient outcomes. A rigorous comparative effectiveness analysis of protected sleep times vs. 16-hour shifts in improving intern alertness and cognitive function and patient outcomes could have a significant effect on policy. To the extent that protected sleep periods are feasible and improve alertness, they may provide a reasonable alternative to mandated shorter shifts,” the authors conclude.

(JAMA. 2012;308[21]:2208-2217. Available pre-embargo to the media at https://media.jamanetwork.com)

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, December 4 at this link.

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Embargoed for Release: 3 p.m. CT Tuesday, December 4, 2012

Media Advisory: To contact Brian P. Lucas, M.D., M.S., call Nancy Di Fiore at 312-942-5159 or email Nancy_DiFiore@rush.edu.

Brian P. Lucas, M.D., M.S., of the Cook County Health and Hospitals System and Rush Medical College, Chicago, and colleagues conducted a study to compare the effects of 2- vs. 4-week inpatient attending physician rotations on unplanned patient revisits (a measure to assess the effect on patients), attending evaluations by trainees, and attending propensity for burnout.

“Trainees learn inpatient medicine on the job, providing clinical care to patients as members of ward teams led by attending physicians. Although the structures of these ward teams vary by local educational heritage and hospital policy, a prevailing trait is that attending physicians are assigned to them for only 2 continuous weeks—a duration that is half of the previous standard,” according to background information in the article. Data are sparse on the effect of varying the duration of rotations.

The study included 62 attending physicians who staffed at least 6 weeks of inpatient service (8,892 patients whom they discharged), and the 147 house staff and 229 medical students who evaluated their performance. Participants were assigned to random sequences of 2- and 4-week rotations at a university-affiliated teaching hospital in academic year 2009.

Among the 8,892 patients, there were 2,437 unplanned revisits. The percentage of 30-day unplanned revisits for patients of attending physicians on 2-week rotations was 21.2 percent compared with 21.5 percent for 4-week rotations. Average length of hospital stay was not significantly different for the rotations. “Attending physicians were more likely to score lower in their ability to evaluate trainees after 2- vs. 4-week rotations by both house staff and medical students. They were less likely to report higher scores of both burnout severity (16 percent vs. 35 percent) and emotional exhaustion (19 percent vs. 37 percent) after 2- vs. 4-week rotations,” the authors write.

(JAMA. 2012;308[21]:2199-2207. Available pre-embargo to the media at https://media.jamanetwork.com)

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

Media Advisory: To contact Colin P. West, M.D., Ph.D., call Alyson Fleming at 507-284-5005 or email newsbureau@mayo.edu.

Colin P. West, M.D., Ph.D., and Denise M. Dupras, M.D., Ph.D., of Mayo Clinic, Rochester, Minn., conducted a study to evaluate career plans of internal medicine residents.

“General internists provide comprehensive and coordinated care for both acute and chronic diseases. General internists are expected to play an increasingly critical role in health care provision as the population ages, the burden of chronic disease grows, and health care reform targets coverage of tens of millions of currently uninsured patients,” according to background information in the article. “Current medical training models in the United States are unlikely to produce sufficient numbers of general internists and primary care physicians. Differences in general internal medicine (GIM) career plans between internal medicine residency program types and across resident demographics are not well understood.”

The researchers used an annual survey linked to the Internal Medicine In-Training Examination taken in October of 2009-2011 to evaluate career plans by training program, sex, and medical school location. Of 67,207 U.S. eligible categorical and primary care internal medicine residents, 57,087 (84.9 percent) completed and returned the survey. Demographic data provided by the National Board of Medical Examiners were available for 52,035 (77.4 percent) of these residents, of whom 51,390 (76.5 percent) responded to all survey items and an additional 645 (1.0 percent) responded to at least 1 survey item. Data were analyzed from the 16,781 third-year residents (32.2 percent) in this sample.

The authors found that a GIM career plan was reported by 3,605 graduating residents (21.5 percent). A total of 562 primary care program (39.6 percent) and 3,043 categorical (19.9 percent) residents reported GIM as their ultimate career plan. “Conversely, 10,008 categorical (65.3 percent) and 745 primary care program (52.5 percent) residents reported a subspecialty career plan. GIM career plans were reported more frequently by women than men. U.S. medical graduates were slightly more likely to report GIM career plans than international medical graduates. Within primary care programs, U.S. medical graduates were much more likely to report GIM career plans than international medical graduates.”

“This study of a large national sample of internal medicine residents confirms that general medicine remains a less common career plan overall than subspecialty medicine. Combined with the fact that only a small minority of medical students express interest in general medicine and primary care careers, the small number of internal medicine residents reporting plans for generalist careers means a very limited number of generalists can be expected to enter practice each year.”

(JAMA. 2012;308[21]:2241-2247. Available pre-embargo to the media at https://media.jamanetwork.com)

Please Note: An author podcast on this study will be available post-embargo on the JAMA website.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 27, 2012

Earnings of U.S. Physicians Grow Less Than Other Health Professionals  

“Understanding trends in physician earnings is important given health care cost growth and proposed Medicare physician fee reductions,” writes Seth A. Seabury, Ph.D., of the RAND Corporation, Santa Monica, Calif., and colleagues. National surveys find that annual physician incomes decreased between 1995 and 2003. Other surveys suggest that physician incomes increased only slightly since 2004. “However, little is known about how growth in physician earnings compares with other health professionals. Comparing physicians and other health professionals is necessary to assess whether physician labor earnings have outpaced or lagged behind earnings growth of other workers in the health care sector.”

As reported in a Research Letter, the authors estimated annual earnings and hourly wages of physicians and other health professionals from the Current Population Survey (CPS), a nationally representative monthly survey of approximately 60,000 households, and examined growth rates from 1987-1990 to 1996-2000 and from 1996-2000 to 2006-2010. This sample included 30,556 respondents across all years who reported working as health professionals, including 6,258 physicians (20.5 percent).

The researchers found that physician earnings fluctuated over the study period. During 1987-1990, median (midpoint) earnings for physicians were $143,963 compared with $157,751 during 2006-2010 ($13,788 increase or growth of 9.6 percent). Other health professionals experienced larger growth in earnings from 1987-1990 to 2006-2010 (e.g., pharmacists earnings increased by $30,938 or 44.0 percent). From 1996-2000 to 2006-2010, there was no significant growth in adjusted earnings for physicians (-1.6 percent). Adjusted earnings continued to increase for other health professionals from 1996-2000 to 2006-2010 (e.g., pharmacists, 34.4 percent). Similar patterns were noted for wages.

“Despite attention paid to higher earnings of physicians in the United States compared with other countries, physician earnings grew less than those of other health professionals in the last 15 years. Possible explanations include managed care growth, Medicaid payment cuts, sluggish Medicare payment growth, or bargaining by insurance companies. Despite lack of recent growth, physician earnings remain higher than other occupations.”

(JAMA. 2012;308[20]:2083-2085. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Medical Documentation in the Electronic Era

C. Jason Wang, M.D., Ph.D., of Stanford University, Stanford, Calif., examines the challenges presented by the implementation and use of electronic health records for patient-centered care.

“The current era of electronic communication has both benefits and perils. Electronic health records can serve as a platform with personal health records for coordinated patient-centered care by allowing clinicians to communicate quickly with one another and providing patients critical information about their own health. To fully realize these benefits, ‘search’ and ‘retrieval’ mechanisms must be supported by simple, unambiguous, standardized language. Electronic health records also must include mechanisms to promote synthesis of clinical data to avoid information overload. However, by relying on the GPS (global positioning system) mentality that ‘the computer will help me find it,’ clinicians will gradually be relegated to technicians.”

(JAMA. 2012;308[20]:2091-2092. Available pre-embargo to the media at https://media.jamanetwork.com)

Toward a Harmonized and Centralized Conflict of Interest Disclosure – Progress From an IOM Initiative

In this Viewpoint, Allen S. Lichter, M.D., of the American Society of Clinical Oncology, Alexandria, Va., and Ross McKinney, M.D., of Duke University School of Medicine, Durham, N.C., discuss the need and development of a “harmonized, centralized [conflict of interest] disclosure system to be created for the benefit of everyone who must produce or receive disclosure information.”

“Such a system can be designed and implemented as one element in a process to help ensure that research can progress in a trusted, transparent fashion, thereby increasing trust among the public and health care professionals in new medical products that are brought to the benefit of patients.”

(JAMA. 2012;308[20]:2093-2094. Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 27, 2012

Media Advisory: To contact Charlotte Merie, M.D., email c.merie@mail.dk. To contact editorial co-author Shamir R. Mehta, M.D., M.Sc., call Veronica McGuire at 905-525-9140, ext. 22169, or email vmcguir@mcmaster.ca.

CHICAGO – Although current guidelines recommend 3 months of anticoagulation treatment after bioprosthetic aortic valve replacement surgery, a study that included more than 4,000 patients found that patients who had warfarin therapy continued between 3 and 6 months after surgery had a lower rate of cardiovascular death, according to a study in the November 28 issue of JAMA.

“Biological prostheses are preferred to mechanical valves for aortic valve replacement (AVR) surgery in elderly patients older than 65 years because of shorter life expectancy and lack of a need to use anticoagulation treatment in the long-term. Especially in these patients, the tradeoff between thromboembolic complications due to the valve implant and bleeding events as adverse effects from anticoagulation therapy must be balanced. Nevertheless, appropriate duration of anticoagulation treatment postoperatively is yet to be established because the risk of complications when the treatment is discontinued is unknown,” according to background information in the article. The current recommendation of 3 months of warfarin treatment after bioprosthetic AVR surgery is primarily based on results from 1 retrospective study with a limited number of events.

Charlotte Merie, M.D., of the Copenhagen University Hospital Gentofte, Copenhagen, Denmark and colleagues investigated whether discontinuation of warfarin treatment within prespecified periods after bioprosthetic AVR surgery was associated with increased risk of thromboembolic complications, cardiovascular death, and bleeding incidents. Through a search in the Danish National Patient Registry, 4,075 patients were identified who had bioprosthetic AVR surgery performed between January 1997 and December 2009. The researchers determined the incidence rate ratios (IRRs) of strokes, thromboembolic events, cardiovascular deaths, and bleeding incidents by discontinuing warfarin as opposed to continued treatment at 30 to 89 days, 90 to 179 days, 180 to 364 days, 365 to 729 days, and at least 730 days after surgery. Average age of the patients was 75 years; 41 percent were women.

Overall, 361 patients (8.9 percent) experienced a stroke, 615 (15.1 percent) had a thromboembolic event, and 364 (8.9 percent) encountered a bleeding incident after the date of surgery. During the observation period, 1,156 patients (28.4 percent) died, with 879 (76.0 percent) of these deaths related to cardiovascular disease. The IRRs for patients not treated with warfarin compared with those treated with warfarin were 2.46 for stroke; 2.93 for thromboembolic events; 2.32 for bleeding incidents; and 7.61for cardiovascular deaths within 30 to 89 days after surgery; and 3.51 for cardiovascular deaths within 90 to 179 days after surgery.

“Our study demonstrates that discontinuing warfarin therapy within the first 3 months after surgery is associated with a significant increase in the risk of stroke, thromboembolic complications, and cardiovascular death. The novelty of our study is the finding that discontinuing warfarin therapy within 90 to 179 days after surgery is associated with a significant increase in the risk of cardiovascular death,” the authors write.

“International guidelines on anticoagulation after a bioprosthetic AVR have been written with limited data on the appropriate duration of warfarin treatment after surgery. Consequently, our study challenges current guidelines on the duration of antithrombotic treatment after AVR surgery with biological valves by presenting results suggesting that these patients will gain from an additional 3 months of warfarin treatment in terms of reduced cardiovascular death without risking a significant increase in bleeding events.”

(JAMA. 2012;308(20):2097-2107; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by the Research Fund of the Department of Cardiology at Copenhagen University Hospital Gentofte, Gentofte, Denmark. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Warfarin After Bioprosthetic Aortic Valve Implantation

Shamir R. Mehta, M.D., M.Sc., and Jeffrey I. Weitz, M.D., of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, comment on the findings of this study in an accompanying editorial.

“Will the results of this study change practice in patients undergoing bioprosthetic aortic valve replacement? Should all of these patients receive warfarin for 3 months, or even for 6 months, as the authors suggest? Although there are limitations to this study, the answer to both of these questions is yes. This study shows that the rates of stroke and thromboembolic events in the first 6 months after bioprosthetic aortic valve replacement are substantial among patients not treated with warfarin. Use of warfarin was associated with a reduction in this risk and a reduction in cardiovascular mortality; these benefits are difficult to ignore.”

(JAMA. 2012;308(20):2147-2148; 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. Mehta reported serving as a consultant for AstraZeneca, Eli Lilly, and Sanofi. Dr. Weitz reported serving as a consultant for Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 27, 2012

Media Advisory: To contact Lara K. Misegades, Ph.D., M.S., call Alison Patti at 404-639-3286 or email APatti@cdc.gov. To contact editorial co-author Eugene D. Shapiro, M.D., call Karen Peart at 203-432-1326 or email karen.peart@yale.edu.

CHICAGO – In an examination of cases of childhood pertussis in California, researchers found that children with pertussis had lower odds of having received all 5 doses of the diphtheria, tetanus, and acellular pertussis vaccine (DTaP) vaccine series; however the odds increased as the time since last DTaP dose lengthened, which is consistent with a progressive decrease in estimated vaccine effectiveness each year after the final dose of DTaP vaccine, according to a study in the November 28 issue of JAMA.

“Pertussis remains a poorly controlled vaccine-preventable disease in the United States, despite a well-established childhood vaccination program and high coverage. Although infants have substantially higher rates of pertussis compared with other age groups, data from the National Notifiable Diseases Surveillance System reflect a recent increase in the number of reported pertussis cases among children aged 7 to 10 years,” according to background information in the article. “Recent studies have demonstrated waning protection following the current 5-dose DTaP schedule, but no study, to our knowledge, has compared fully vaccinated with unvaccinated children to estimate the durability of protection afforded by the childhood series.”

Lara K. Misegades, Ph.D., M.S., of the Centers for Disease Control and Prevention, Atlanta, and colleagues conducted a study to evaluate the association between pertussis and receipt of 5 DTaP doses by time since the fifth DTaP dose in 15 California counties. Cases (n = 682) were all suspected, probable, and confirmed pertussis cases among children ages 4 to 10 years reported from January through December 14, 2010; controls (n = 2,016) were children in the same age group who received care from the clinicians reporting the cases. Three controls were selected per case. Vaccination histories were obtained from medical records and immunization registries.

Cases were more likely than controls to be unvaccinated (7.8 percent vs. 0.9 percent), female and older (the median [midpoint] ages of cases and controls were 9 and 7 years, respectively). Compared with controls, children with pertussis had a 89 percent lower odds of having received all 5 doses of DTaP. When children were categorized by time since completion of the series, using an unvaccinated reference group, children with pertussis compared with controls were less likely to have received their fifth dose within the prior 12 months (19 [2.8 percent] vs. 354 [17.6 percent]; estimated vaccine effectiveness [VE], 98.1 percent). This association was evident with longer time since vaccination, with odds ratios increasing with time since the fifth dose. At 60 months or longer (range, 60-83 months; n = 231 cases [33.9 percent] and n = 288 controls [14.3 percent]), the estimated VE was 71.2 percent. The estimated relative decline in VE was 27.4 percent from less than 12 months to 60 months or longer since fifth DTaP dose. Accordingly, the estimated VE declined each year after receipt of the fifth dose of DTaP.

“The increasing incidence of pertussis, changing epidemiology, and demonstrated decline in the estimated DTaP VE over time have raised concerns about the current U.S. pertussis vaccine program and may prompt consideration of alternative schedules,” the authors write. “Ultimately, improved control of pertussis may require a vaccine that provides longer duration of protection or differently affects transmission in the community.”

(JAMA. 2012;308(20):2126-2132; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, November 27 at this link.

Editorial: Acellular Vaccines and Resurgence of Pertussis

“Strategies to use the current vaccines to provide optimal benefit need to be implemented,” writes Eugene D. Shapiro, M.D., of the Yale University School of Medicine and Yale Graduate School of Arts and Sciences, New Haven, Conn., in an accompanying editorial.

“The most important consideration is to try to protect infants, who have the most morbidity and mortality from pertussis. The highest rates both of hospitalizations for and of deaths from pertussis occur in children younger than 2 months. Immunization of all pregnant women and of all household and day-care contacts (both adults and children) of children younger than 1 year is one important strategy that may help alleviate this problem. Public health authorities will need to assess the feasibility and safety of different schedules for administering currently available vaccines, including the possibility of shorter periods between primary and booster doses (more frequent administration of tetanus toxoid may be associated with more severe local adverse reactions).”

(JAMA. 2012;308(20):2149-2150; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This publication was made possible in part by support from CTSA grants from the National Center for Research Resources and the National Center for Advancing Translational Science, components of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 27, 2012

Media Advisory: To contact Adrian F. Hernandez, M.D., M.H.S., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu. To contact Lars H. Lund, M.D., Ph.D., email lars.lund@alumni.duke.edu. To contact editorial author James C. Fang, M.D., call Mike Ferrari at 216-844-7239 or email Mike.Ferrari@uhhospitals.org.

CHICAGO – An analysis of two heart failure therapies finds differing outcomes regarding improvement in survival, according to two studies appearing in the November 28 issue of JAMA.

In one study, Adrian F. Hernandez, M.D., M.H.S., of the Duke Clinical Research Institute, Durham, N.C., and colleagues examined the clinical effectiveness of aldosterone antagonist therapy and associations with long-term outcomes of older patients discharged from a hospitalization for heart failure.

“Aldosterone antagonist therapy [a diuretic drug] for heart failure and reduced ejection fraction [a measure of how well the left ventricle of the heart pumps with each contraction] has been highly efficacious in randomized trials. However, questions remain regarding the effectiveness and safety of the therapy in clinical practice,” according to background information in the article.

The researchers examined outcomes of eligible patients hospitalized with heart failure and reduced ejection fraction using clinical registry data linked to Medicare claims from 2005 through 2010. The primary outcomes measured for the study were all-cause mortality, cardiovascular readmission, and heart failure readmission at 3 years, and readmission associated with hyperkalemia (higher than normal levels of potassium in the circulating blood) at 30 days and 1 year.

Of the 5,887 patients (average age, 78 years) who met the inclusion criteria from 246 hospitals, 1,070 (18.2 percent) received a prescription for an aldosterone antagonist at hospital discharge. The researchers found that rates of all-cause mortality (49.9 percent vs. 51.2 percent) and cardiovascular readmission (63.8 percent vs. 63.9 percent) were similar between the treatment groups at 3 years. The cumulative incidence rates of arrhythmia (5.4 percent vs. 3.9 percent) and elective readmission for an arrhythmia control device (6.5 percent vs. 4.2 percent) were higher for the treated group. Analysis of the data indicated that there were no significant differences in mortality and cardiovascular readmission.

The authors also found that the cumulative incidence of the first heart failure readmission was significantly lower in the treated group (38.7 percent vs. 44.9 percent). The hyperkalemia readmission rates at 30 days (2.9 percent vs. 1.2 percent) and 1 year (8.9 percent vs. 6.3 percent) were higher in the treated group; however, hyperkalemia was seldom the primary diagnosis for these readmissions, and the absolute increase in hyperkalemia as a primary diagnosis was small.

The authors add that a potential explanation for their findings is that aldosterone antagonists have limited effectiveness regarding mortality in real-world settings among older patients. “One potential reason for limited effectiveness may be a lack of adherence to or persistence with therapy. … Our findings highlight the importance of conducting clinical trials that can be easily generalized to real-world practice and in which the most vulnerable patient groups are well represented.”

(JAMA. 2012;308(20):2097-2107; 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.

Use of ACE Inhibitors, ARB’s, Associated With Improved Survival Among Certain Patients With Heart Failure

In another study, Lars H. Lund, M.D., Ph.D., of the Karolinska Institutet, Stockholm, Sweden, and colleagues conducted a study to examine whether renin-angiotensin system (RAS) antagonists (i.e., angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs] are associated with reduced mortality in heart failure patients with preserved ejection fraction.

“Up to half of patients with heart failure have normal or near-normal ejection fraction, termed heart failure with preserved ejection fraction (HFPEF) or diastolic heart failure. The mortality in HFPEF may be as high as in heart failure with reduced ejection fraction (HFREF) or systolic heart failure, but there is no proven therapy,” according to background information in the article.

The study included 41,791 patients in the Swedish Heart Failure Registry, from 64 hospitals and 84 outpatient clinics between 2000 and 2011. Of these, 16,216 patients with HFPEF (ejection fraction of 40 percent or greater; average age, 75 years; 46 percent women) were either treated (n = 12,543) or not treated (n = 3,673) with RAS antagonists. Analyses was conducted of the data to determine the association between use of RAS antagonists and all-cause mortality, with use of a matched cohort. The researchers included 20,111 patients with ejection fraction of less than 40 percent for the HFREF consistency analysis.

In the overall HFPEF group, crude 1-year survival was 86 percent for patients receiving RAS antagonists vs. 69 percent for patients not receiving RAS antagonists; and 5-year survival was 55 percent vs. 32 percent, respectively. In the matched HFPEF cohort, 1-year survival was 77 percent for treated patients vs. 72 percent for untreated patients. Five-year survival was 36 percent vs. 34 percent, respectively.

“There is currently no consensus on the use of RAS antagonists in patients with HFPEF. In our study, use of RAS antagonists was associated with reduced all-cause mortality in a broad unselected population of patients with HFPEF. Our results together with the signal toward benefit in randomized controlled trials suggest that RAS antagonists may be beneficial in patients with HFPEF, but this should be confirmed in an appropriately powered randomized trial,” the authors conclude.

(JAMA. 2012;308(20):2108-2117; 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: Heart Failure Therapy – What Should Clinicians Believe?

In an accompanying editorial, James C. Fang, M.D., of University Hospitals Case Medical Center, Cleveland, examines the question of what physicians should conclude from these 2 observational studies that would appear to contradict the clinical trial evidence.

“If all of the evidence is carefully considered in its totality, it would be sound to conclude that (1) renin-angiotensin system antagonists are reasonable agents to control hypertension in heart failure with preserved ejection fraction, and (2) aldosterone antagonists are effective drugs in heart failure with reduced ejection fraction but should be used carefully and selectively. Although clinical trials should remain the gold standard for testing hypotheses, observational studies bridge the gap from the scientific rigor of clinical trials to real-world experience. Clinical trials are a reminder of the rigor of medicine as a science; observational studies are a reminder that medicine is still an art.”

(JAMA. 2012;308(20):2144-2146; 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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