EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 10, 2015

Media Advisory: To contact Amar Rangan, F.R.C.S. (Tr. & Orth.), email amar.rangan@stees.nhs.uk.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1629

No Significant Difference in Outcomes Found for Surgical vs Non-Surgical Treatment of Displaced Fracture of Upper Arm

Among patients with a displaced fracture in the upper arm near the shoulder (proximal humeral), there was no significant difference between surgical treatment and nonsurgical treatment in patient-reported outcomes over two years following the fracture, results that do not support the trend of increased surgery for patients with this type of fracture, according to a study in the March 10 issue of JAMA.

Proximal humeral fractures account for 5 percent to 6 percent of all adult fractures; an estimated 706,000 occurred worldwide in 2000. The majority occur in people older than 65 years, and the age-specific incidence of these fractures is increasing. Approximately half of these fractures are displaced, the majority of which involve the surgical neck (located on the upper portion of the humerus). Surgical treatment is being increasingly used, contributing to increased treatment costs for upper limb fractures. A review of results from randomized clinical trials found insufficient evidence to conclude whether surgical intervention produces consistently better outcomes than nonsurgical treatment, according to background information in the article.

Amar Rangan, F.R.C.S. (Tr. & Orth.), of James Cook University Hospital, Middlesbrough, England, and colleagues randomly assigned 250 patients (average age, 66 years) who sustained a displaced fracture of the proximal humerus involving the surgical neck to surgical treatment (fracture fixation or humeral head replacement) or nonsurgical treatment (sling immobilization). Standardized outpatient and community-based rehabilitation was provided to both groups. Patients were followed up for 2 years and 215 had complete follow-up data. The data for 231 patients (114 in surgical group and 117 in nonsurgical group) were included in the primary analysis.

The researchers found that there were no statistically or clinically significant differences between surgical and non-surgical treatment either overall or at individual time points (at 6, 12, and 24 months) for the Oxford Shoulder Score (OSS), a shoulder-specific outcome measure that provides a total score based on the patient’s subjective assessment of pain and function. In addition, there were no clinically or significant differences on measures of health-related quality of life, complications related to surgery or shoulder fracture, complications requiring secondary surgery or treatment, and death.

Ten medical complications (2 cardiovascular events, 2 respiratory events, 2 gastrointestinal events, and 4 others) occurred in the surgical group during the postoperative hospital stay.

“These results do not support the trend of increased surgery for patients with displaced fractures of the proximal humerus,” the authors conclude.

(doi:10.1001/jama.2015.1629; 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: 11 A.M. (ET) TUESDAY, MARCH 10, 2015

Media Advisory: To contact John J. P. Kastelein, M.D., Ph.D., email j.j.kastelein@amc.nl. To contact editorial co-author David Preiss, M.D., Ph.D., email david.preiss@glasgow.ac.uk.

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Lower Prevalence of Diabetes Found Among Patients With Inherited High Cholesterol Disorder

The prevalence of type 2 diabetes among 25,000 patients with familial hypercholesterolemia (a genetic disorder characterized by high low-density lipoprotein [LDL] cholesterol levels) was significantly lower than among unaffected relatives, with the prevalence varying by the type of gene mutation, according to a study in the March 10 issue of JAMA.

Statins have been associated with increased risk for diabetes, but the cause for this is not clear. One theory is that statins increase expression of LDL receptors and increase cholesterol uptake into cells including the pancreas, which could cause pancreatic dysfunction. Familial hypercholesterolemia causes decreased LDL transport into cells. Researchers have hypothesized that with familial hypercholesterolemia, decreased pancreatic LDL transport would lessen cell death and ultimately lead to lower rates of diabetes.

John J. P. Kastelein, M.D., Ph.D., of the Academic Medical Centre, Amsterdam, the Netherlands, and colleagues assessed the prevalence of type 2 diabetes between patients with familial hypercholesterolemia and their unaffected relatives. The study included all individuals (n = 63,320) who underwent DNA testing for familial hypercholesterolemia in the national Dutch screening program between 1994 and 2014.

The prevalence of type 2 diabetes was 1.75 percent in familial hypercholesterolemia patients (n = 440/25,137) vs 2.93 percent in unaffected relatives (n = 1,119/38,183), with adjusted figures indicating that patients with familial hypercholesterolemia had a 51 percent lower odds of having type 2 diabetes. Prevalence varied by the type of gene mutation. The researchers observed an inverse dose-response relationship between the severity of the familial hypercholesterolemia causing mutation and prevalence of type 2 diabetes.

“The small absolute difference in prevalence of type 2 diabetes between patients with familial hypercholesterolemia and unaffected relatives will not have a major influence on individual risk for type 2 diabetes. However, the substantial relative difference of 50 percent, together with previous findings, might suggest an effect of intracellular cholesterol metabolism on pancreatic beta cell function. Nevertheless, a plethora of pathways contribute to development of type 2 diabetes, and therefore, the mechanism we discuss here can only be 1 part of the pathogenesis of this highly complex disease,” the authors write.

“If these findings are confirmed in longitudinal studies, they might provide support for development of new approaches to the prevention and treatment of type 2 diabetes by improving function and survival of pancreatic beta cells.”

(doi:10.1001/jama.2015.1206; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Does the LDL Receptor Play a Role in the Risk of Developing Type 2 Diabetes?

David Preiss, M.D., Ph.D., and Naveed Sattar, M.D., Ph.D., of the University of Glasgow, United Kingdom, comment on the findings of this study in an accompanying editorial.

“What are the implications of these findings? This report adds to the growing literature of a complex interplay between lipids, glycemia, and adiposity, in which statins and other lipid-modifying agents appear to affect diabetes risk. The study also provides mechanistic insight into the potential roles of the LDL receptor and intracellular cholesterol accumulation. From a clinical perspective, the findings should allay any concerns about the potential diabetogenic effect of statins when treating patients with familial hypercholesterolemia from childhood or young adulthood given that these patients appear to be at a low risk for diabetes.”

“The study by Besseling et al contributes important evidence to strengthen the previously observed relationship between statin therapy and diabetes risk. However, this does not, and should not, alter guidance regarding the use of these important medications in patients at elevated cardiovascular risk given the clear overall benefit of statin therapy.”

(doi:10.1001/jama.2015.1275; 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: 11 A.M. (ET) TUESDAY, MARCH 10, 2015

Media Advisory: To contact David R. Holmes Jr., M.D., email Traci Klein at Klein.Traci@mayo.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1474

Study Examines Outcomes for Patients One Year After Transcatheter Aortic Valve Replacement

In an analysis of outcomes of about 12,000 patients who underwent transcatheter aortic valve replacement, death rate after one year was nearly one in four; of those alive at 12 months, almost half had not been rehospitalized and approximately 25 percent had only one hospitalization, according to a study in the March 10 issue of JAMA.

Following U.S. Food and Drug Administration approval in 2011, transcatheter aortic valve replacement (TAVR) has been used with increasing frequency for the treatment of severe aortic stenosis in patients who have high risks with conventional surgical AVR. TAVR, a less invasive procedure than open heart-valve surgery, involves replacing the aortic valve using a catheter inserted in the patient’s groin. Introducing new medical devices into routine practice raises concerns because patients and outcomes may differ from those in clinical trials, according to background information in the article.

David R. Holmes Jr., M.D., of Mayo Clinic, Rochester, Minn., and colleagues examined 1-year outcomes for TAVR patients who had 30-day outcomes previously reported. Data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry were linked with patient-specific Centers for Medicare & Medicaid Services administrative claims data. The authors identified 12,182 patients with linked CMS data that underwent TAVR procedures at 299 U.S. hospitals from November 2011 through June 2013; the end of the follow-up period was June 30, 2014.

The median age of patients was 84 years and 52 percent were women. Following the TAVR procedure, 60 percent were discharged to home and the 30-day mortality rate was 7.0 percent. By 1 year, the overall mortality rate was 24 percent, the stroke rate was 4.1 percent, and the rate of the composite outcome of mortality and stroke was 26 percent. In addition, 47 percent of patients who remained alive at 12 months had not been rehospitalized, 24 percent were rehospitalized once and 12.5 percent were rehospitalized twice. Readmission for a composite of stroke, heart failure, or repeat aortic valve intervention occurred in 19 percent of patients.

Characteristics significantly associated with 1-year mortality included advanced age, male sex, end-stage renal disease and severe chronic obstructive pulmonary disease. Compared with men, women had a higher risk of stroke.

The authors note that the rate of l-year mortality reported with this registry is similar to that in other comprehensive reports. “Although this study includes only patients considered to have high risks with AVR, the majority of this mortality does not represent periprocedural complications, as 30-day mortality was only 7.0 percent. As such, this makes it imperative to focus on better prediction of the overall risks and benefits of the procedure, particularly given the existing comorbidities of the group of patients being considered for TAVR.”

They add that it may be possible to identify patients who may not benefit from this procedure and who should be counseled accordingly.

“Although 3 randomized trials and multiple single-center and multicenter registry studies have been published, the profile and longer-term outcomes of U.S. TAVR cases in routine clinical practice remains limited,” the researchers write. “These findings should be helpful in discussions with patients undergoing TAVR.”

(doi:10.1001/jama.2015.1474; 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: 11 A.M. (ET) TUESDAY, MARCH 10, 2015

Media Advisory: To contact Hallie C. Prescott, M.D., M.Sc., email Kara Gavin at kegavin@med.umich.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1410

Hospital Readmissions Following Severe Sepsis Often Preventable

In an analysis of about 2,600 hospitalizations for severe sepsis, readmissions within 90 days were common, and approximately 40 percent occurred for diagnoses that could potentially be prevented or treated early to avoid hospitalization, according to a study in the March 10 issue of JAMA.

Patients are frequently rehospitalized within 90 days after having severe sepsis. Little is known, however, about the reasons for readmission and whether they can be reduced. Hallie C. Prescott, M.D., M.Sc., of the University of Michigan, Ann Arbor, and colleagues examined the most common readmission diagnoses after hospitalization for severe sepsis, the extent to which readmissions may be potentially preventable by posthospitalization ambulatory care, and whether the pattern of readmission diagnoses differs compared with that of other acute medical conditions.

The study included participants in the nationally representative U.S. Health and Retirement Study, a sample of households with adults 50 years of age or older, that is linked to Medicare claims (1998-2010). For the analysis, the researchers identified 2,617 hospitalizations for severe sepsis, which were matched to hospitalizations for other acute medical conditions. To gauge what proportion of rehospitalizations may be potentially preventable, ambulatory care sensitive conditions (ACSCs) were measured, which are diagnoses for which effective outpatient care may reduce hospitalization rates.

There were 1,115 severe sepsis survivors (42.6 percent) rehospitalized within 90 days. The 10 most common readmission diagnoses following severe sepsis included several ACSCs (e.g., heart failure, pneumonia, chronic obstructive pulmonary disease exacerbation, and urinary tract infection). Collectively, ACSCs accounted for 22 percent of 90-day readmissions.

Readmissions for a primary diagnosis of infection (sepsis, pneumonia, urinary tract, and skin or soft tissue infection) occurred in 12 percent of severe sepsis survivors compared with 8.0 percent of matched acute medical conditions. Readmissions for ACSCs were more common after severe sepsis (22 percent) vs matched  acute conditions (19 percent) and accounted for a greater proportion of all 90-day readmissions (42 percent vs 37 percent, respectively).

“The high prevalence and concentration of specific diagnoses during the early postdischarge period suggest that further study is warranted of the feasibility and potential benefit of postdischarge interventions tailored to patients’ personalized risk for a limited number of common conditions,” the authors write.

(doi:10.1001/jama.2015.1410; 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: 11 A.M. (ET) THURSDAY, MARCH 5, 2015

Media Advisory: To contact Mark J. Mulligan, M.D., email Vincent Dollard at vdollar@emory.edu. To contact editorial author Thomas W. Geisbert, Ph.D., email Raul Reyes at rareyes@utmb.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1995

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Researchers Examine Effect of Experimental Ebola Vaccine After High-Risk Exposure

A physician who received an experimental Ebola vaccine after experiencing a needle stick while working in an Ebola treatment unit in Sierra Leone did not develop Ebola virus infection, and there was strong Ebola-specific immune responses after the vaccination, although because of its limited use to date, the effectiveness and safety of the vaccine is not certain, according to a study appearing in JAMA.

On September 26, 2014, a 44-year-old physician from the United States caring for patients in an Ebola treatment unit in Sierra Leone experienced an accidental needle stick, which was estimated to pose a significant risk of infection. Given the concern about potentially lethal Ebola virus disease, the patient was offered, and provided his consent for, postexposure vaccination with an experimental vaccine, VSVΔG-ZEBOV (which has entered a clinical trial for the prevention of Ebola in West Africa). Forty-three hours after exposure, the patient boarded a jet for medical evacuation to the United States and received the vaccine intramuscularly.

Mark J. Mulligan, M.D., of Emory University, Atlanta, and colleagues assessed the patient’s response to the vaccine. The patient developed malaise, nausea and fever 12 hours after the vaccination while on the transport jet. A physical exam in the U.S. approximately 14 hours postvaccination (performed at the National Institutes of Health Special Clinical Studies Unit) indicated the patient was in mild to moderate distress from fever, nausea, malaise, myalgia (muscle pain), and chills. On day 2, the fever declined; however, severe symptoms continued along with mild nausea and arthralgia (joint pain). On days 3 through 5, the patient experienced resolution of symptoms and laboratory abnormalities. By day 7, he was completely asymptomatic.

Blood tests detected Ebola virus glycoprotein-specific antibodies and strong Ebola-specific adaptive immune responses. “The clinical syndrome and laboratory evidence were consistent with vaccination response and no evidence of Ebola virus infection was detected,” the authors write.

“In the current patient, a self-limited, moderate to severe clinical syndrome began at 12 hours postvaccination. Future decision making about using this experimental vaccine for postexposure vaccination will need to balance the risks of harm from the vaccine or possible Ebola infection (both were unknowns at the time of the patient’s exposure) against the possible benefit of vaccination (also unknown at the time of the patient’s treatment).”

“Neither the safety nor the efficacy of the VSVΔG-ZEBOV vaccine for postexposure protection can be learned from this single case, but the clinical and laboratory parameters are informative at a time when there is a need to garner all information available on Ebola vaccines.”

(doi:10.1001/jama.2015.1995; 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: Emergency Treatment for Exposure to Ebola Virus

Thomas W. Geisbert, Ph.D., of the University of Texas Medical Branch, Galveston, writes in an accompanying editorial that the most effective way to prevent and control outbreaks and to protect high-risk personnel, including medical staff and laboratory workers, is through the use of preventive vaccines along with use of appropriate personal protective equipment.

“Historically, there has been a small global market for developing an Ebola virus vaccine and there was no financial interest for large pharmaceutical companies to become involved. The current epidemic has spurred substantial scientific activity to develop vaccines.”

“Although it is not possible to know with absolute certainty whether the first-generation VSVΔG-ZEBOV vaccine used to treat the potential high-risk exposure had any influence on survival of the exposed patient in the report by Lai et al, this incident serves as an example of how important it is to have safe and effective countermeasures available in sufficient quantities that can be rapidly deployed for emergency use for both medical workers and affected populations.”

(doi:10.1001/jama.2015. 2057; 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: 11 A.M. (ET) TUESDAY, MARCH 3, 2015

Media Advisory: To contact Hari R. Mallidi, M.D., email Julia Parsons at Julia.parsons@bcm.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1175

Study Examines Outcomes of Lung Transplantations Since Implementation of Need-Based Allocation System

Since implementation of a medical need-based allocation system of donor lungs in 2005, double-lung transplantation has been associated with better graft survival than single-lung transplantation in patients with idiopathic pulmonary fibrosis (IPF); at 5 years, there has been no survival difference between single- and double-lung transplant recipients in patients with chronic obstructive pulmonary disease (COPD), according to a study in the March 3 issue of JAMA.

Before 2005, lung transplant allocation in the United States was based on accumulated time on the lung transplant waiting list after matching for ABO blood type. In response to increasing wait times, the U.S. Department of Health and Human Services mandated the development of an allocation system based on medical need instead of waiting time. The resulting system—the Lung Allocation Score (LAS) organ allocation algorithm—was implemented in May 2005. A patient’s LAS is based on risk factors associated with either wait list or post-transplantation mortality. The use of the LAS has brought with it a change in the demographics of single- and double-lung transplant recipients; what effect this may have on post-transplantation outcomes has not been assessed, according to background information in the article.

Hari R. Mallidi, M.D., of the Baylor College of Medicine, Houston, and colleagues reviewed data from the United Network for Organ Sharing thoracic registry to summarize the contemporary demographics and outcomes in adults with IPF or COPD who underwent single- or double­ lung transplantation in the United States between May 2005 and December 2012.

Since May 2005, the researchers identified 4,134 patients with IPF (of whom 2,010 underwent single-lung and 2,124 underwent double-lung transplantation) and 3,174 patients with COPD, of whom 1,299 underwent single-lung and 1,875 underwent double-lung transplantation. The median follow-up time was 23.5 months. Of the patients with IPF, 33.4 percent died and 2.8 percent underwent retransplantation; of the patients with COPD, 34.0 percent died and 1.9 percent underwent retransplantation. Further analysis indicated that double-lung transplants were associated with better graft survival in patients with IPF (adjusted median survival, 65.2 months vs 50.4 months) but not in patients with COPD (adjusted median survival, 67.7 months vs 64.0 months).

“The interaction between diagnosis (COPD or IPF) and treatment type (single- and double-lung transplantation) was significant, supporting the finding that the benefit of double-lung transplantation may differ by diagnosis. Like­wise, prognostic models designed to account for the time­varying effect of double-lung transplantation (compared with single-lung transplantation) showed that double-lung transplantation was significantly associated with graft survival among patients with IPF but not among patients with COPD,” the authors write.

Other variables associated with graft failure included age, excessively high or low body mass index, worse functional status, poor 6-minute walk test performance, pulmonary hypertension (in patients with COPD), and donor age. Variables associated with graft survival included undergoing transplantation at a high-performing center, undergoing transplantation at a moderate- or high­ volume transplant center, receiving a locally allocated organ, and donor-recipient race match (in patients with IPF).

(doi:10.1001/jama.2015.1175; 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: 11 A.M. (ET) TUESDAY, MARCH 3, 2015

Media Advisory: To contact Julie M. Zito, Ph.D., email Karen Robinson at karobinson@umaryland.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.0763

Most States Have Implemented Prior Authorization Policies for Atypical Antipsychotic Prescribing To Children

With a concern about inappropriate prescribing of antipsychotic medications to children, 31 states have implemented prior authorization policies for atypical antipsychotic prescribing, mostly within the past 5 years, and with most states applying their policies to children younger than 7 years of age, according to a study in the March 3 issue of JAMA.

Over the past two decades, antipsychotic prescribing to youth, almost exclusively comprising atypical antipsychotic medications, was estimated to have increased from 0.16 percent in 1993- 1998 to 1.07 percent in 2005-2009 in office-based physician visits. Antipsychotic use is also 5-fold greater in Medicaid-insured youth than in privately insured youth, and occurs mostly for indications not approved by the U.S. Food and Drug Administration (FDA). In light of antipsychotic treatment-emergent cardiometabolic adverse events, several government reports called for efforts to improve pediatric psychotropic medication oversight in state Medicaid agencies. Such efforts have included age­restricted prior authorization policies, which require clinicians to obtain preapproval from Medicaid agencies to prescribe atypical antipsychotics to children younger than a certain age as a condition for coverage, according to background information in the article.

Julie M. Zito, Ph.D., of the University of Maryland, Baltimore, and colleagues reviewed antipsychotic-related Medicaid prior authorization policies for youth (<18 years) in 50 states plus the District of Columbia between June 2013 and August 2014 and characterized these policies according to age­restriction criteria and whether a peer review process was present. A subset of prior authorization policies, classified as “peer review”, brings clinical expertise into the review process by requiring contracted clinicians (peer reviewers) to adjudicate antipsychotic prescriptions for children.

The researchers found that 31 states have implemented prior authorization policies for atypical antipsychotic prescribing to children, mostly within the past 5 years. Most states apply their policies to children younger than 5, 6, or 7 years of age. Only 7 states (Alabama, Kentucky, Maryland, Nevada, North Carolina, Pennsylvania, Tennessee) apply their policies to Medicaid-insured youth up to age 18 years. Seven other states (California, Colorado, Georgia, Mississippi, Nebraska, New York, Washington) have age-restriction criteria that vary by drug entity.

Of the 31 states, 15 have incorporated a peer review process, wherein the adjudication process usually involves a psychiatrist or other physician specialty. The programs without a peer review process use automated systems or non­physician manual reviews for adjudication.

“The findings may inform pediatric research to assess the effect of these policies on atypical antipsychotic use to ensure clinical appropriateness and to minimize unintended consequences,” the authors write.

They add that potential unintended consequences of these restrictive policies include inadequate treatment, substitution of potentially inappropriate, off-label psychotropic medication classes such as anticonvulsant mood stabilizers and antidepressants, and administrative burden on prescribers.

“Additionally, Medicaid oversight programs should be concerned not only with unnecessary antipsychotic use, but also should ensure adherence to appropriate cardiometabolic monitoring practices at baseline and during antipsychotic treatment, and support access to alternative evidence-based nonpharmacological treatments.”

(doi:10.1001/jama.2015.0763; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by the U.S. Food and Drug Administration (FDA). Mr. Schmid was supported in part by a fellowship administered by the Oak Ridge Institute for Science and Education and funded by the U.S. FDA. 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: 11 A.M. (ET) TUESDAY, MARCH 3, 2015

Media Advisory: To contact Sebastiano Filetti, M.D., email sebastiano.filetti@uniroma1.it. To contact editorial co-author Anne R. Cappola, M.D., Sc.M., email Holly Auer at holly.auer@uphs.upenn.edu.

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Long-Term Follow-up of Benign Thyroid Nodules Shows Favorable Prognosis

After five years of follow-up, a majority of asymptomatic, benign thyroid nodules exhibited no significant change in size, or actually decreased in size, and diagnoses of thyroid cancer were rare, according to a study in the March 3 issue of JAMA.

Detection of asymptomatic thyroid nodules has increased, largely from improved detection of small incidentally discovered nodules. Consensus is lacking regarding the optimal follow-up of cytologically (analysis of aspirated cells) proven benign lesions and sonographically (an imaging technique using ultrasonic waves) nonsuspicious nodules. Current guidelines recommend serial ultrasound examinations and repeat cytology exam if significant growth in the nodule is observed. However, little is known about the actual frequency and magnitude of nodule growth, and there is no reliable method for identifying patients likely to experience growth. The assumption that growing nodules increase a patient’s risk of malignancy has been untested, according to background information in the article.

Sebastiano Filetti, M.D., of the Universita di Roma Sapienza, Rome, and colleagues studied the frequency, magnitude, and factors associated with changes in thyroid nodule size. The study involved 992 patients with 1 to 4 asymptomatic, sonographically or cytologically benign thyroid nodules. Patients were recruited from 8 hospital-based thyroid-disease referral centers in Italy between 2006 and 2008. Data collected during the first 5 years of follow-up, through January 2013, were analyzed.

Nodule growth occurred in 153 patients (15.4 percent). One hundred seventy-four of the 1,567 original nodules (11.1 percent) increased in size. Nodule growth was associated with presence of multiple nodules. In 184 individuals (18.5 percent), nodules shrank. Thyroid cancer was diagnosed in 5 original nodules (0.3 percent), only 2 of which had grown. New nodules developed in 93 patients (9.3 percent), with detection of one cancer.

“One of the goals of surveillance is the prompt detection and treatment of thyroid cancers that arise during follow-up or have been missed on the initial assessment. In the population we studied, these events were rare,” the authors write.

“Only 2 of the 5 diagnoses of cancer in an established nodule were preceded by significant growth of the cancerous nodule. These data suggest that the American Thyroid Association’s recommendation for indication for repeat cytology should be revised. Clinical and sonographic findings should probably play larger roles in the decision-making process.”

(doi:10.1001/jama.2015.0956; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was funded by research grants from the Umberto Di Mario Foundation, Banca d’ltalia, and the Italian Thyroid Cancer Observatory Foundation. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Improving the Long-term Management of Benign Thyroid Nodules

In an accompanying editorial, Anne R. Cappola, M.D., Sc.M., and Susan J. Mandel, M.D., M.P.H., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, (Dr. Cappola is also an Associate Editor, JAMA), write that this study has four important implications for the follow-up of thyroid nodules.

“First, these prospective data provide reassurance about the validity of a benign cytology result obtained by ultrasound-guided fine-needle aspiration and confirm a very low false-negative rate, at 1.1 percent. Second, the practice of routine sonographic surveillance with repeat fine-needle aspiration for growth, as recommended by published guidelines, is not the most efficient strategy to detect the very small number of missed cancers among previously sampled cytologically benign nodules. The one-size-fits-all approach simply does not work. Instead, surveillance strategies should be individualized based on a nodule’s sonographic appearance.”

“Third, many nodules detected on ultrasound are small (i.e., < 1 cm) and not sonographically suspicious. In fact, fifty-four percent of nodules followed up in this study were initially classified as benign not through fine-needle aspiration but because they were smaller than 1 cm and lacked suspicious sonographic features. How reliable is the absence of these features at predicting benign disease? The answer is excellent. … Fourth, although 69 percent of nodules remained stable in size, size increase was not a harbinger of malignancy, especially if the nodule had no sonographically suspicious features. Benign nodules grow and Durante et al provide insights about predicting when growth is most likely to occur, e.g., in multinodular glands, larger nodule size, and younger patients.”

“Thyroid nodules are pervasive, whereas thyroid cancer is not. The findings from Durante et al represent an important step in improving the efficiency and mitigating the expense of follow-up for the vast majority of thyroid nodules that are either cytologically or sonographically benign.”

(doi:10.1001/jama.2015.0836; 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: 11 A.M. (ET) TUESDAY, MARCH 3, 2015

Media Advisory: To contact Axel Maurice-Szamburski, M.D., email amszamburski@gmail.com.

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Findings Question Benefit of Administering Sedatives Before Surgery for Patients Receiving General Anesthesia

Although sedatives are often administered before surgery, a randomized trial finds that among patients undergoing elective surgery under general anesthesia, receiving the sedative lorazepam before surgery, compared with placebo or no premedication, did not improve the self-reported patient experience the day after surgery, but was associated with longer time till removal off a breathing tube (extubation) and a lower rate of early cognitive recovery, according to a study in the March 3 issue of JAMA.

Patients scheduled for surgery may experience considerable stress and anxiety. Benzodiazepine (a class of sedatives) premedication is frequently used to reduce anxiety but also causes amnesia, drowsiness, and cognitive impairment. Treating anxiety is not necessarily associated with a better perioperative (before and after surgery) experience for the patient. More needs to be known about the efficacy of preoperative anxiety treatment to better counsel patients to make informed decisions, according to background information in the article.

Axel Maurice-Szamburski, M.D., of the Hôpital de la Timone Adulte, Marseille, France, and colleagues randomly assigned 1,062 adult patients (younger than 70 years of age) who had been scheduled for various elective surgeries under general anesthesia at 5 French teaching hospitals to receive either 2.5 mg of lorazepam (approximately two hours before being transferred to the operating room), placebo, or no premedication. The perioperative patient experience was assessed 24 hours after surgery with a questionnaire.

The researchers found that premedication with lorazepam did not improve a measure of overall patient satisfaction compared with no premedication or placebo. Of the most anxious patients, no significant differences were found for overall patient satisfaction between the groups.

The time to extubation was significantly longer in the lorazepam group (17 minutes) than in the no premedication (12 minutes) and placebo (13 minutes) groups. Forty minutes after the end of anesthesia, the rate of patients scoring as recovered regarding cognition was significantly lower in the lorazepam group (51 percent) than in the no pre­medication group (71 percent) and the placebo group (64 percent). On postoperative day 1, the number of patients with amnesia during the perioperative period was higher in the lorazepam group than in the other groups.

“Compared with placebo, lorazepam did reduce patient anxiety upon arrival to the operating room. Because there was no overall benefit from preoperative anxiety treatment, it is possible that anxiety arising upon arrival to the operating room does not influence overall patient satisfaction,” the authors write.

“The findings suggest a lack of benefit with routine use of lorazepam as sedative pre-medication in patients undergoing general anesthesia.”

(doi:10.1001/jama.2015.1108; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by a grant from the French Institutional Clinical Hospital Research Program, Ministry of Health. 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: 11 A.M. (ET) TUESDAY, MARCH 3, 2015

Media Advisory: To contact Vicky Stergiopoulos, M.D., or Stephen W. Hwang, M.D., email Leslie Shepherd at ShepherdL@smh.ca. To contact editorial author Mitchell H. Katz, M.D., email Michael Wilson at micwilson@dhs.lacounty.gov.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1163

This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1277

Intervention Results in More Stable Housing for Homeless Adults, But Does Not Improve Health-Related Quality of Life

A program that included scattered-site supportive housing using rent supplements and case management services led to more stable housing for homeless adults with mental illness in four cities in Canada, compared with usual access to existing housing and community services, but the intervention did not result in significant improvements in health-related quality of life, according to a study in the March 3 issue of JAMA.

Homelessness affects large numbers of people in many countries and is associated with enormous personal and societal costs. One-year prevalence estimates indicate there were at least 150,000 homeless people in Canada in 2009 and 1.5 million in the United States in 2012. Large numbers of homeless adults have mental illness, with or without substance use disorders. Although the intervention Assertive Community Treatment (ACT) provides support via a resource-intensive interdisciplinary team (including a psychiatrist and nurses) and small case­loads, Intensive Case Management (ICM) is a less-intensive intervention in which individual case managers broker necessary services to other supports in the community. Intensive Case Management may be an appropriate and less-costly treatment option for homeless individuals not requiring ACT service intensity, according to background information in the article.

Vicky Stergiopoulos, M.D., and Stephen W. Hwang, M.D., of St. Michael’s Hospital, Toronto, and colleagues conducted a study in which 1,198 homeless adults with mental illnesses (recruited in Vancouver, Winnipeg, Toronto, and Montreal) were randomly assigned to the intervention group (n = 689) or usual care group (n = 509), and followed up for 24 months. The intervention consisted of scattered-site housing (using rent supplements) and off-site ICM services. The usual care group had access to existing housing and support services in their communities.

The researchers found that during the 24 months following randomization, the percentage of days stably housed was higher among the intervention group than the usual care group: Site A, 63 percent vs 30 percent; Site B, 73 percent vs 24 percent; Site C, 74 percent vs 39 percent; and Site D, 77 percent vs 32 percent.

On a measure of quality of life, assessed by a health questionnaire, the average change of the score from baseline to 24 months was not statistically different between intervention or usual care participants. Additional analyses suggested significant gains in condition-specific quality of life among the intervention group compared with the usual care group, such as for measures of living situation and safety.

“Our findings highlight that scattered-site housing with ICM services is effective in reducing homelessness among a broader spectrum of the homeless population who may have a severe mental illness but do not require ACT support, best reserved for a smaller group of homeless adults with high needs for mental health and other support services,” the authors write.

(doi:10.1001/jama.2015.1163; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research has been made possible through a financial contribution from Health Canada. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Housing as a Remedy for Chronic Homelessness

Mitchell H. Katz, M.D., of the County of Los Angeles, Department of Health Services, Los Angeles, comments on this topic in an accompanying editorial.

“Clinicians who provide care for homeless persons are aware that they can order a variety of reimbursable tests and treatments for them, except the one intervention that most likely would make all the difference—supportive housing. There are many conditions medicine cannot cure; chronic homelessness does not need to be one of them.”

“More than half a million persons are homeless in the United States on a given night. The study by Stergiopoulos et al suggests that there is a solution to what has been a difficult and emotionally distressing problem in the United States, Canada, and around the world.”

(doi:10.1001/jama.2015.1277; 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: 11 A.M. (ET) MONDAY, FEBRUARY 23, 2015

Media Advisory: To contact Mark S. Sulkowski, M.D., email Ekaterina Pesheva at Epeshev1@jhmi.edu. To contact Shyam Kottilil, M.D., Ph.D., email Nora Grannell at NGrannell@ihv.umaryland.edu. To contact editorial author Camilla S. Graham, M.D., M.P.H., email Jerry Berger at jberger@bidmc.harvard.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the 1^st study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1328. This link to the 2^nd study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1373. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1111

Two Studies Show Promising Results in Treating Hepatitis C in Patients Co-Infected with HIV

With there being a need for interferon-free treatment because of potential toxicities for patients with hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1), two studies appearing in JAMA using interferon-free drug regimens resulted in high rates of sustained virologic response, which is a lack of detectable HCV RNA at least 12 weeks after completion of treatment.

Hepatitis C virus and HIV-1 co-infections are common because of similar routes of transmission, including injection drug use, blood transfusion, or sexual contact. Since the advent of effective antiretroviral therapy, liver-related disease has emerged as a leading cause of illness and death in HCV/HIV-1 co-infected patients, who are at greater risk for progression to liver cirrhosis and hepatitis or liver-related death than individuals with HCV and not HIV-1.

Interferon-based treatments for HCV infection have significant toxicities, limiting their use; a significant unmet need exists for a highly efficacious, interferon-free treatment. Mark S. Sulkowski, M.D., of Johns Hopkins University, Baltimore, and colleagues assessed the three oral direct-acting antiviral (3D) regimen of ombitasvir, paritaprevir (co-dosed with ritonavir [paritaprevir/r]), dasabuvir, and ribavirin in 63 HCV genotype 1-infected adults with HIV-1 co-infection, including patients with cirrhosis, randomly assigned to either 12 or 24 weeks of treatment. The patients had not received prior HCV treatment or had history of prior treatment failure with peginterferon plus ribavirin therapy. The study was conducted at 17 sites in the United States and Puerto Rico between September 2013 and August 2014.

Plasma HCV RNA suppression was rapid in patients receiving 3D plus ribavirin; 58 of 63 patients (92 percent) had an HCV RNA below the lower limit of quantitation at treatment week 2; after 12 or 24 weeks of treatment with 3D plus ribavirin, 29 of 31 patients (94 percent) and 29 of 32 patients (91 percent) achieved SVR12 (sustained virologic response at posttreatment week 12), respectively; the difference between treatment groups was not statistically significant.

The most common treatment-emergent adverse events were fatigue (48 percent), insomnia (19 percent), nausea (18 percent), and headache (16 percent).Adverse events were generally mild, with none reported as serious or leading to discontinuation of treatment.

“In this open-label, randomized uncontrolled study, treatment with the all-oral, interferon-free 3D-plus-ribavirin regimen resulted in high SVR rates among patients co-infected with HCV genotype 1 and HIV-1 whether treated for 12 or 24 weeks. Further phase 3 studies of this regimen are warranted in co­infected patients,” the authors write.

(doi:10.1001/jama.2015.1328; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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In another study, Shyam Kottilil, M.D., Ph.D., of the University of Maryland School of Medicine and the Institute of Human Virology, Baltimore, and colleagues evaluated the rates of SVR following a treatment regimen of the antiviral agents ledipasvir and sofosbuvir in 50 patients co-infected with HCV genotype 1 and HIV who were never before treated for HCV. The patients, who did not have cirrhosis, were prescribed a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily for 12 weeks. The study was conducted from June 2013 to September 2014 at the Clinical Research Center of the National Institutes of Health.

Forty-nine of 50 participants (98 percent) achieved sustained viral response 12 weeks after the end of treatment. One patient experienced relapse at week 4 following treatment; further analysis indicated a genetic mutation associated with resistance to inhibitors such as ledipasvir.

The most common adverse events were nasal congestion (16 percent of patients) and myalgia (14 percent; pain in the muscles or within muscle tissue). There were no discontinuations or serious adverse events attributable to the study drug.

“In this open-label, uncontrolled, pilot study enrolling patients co-infected with HCV genotype 1 and HIV, administration of an oral combination of ledipasvir and sofosbuvir for 12 weeks was associated with high rates of SVR after treatment completion. Larger studies that also include patients with cirrhosis and lower CD4 T-cell counts are required to understand if the results of this study generalize to all patients co-infected with HCV and HIV,” the authors write.

“These results show for the first time, to our knowledge, that an interferon- and ribavirin-free therapy is associated with high SVR rates in patients co-infected with HCV and HIV.”

(doi:10.1001/jama.2015.1373; 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: Hepatitis C and HIV Co-infection

Camilla S. Graham, M.D., M.P.H., of the Beth Israel Deaconess Medical Center, Boston, comments on the findings of these studies in an accompanying editorial.

“Liver disease represents the second leading cause of death in persons infected with HIV. The high SVR rates in these 2 studies suggest that future barriers to prevention of unnecessary deaths due to HCV may be related to failures of the health care system. Clinicians who care for patients with HIV infection are already skilled at selecting regimens, managing drug­drug interactions, optimizing adherence, and providing harm reduction counseling. These skills are exactly what is needed to treat patients with hepatitis C and to ensure that the successes seen in research trials are replicated in clinical practice.”

“Many clinicians also have experience advocating for their patients, and this skill may be as valuable now as it was in the early days of HIV. With the current concern about the high price of these regimens, it is critical that the patients who are living with hepatitis C and the value of treating this disease remain front and center.”

(doi:10.1001/jama.2015.1111; 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.

Previous Related Content From JAMA: Sofosbuvir and Ribavirin for Hepatitis C in Patients With HIV Co-infection (July 23/30, 2014); available at this link: https://ja.ma/1ESyOWw

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, FEBRUARY 24, 2015

Media Advisory: To contact Hagen B. Huttner, M.D., email hagen.huttner@uk-erlangen.de.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.0846

Findings May Help With the Management of Anticoagulant-Related Bleeding Within the Brain

Among patients with oral anticoagulation-associated intracerebral hemorrhage (bleeding within the brain), reversal of international normalized ratio (INR; a measure used to determine the clotting tendency of blood while on medication) below a certain level within 4 hours and systolic blood pressure less than 160 mm Hg at 4 hours were associated with lower rates of hematoma (a localized swelling filled with blood) enlargement, and resumption of anticoagulant therapy was associated with a lower risk of ischemic events without increased bleeding complications, according to a study in the February 24 issue of JAMA.

The prevalence of cardiovascular diseases requiring long-term oral anticoagulation (OAC) is increasing. The most significant complication of OAC is intracerebral hemorrhage (ICH). Among all types of stroke, there is a substantial lack of data about how to manage OAC-ICH. Two of the most pressing unsettled questions are how to prevent hematoma enlargement and how to manage anticoagulation in the long-term. Consensus exists that elevated INR levels should be reversed to minimize hematoma enlargement, yet mode of reversal, timing, and extent of INR reversal are unclear. Valid data on safety and clinical benefit of OAC resumption are missing and remain to be established, according to background information in the article.

Hagen B. Huttner, M.D., of the University of Erlangen-Nuremberg, Erlangen, Germany, and colleagues conducted a study to assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption. The study, conducted at 19 German tertiary care centers (2006-2012), included 1,176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption.

Hemorrhage enlargement occurred in 307 of 853 patients (36.0 percent). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8 percent]) vs INR of ≥ 1.3 (264/636 [41.5 percent]) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1 percent]) vs ≥ 160 mm Hg (98/187 [52.4 percent]).The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (18.1 percent vs 44.2 percent not achieving these values) and lower rates of in-hospital death (13.5 percent vs 20.7 percent).

OAC was resumed in 172 of 719 survivors (23.9 percent). OAC resumption showed fewer ischemic complications (5.2 percent vs no OAC, 15.0 percent) and not significantly different hemorrhagic complications (8.1 percent vs no OAC, 6.6 percent).

“The study represents the largest cohort of patients with OAC­ICH to date and reports 2 clinically valuable associations. First, rates of hematoma enlargement were decreased in patients with INR values reversed below 1.3 within 4 hours of admission and systolic blood pressures of less than 160 mm Hg at 4 hours. Second, rates of ischemic events were decreased among patients who restarted OAC without increased rates of bleeding complications,” the authors write.

“These retrospective findings require replication and assessment in prospective studies.”

(doi:10.1001/jama.2015.0846; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by a research grant from the Johannes and Frieda Marohn Foundation, University of Erlangen, Germany. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, FEBRUARY 24, 2015

Media Advisory: To contact Ping Yang M.D., Ph.D., email Joe Dangor at dangor.yusuf@mayo.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.413

Study Suggests Need for More Sensitive Lung Cancer Screening Criteria

An analysis of lung cancer incidence and screening found a decline in the proportion of patients with lung cancer meeting high-risk screening criteria, suggesting that an increasing number of patients with lung cancer would not have been candidates for screening, according to a study in the February 24 issue of JAMA.

Lung cancer screening using low-dose computed tomography is recommended for high-risk individuals by professional associations, including the U.S. Preventive Services Task Force (USPSTF). Ping Yang M.D., Ph.D., of the Mayo Clinic, Rochester, Minn., and colleagues conducted a study to examine the trends in the proportion of patients with lung cancer meeting the USPSTF screening criteria.

The study population included all Olmsted County, Minn., residents older than 20 years from 1984 through 2011, comprising approximately 140,000 people, of whom 83 percent were non-Hispanic white and socioeconomically similar to the general Midwestern U.S. population. All pathologically confirmed incident cases of primary lung cancer were identified using the Rochester Epidemiology Project database. Trends in lung cancer incidence rates were determined based on census data adjusted for the age and sex distribution of the U.S. population in 2000. The proportion of cases meeting USPSTF screening criteria were identified. The criteria included asymptomatic adults 55 to 80 years of age, having a 30 pack-year (a measure of cigarette consumption equivalent to smoking one pack a day for a year) smoking history, and currently smoking or having quit within the past 15 years.

There were 1,351 patients with a new diagnosis of primary lung cancer between 1984 and 2011. The proportion of patients with lung cancer who smoked more than 30 pack-years declined, and the proportion of former smokers, especially those who quit smoking more than 15 years ago, increased. The researchers found there was a decline in the relative proportion of patients with lung cancer meeting the USPSTF criteria overall, from 57 percent in 1984-1990 to 43 percent in 2005-2011. The proportion of patients who would have been eligible under the criteria decreased among women from 52 percent to 37 percent, and from 60 percent to 50 percent among men.

“Our findings may reflect a temporal change in smoking patterns in which the proportion of adults with a 30 pack-year smoking history and having quit within 15 years declined,” the authors write.

“The decline in the proportion of patients meeting USPSTF high-risk criteria indicates that an increasing number of patients with lung cancer would not have been candidates for screening. More sensitive screening criteria may need to be identified while balancing the potential harm from computed tomography.”

(doi:10.1001/jama.2015.413; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by grants from the National Institutes of Health, a grant from the National Institute on Aging, and funding from the Mayo Clinic Foundation. 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: 11 A.M. (ET) TUESDAY, FEBRUARY 24, 2015

Media Advisory: To contact William E. Evans, Pharm.D., email media@stjude.org. To contact editorial author Howard L. McLeod, Pharm.D., email Kim Polacek at Kim.Polacek@Moffitt.org.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.0894. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1086.

Gene Variant Associated With Increased Risk and Severity of Nerve Disorder Linked to Widely-Prescribed Cancer Drug

Children with acute lymphoblastic leukemia who had a certain gene variant experienced a higher incidence and severity of peripheral neuropathy after receiving treatment with the cancer drug vincristine, according to a study in the February 24 issue of JAMA.

Cancer remains the leading cause of death by disease in U.S. children despite major advances in the last 20 years. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and as cure rates have surpassed 85 percent, it becomes increasingly important to lessen the toxicities of treatment that adversely affect quality of life and longevity. Vincristine is one of the most widely used and effective anticancer agents for treating leukemias in both adults and children. The dose-limiting toxic effect of vincristine is peripheral neuropathy (damage to the nerves), characterized by neuropathic (nerve) pain and impaired manual dexterity, balance, and altered gait. Currently, there are no reliable means of identifying patients at high risk of vincristine­induced neuropathy nor strategies to reduce this drug toxicity, according to background information in the article.

William E. Evans, Pharm.D., of St. Jude Children’s Research Hospital, Memphis, and colleagues performed a genome-wide association study to determine whether there are genetic variants associated with vincristine-induced neuropathy. The study included patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genetic analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years) enrolled in 1994-1998 in a St. Jude Children’s Research Hospital cohort; and 99 patients (median age, 11.4 years) enrolled in 2007-2010 in a Children’s Oncology Group (COG) cohort.

Grade 2 (moderate) to 4 (life threatening) vincristine-induced neuropathy during therapy occurred in 28.8 percent of patients (64/222) in the St. Jude cohort and in 22.2 percent (22/99) in the COG cohort. The researchers found that an inherited variant in the gene CEP72 was associated with a higher incidence and severity of vincristine-related peripheral neuropathy in children with ALL. Among patients with the gene variant, 28 of 50 (56 percent) developed at least 1 episode of grade 2 to 4 neuropathy, compared with 21 percent (58/271) of other patients.

“If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent,” the authors write.

(doi:10.1001/jama.2015.0894; 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: Precision Medicine to Improve the Risk and Benefit of Cancer Care

“The study by Diouf et al has many key elements; genome-wide discovery in patients from well-conducted clinical trials, replication in a multicenter cohort, statistical robustness, and laboratory correlative findings that contribute biologic plausibility,” writes Howard L. McLeod, Pharm.D., of the Moffitt Cancer Center, Tampa, Fla., in an accompanying editorial.

“However, vincristine remains a component of the most widely accepted treatment regimens for childhood ALL, although there is variation in both dose and intensity. It is not clear that vincristine can be removed from the treatment options for a child with CEP72 variants, although this study suggests that the resulting increase in leukemia cellular sensitivity makes vincristine dose reductions possible without compromising antileukemic effect.”

“However, there is value in the association of CEP72 with vincristine-induced peripheral neuropathy (VIPN). The ability to objectively ascribe a degree of heightened VIPN risk will allow for greater transparency in discussions of risk and benefits of therapy with patients and their family members. This also may lead to developmental therapeutic approaches to modulate CEP72 function as either primary prevention or treatment of chronic VIPN. This study also represents an initial robust effort to generate predictors for adverse drug reactions in cancer care.”

(doi:10.1001/jama.2015.1086; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. McLeod reports stock options for Cancer Genetics Inc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, FEBRUARY 24, 2015

Media Advisory: To contact Anne-Marie Schjerning Olsen, M.D., Ph.D., email aols0073@geh.regionh.dk. To contact editorial co-author David J. Moliterno, M.D., email Kristi Lopez at Kristi.lopez@uky.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.0809.

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Taking NSAIDs With Anti-Clotting Medications Following Heart Attack Associated With Increased Risk of Bleeding, Cardiovascular Events

Among patients receiving antithrombotic therapy (to prevent the formation of blood clots) after a heart attack, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an increased risk of bleeding and events such as heart attack, stroke or cardiovascular death, even after short-term treatment, according to a study in the February 24 issue of JAMA.

Guidelines recommend that all patients with myocardial infarction (MI; heart attack) should be prescribed dual antithrombotic therapy (aspirin and clopidogrel) for up to 12 months and one agent thereafter. Although bleeding risks associated with antithrombotic agents are increased by NSAIDs, certain NSAID agents (e.g., ibuprofen) may also impede the antithrombotic effects of aspirin and may increase risk of cardiovascular events. These risks are of considerable public health concern, given the widespread use of NSAIDs, according to background information in the article.

Anne-Marie Schjerning Olsen, M.D., Ph.D., of Copenhagen University Hospital Gentofte, Hellerup, Denmark, and colleagues examined the risk of bleeding and cardiovascular events among patients with prior MI taking antithrombotic drugs and for whom NSAID therapy was then prescribed. The researchers used nationwide administrative registries in Denmark (2002-2011) and included patients 30 years or older admitted with first-time MI and alive 30 days after hospital discharge. Subsequent treatment with aspirin, clopidogrel, or other oral anticoagulants and their combinations, as well as ongoing concomitant (accompanying) NSAID use was determined.

The study included 61,971 patients (average age, 68 years); of these, 34 percent filled at least 1 NSAID prescription. The number of deaths during a median follow-up of 3.5 years was 18,105 (29.2 percent). A total of 5,288 bleeding events (8.5 percent) and 18,568 cardiovascular events (30.0 percent) occurred. Analysis indicated that there was about twice the risk of bleeding with NSAID treatment compared with no NSAID treatment, and the cardiovascular risk was also increased. An increased risk of bleeding and cardiovascular events was evident with accompanying use of NSAIDs, regardless of antithrombotic treatment, types of NSAIDs, or duration of use.

“There was no safe therapeutic window for concomitant NSAID use, because even short-term (0-3 days) treatment was associated with increased risk of bleeding compared with no NSAID use. Confirming previous studies and despite increased bleeding complications, NSAIDs were not associated with decreased cardiovascular risk,” the authors write.

“More research is needed to confirm these findings; however, physicians should exercise appropriate caution when prescribing NSAIDs for patients who have recently experienced MI.”

(doi:10.1001/jama.2015.0809; 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: Potential Hazards of Adding Nonsteroidal Anti-inflammatory Drugs to Antithrombotic Therapy After Myocardial Infarction

In an accompanying editorial, Charles L. Campbell, M.D., of the University of Tennessee-Chattanooga, and David J. Moliterno, M.D., of the University of Kentucky, Lexington, comment on the findings of this study.

“The cumulative evidence available is an important reminder that the while NSAIDs can be helpful and at times necessary medications for satisfactory quality of life, use of these medications among patients with a history of a recent MI is likely to be associated with clinically meaningful bleeding and ischemic risks. Because the present study tracked only prescription NSAID use, it is plausible that an even greater health care effect might occur in many countries, such as the United States, where NSAIDs are widely available as over-the-counter medications and physicians may be unaware whether their patients are taking NSAIDs.”

(doi:10.1001/jama.2015.0567; 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: 11 A.M. (ET) TUESDAY, FEBRUARY 17, 2015

Media Advisory: To contact Pramod K. Mistry, M.D., Ph.D., F.R.C.P., email Ziba Kashef at ziba.kashef@yale.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.459

Drug Improves Measures of Genetic Disease That Affects Liver, Spleen

Among previously untreated adults with Gaucher disease type 1, a genetic disease in which there is improper metabolism due to a defect in an enzyme, treatment with the drug eliglustat resulted in significant improvements in liver and spleen size hemoglobin level, and platelet count, according to a study in the February 17 issue of JAMA.

Gaucher disease type 1 is characterized by enlargement of the spleen and liver, anemia, low blood platelets, chronic bone pain, and the failure to grow properly.  Untreated Gaucher disease type 1 is a chronic and progressive disorder associated with disability, reduced life expectancy, and, in some patients, life-threatening complications. The current standard of care is enzyme replacement therapy, which requires lifelong intravenous infusions every other week. A safe, effective oral therapy is needed, according to background information in the article.

Pramod K. Mistry, M.D., Ph.D., F.R.C.P., of the Yale University School of Medicine, New Haven, Conn., and colleagues randomly assigned 40 untreated adults with Gaucher disease type 1 to receive eliglustat (twice daily; n = 20) or placebo (n = 20) for 9 months. Eliglustat is a novel oral medication, which showed favorable results for patients with this disease in a phase 2 trial. This phase 3 trial was conducted at 18 sites in 12 countries.

The researchers found that administration of eliglustat resulted in a reduction in spleen volume of approximately 30 percent compared with placebo, as well as improvements in hemoglobin level, decreased liver volume (-6.6 percent), and increased platelet count (41 percent).  No serious adverse events occurred.  No patient discontinued treatment over the course of the 9-month study because of a treatment-emergent adverse event.

The authors add that more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up.

(doi:10.1001/jama.2015.459; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, FEBRUARY 17, 2015

Media Advisory: To contact Ollie Jay, Ph.D., email Michelle Blowes at michelle.blowes@sydney.edu.au.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.153

Study Shows Beneficial Effect of Electric Fans in Extreme Heat and Humidity

Although some public health organizations advise against the use of electric fans in severe heat, a new study published in the February 17 issue of JAMA demonstrated that electric fans prevent heat-related elevations in heart rate and core body temperature.

One review of previous research concluded “no evidence currently exists supporting or refuting the use of electric fans during heat waves” for mortality and illness. However, public health guidance typically warns against fan use in hot weather, with some research suggesting that fan use could potentially accelerate body heating, according to background information in the article.

Ollie Jay, Ph.D., of the University of Sydney, New South Wales, Australia, and colleagues examined the effect of fan use at temperatures and humidities that can no longer be physiologically tolerated without rapid increases in heart rate and core body temperature. Sweat evaporation declines with increasing humidity, so in more humid environments fans may not prevent heat­induced elevations in cardiovascular and thermal (core temperature) strain.

Wearing shorts and t-shirts, eight healthy males (average age, 23 years) sat in a chamber maintained at temperatures equal to (36°C; 97°F) or exceeding (42°C; 108°F), the limits currently recommended for fan use. Each temperature was tested with and without an 18-inch fan facing the participant (from about 3 feet). After a 20-minute baseline period, relative humidity was increased in 15 equal steps from 25 percent to 95 percent at 97°F and from 20 percent to 70 percent at 108°F. Heart rate and core temperature of the study participants were measured throughout.

The researchers found that the electric fans prevented heat-related elevations in heart and core temperature up to approximately 80 percent relative humidity at 97°F and 50 percent relative humidity at 108°F. “Thus, contrary to existing guidance, fans may be effective cooling devices for those without air conditioning during hot and humid periods,” the authors write. “Advice to the public to stop using fans during heat waves may need to be reevaluated.”

The authors note that only young participants were assessed, so similar results would need to be derived for other populations (e.g., elderly with illnesses) and those with diminished sweat production.

(doi:10.1001/jama.2015.153; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by a discovery grant from the Natural Sciences and Engineering Research Council of Canada. 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: 11 A.M. (ET) TUESDAY, FEBRUARY 17, 2015

Media Advisory: To contact Karolina Szummer, M.D., Ph.D., email karolina.szummer@karolinska.se.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.517

Anticoagulant Fondaparinux Associated With Lower Risk of Bleeding and Death Following Heart Attack Compared to Heparin

Patients who experienced a certain type of heart attack who received the anticoagulant fondaparinux had a lower risk of major bleeding events and death both in the hospital and after six months compared to patients who received low-molecular-weight heparin (LMWH), although both groups had similar rates of subsequent heart attack or stroke, according to a study in the February 17 issue of JAMA.

Reducing bleeding events in patients receiving antithrombotic therapy is important since bleeding events are associated with increased mortality. Fondaparinux was associated with reduced major bleeding events and improved survival compared with LMWH (a class of anticoagulant medications) in a large randomized clinical trial involving patients with non-ST-segment elevation myocardial infarction (NSTEMI; a certain pattern on an electrocardiogram following a heart attack). Large-scale experience of the use of fondaparinux vs LMWH outside of a clinical trial setting has been lacking, according to background information in the article.

Karolina Szummer, M.D., Ph.D., of the Karolinska Institutet, Stockholm, Sweden, and colleagues analyzed data from a Swedish registry that included 40,616 patients with NSTEMI who received in-hospital treatment with fondaparinux or LMWH between September 2006 through June 2010, with follow-up through December 2010.

Overall, 14,791 patients (36.4 percent) received fondaparinux and 25,825 (63.6 percent) received LMWH. The absolute rate of severe in-hospital bleeding events was lower in the fondaparinux group than the LMWH group (1.1 percent vs 1.8 percent), as was in-hospital mortality (2.7 percent vs 4.0 percent). The differences in major bleeding events and mortality between the two treatments were similar at 30 and 180 days.

The rate of recurrent heart attack in the fondaparinux group was 9.0 percent vs 9.5 percent in the LMWH group at 30 days and was 14.2 percent vs 15.8 percent at 180 days. The rate of stroke was low in both groups.

The results were similar in patients with varying degrees of kidney function and in the subgroup of patients with NSTEMI who had undergone early percutaneous coronary intervention (a procedure used to open narrowed coronary arteries, such as stent placement).

“A randomized clinical trial is often needed to provide definite evidence and an estimate of the treatment effect in a specific, selected, well-defined target patient population. However, the effect of implementing the same treatment in clinical practice might differ and should therefore be investigated in observational cohorts and, preferably, in continuous registries with complete coverage of nonselected patients with an indication for the studied treatment. Outside of a trial setting, the treatment is given to a much more heterogeneous patient population and the treating centers and physicians are less selected. Thus, the balance between benefit and risk can differ between a randomized clinical trial and experience in a nontrial, routine clinical care setting. Therefore, experiences from clinical practice provide important complementary information,” the authors write.

(doi:10.1001/jama.2015.517; 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: 11 A.M. (ET) TUESDAY, FEBRUARY 17, 2015

Media Advisory: To contact Antoni Torres, M.D., Ph.D., email atorres@ub.edu. To contact editorial author Richard G. Wunderink, M.D., email Marla Paul at marla-paul@northwestern.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.88.

This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.115

Corticosteroid Decreases Treatment Failure for Patients with Severe Community-Acquired Pneumonia and High Inflammatory Response

Among patients with severe community-acquired pneumonia and high initial inflammatory response, the use of the corticosteroid methylprednisolone decreased treatment failure, compared with placebo, according to a study in the February 17 issue of JAMA.

Community-acquired pneumonia is the leading infectious cause of death in developed countries, and despite advances in antibiotic treatment, mortality among hospitalized patients is still high, especially in those with severe pneumonia and in those who experience treatment failure (observed in 10-20 percent of patients). Treatment failure is associated with excessive inflammatory response and worse outcomes. Corticosteroids decrease the expression and action of many cytokines (various proteins secreted by cells of the immune system that serve to regulate the immune system) involved in the inflammatory response associated with pneumonia, but the benefit of using corticosteroids for these patients is uncertain, according to background information in the article.

Antoni Torres, M.D., Ph.D., of the Hospital Clinic, Barcelona, Spain, and colleagues randomly assigned patients at three Spanish teaching hospitals with severe community-acquired pneumonia and a high inflammatory response (defined as blood test for C-reactive protein of greater than 150 mg/L at admission) to receive intravenously the corticosteroid methylprednisolone (n = 61) or placebo (n = 59) for 5 days started within 36 hours of hospital admission.

The researchers found that there was less treatment failure (defined using outcomes such as development of shock (abnormally low blood pressure), need for invasive mechanical ventilation, and death within 72 hours of treatment) among patients from the methylprednisolone group (13 percent compared with 31 percent in the placebo group). Patients who received corticosteroid treatment had a 66 percent lower odds of treatment failure.

In-hospital deaths did not differ between groups (10 percent in the methylprednisolone group vs 15 percent in the placebo group). Hyperglycemia (abnormally high blood sugars) occurred in 11 patients (18 percent) in the methylprednisolone group and in 7 patients (12 percent) in the placebo group.

“Among patients with severe community-acquired pneumonia and high initial inflammatory response, the acute use of methylprednisolone compared with placebo decreased treatment failure. If replicated, these findings would support the use of corticosteroids as adjunctive treatment in this clinical population,” the authors write.

(doi:10.1001/jama.2015.88; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be an author audio interview available for this study at JAMA.com at the embargo time.

Editorial: Corticosteroids for Severe Community-Acquired Pneumonia

Richard G. Wunderink, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, comments on the findings of this study in an accompanying editorial.

“A more important question is what exactly are steroids preventing?  Because radiographic progression during the period between 72 hours and 5 days was the primary driver of treatment differences, understanding what this clinical finding represents is key to acceptance of the findings. The 2 logical explanations for radiographic progression are uncontrolled pneumonia and development of acute respiratory distress syndrome. Although the latter is supported by a body of literature, a beneficial effect on uncontrolled pneumonia is less logical. A more intriguing possibility is that corticosteroids block a Jarisch-Herxheimer-like reaction to initiation of antibiotics in patients with high genomic bacterial load.”

(doi:10.1001/jama.2015.115; 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: 11 A.M. (ET) TUESDAY, FEBRUARY 17, 2015

Media Advisory: To contact Jon O. Ebbert, M.D., M.Sc., email Bryan Anderson at Anderson.Bryan@mayo.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.280

For Smokers Unable to Quit Abruptly, Medication Helps With Gradual Reduction and Improves Smoking Cessation

Among cigarette smokers not willing or able to quit smoking in the next month but willing to reduce with the goal of quitting in the next 3 months, use of the nicotine addiction medication varenicline for 24 weeks compared with placebo produced greater reductions in smoking prior to quitting and increased smoking cessation rates at the end of treatment and at 1 year, according to a study in the February 17 issue of JAMA.

In a telephone survey of 1,000 current daily cigarette smokers, 44 percent reported a preference to quit through reduction in the number of cigarettes smoked, and 68 percent would consider using a medication to facilitate smoking reduction. However, U.S. clinical practice guidelines recommend that smokers quit abruptly even though only 8 percent of smokers report being ready to quit in the next month. Developing effective interventions to achieve tobacco abstinence through gradual reduction could engage more smokers in quitting, according to background information in the study.

Jon O. Ebbert, M.D., M.Sc., of the Mayo Clinic, Rochester, Minn., and colleagues randomly assigned 1,510 cigarette smokers to 24 weeks of varenicline or placebo with a reduction target of 50 percent or more in number of cigarettes smoked by 4 weeks, 75 percent or more by 8 weeks, and a quit attempt by 12 weeks. The study was conducted at 61 centers in 10 countries. The participants were smokers who were not willing or able to quit smoking within the next month but willing to reduce smoking and make a quit attempt within the next 3 months.

The varenicline group (n = 760) had significantly higher continuous abstinence rates during weeks 15 through 24 than the placebo group (n = 750) (32.1 percent vs 6.9 percent) and during weeks 21 through 24 (37.8 percent vs 12.5 percent) and weeks 21 through 52 (27.0 percent vs 9.9 percent).

At week 4, 47.1 percent of participants treated with varenicline reduced the number of cigarettes smoked per day compared with baseline by 50 percent or more or abstained completely compared with 31.1 percent of participants treated with placebo; after 8 weeks, 26.3 percent participants in the varenicline group reduced smoking by 75 percent or more from baseline or abstained compared with 15.1 percent participants in the placebo group.

Serious adverse events occurred in 3.7 percent of the varenicline group and 2.2 percent of the placebo group. Varenicline was not associated with significant increases in treatment discontinuations due to adverse events.

“The U.S. Public Health Service and other guidelines recommend smokers set a quit date in the near future and quit abruptly. However, many smokers may be unwilling to commit to a quit date at a clinic visit. Because most clinicians are likely to see smokers at times when a quit date in the next month is not planned, the current study indicates that prescription of varenicline with a recommendation to reduce the number of cigarettes smoked per day with the eventual goal of quitting could be a useful therapeutic option for this population of smokers. The approach of reduction with the goal of quitting increases the options for a clinician caring for a smoker,” the authors write.

(doi:10.1001/jama.2015.280; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Other Content on This Topic: Since January 2014, JAMA has published a number of other randomized trials that included varenicline. The studies are available at these links:

Efficacy of Varenicline Combined With Nicotine Replacement Therapy vs Varenicline Alone for Smoking Cessation; https://ja.ma/16YDvCI

Combination Varenicline and Bupropion SR for Tobacco-Dependence Treatment in Cigarette Smokers; https://ja.ma/16YDSgB

Maintenance Treatment With Varenicline for Smoking Cessation in Patients With Schizophrenia and Bipolar Disorder; https://ja.ma/1zaSsJG

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, FEBRUARY 10, 2015

Media Advisory: To contact Shahinaz M. Gadalla, M.D., Ph.D., email the NCI Press Office at ncipressofficers@mail.nih.gov. To contact editorial co-author Shin Mineishi, M.D., email Beena Thannickal at beenat@uab.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8

Size of Biomarker in Transplanted Blood Cells Associated With Improved Survival Following Transplantation

Among patients with severe aplastic anemia who received stem cell transplant from an unrelated donor, longer leukocyte (white blood cells) telomere length (a structure at the end of a chromosome) was associated with increased overall survival at 5 years, according to a study in the February 10 issue of JAMA.

Telomeres protect chromosome ends and are essential for maintaining chromosomal stability. Telomere length is a biological marker for cellular aging and the capacity to replicate. Aplastic anemia is a blood disorder where the bone marrow fails to make new blood cells, with one of the causes potentially being defects in telomere biology. Allogeneic (genetically different) hematopoietic (blood marrow) cell transplantation (HCT) is recommended as initial therapy for young patients with acquired severe aplastic anemia when a matched sibling donor is available, according to information in the article.

Shahinaz M. Gadalla, M.D., Ph.D., of the National Cancer Institute, National Institutes of Health, Rockville, M.D. and colleagues evaluated the association between recipient and donor pretransplant leukocyte telomere length with outcomes after unrelated donor allogeneic HCT for 330 patients with severe aplastic anemia. The patients and their unrelated donors had pre-HCT blood samples and other clinical results available at the Center for International Blood and Marrow Transplant Research. Patients underwent HCT between 1989 and 2007 in 84 centers and were followed-up to March 2013. Leukocyte telomere length for both recipient and donor analyses was categorized based on the leukocyte telomere length tertiles (one of three groups) in the donors: long (third tertile) and short (first and second tertiles combined).

The researchers found that longer donor leukocyte telomere length was associated with a higher overall survival (5-year overall survival was 56 percent vs 40 percent in the short donor leukocyte telomere length group). After adjusting for donor age and clinical factors associated with survival following HCT in severe aplastic anemia, the risk of post-HCT all-cause mortality remained approximately 40 percent lower in patients receiving HCT from donors with long vs short leukocyte telomere length. Similar patterns were observed by subtypes of the disease.

There was no association between donor leukocyte telomere length and engraftment or graft-vs-host dis­ ease (a complication of bone marrow transplantation). Recipient telomere length was not associated with patient overall survival.

“Among patients with severe aplastic anemia who received unrelated donor allogeneic HCT, longer donor leukocyte telomere length was associated with increased overall survival at 3 and 5 years,” the authors write. “This observational study suggests that donor leukocyte telomere length may have a role in long-term post-transplant survival.”

(doi:10.1001/jama.2015.7; 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: Telomere Length in Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia

“If donor leukocyte telomere length is shown to be associated with survival in other hematopoietic stem cell transplant (HSCT) patient populations, can leukocyte telomere length become one of the factors used to choose the best available donor in matched unrelated donor HSCT (or other types of HSCT),” ask Ayman Saad, M.D., Shin Mineishi, M.D., and Racquel Innis-Shelton, M.D., of the Blood and Marrow Transplantation & Cell Therapy Program, Birmingham, Alabama, in an accompanying editorial.

“The test to determine leukocyte telomere length is widely available, but it is left to each center to determine whether to use it and if so, which test to use. If the procedure is not well standardized, comparison between centers would be difficult or impossible. In addition, leukocyte telomere length may change with aging; thus, leukocyte telomere length results would need to be repeated each time confirmatory typing is performed on the same donor.”

“Many questions and issues need to be resolved before leukocyte telomere length can be used as one of the factors to determine the best available donor. Nevertheless, the report by Gadalla et al opens up a new area of scientific investigation. Further studies are warranted to define and optimize the potential role of leukocyte telomere length in selecting donors and improving outcomes for patients with severe aplastic anemia who receive HSCT.”

(doi:10.1001/jama.2015.8; 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: 11 A.M. (ET) TUESDAY, FEBRUARY 10, 2015

Media Advisory: To contact Karl Kieburtz, M.D., M.P.H., email Mark Michaud at Mark_Michaud@URMC.Rochester.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.120

Creatine Does Not Slow Rate of Parkinson Disease Progression

Treatment with creatine monohydrate for at least 5 years for patients with early and treated Parkinson disease failed to slow clinical progression of the disease, compared with placebo, according to a study in the February 10 issue of JAMA.

Parkinson disease is a progressive neurodegenerative disorder that affects approximately 6 million people worldwide and more than one-half million individuals in the United States. Incidence is expected to increase over the next decade, but neither a cure nor a treatment is available that has been proven to slow progression. Evidence indicates that creatine, an amino acid, plays an important role in cellular energy production, which may be impaired in Parkinson disease. Oral creatine supplementation in mice has suggested a neuroprotective effect, according to information in the article.

Karl Kieburtz, M.D., M.P.H., of the University of Rochester, Rochester, N.Y., and colleagues, randomly assigned 1,741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease to receive placebo or creatine monohydrate (10 g/d) for a minimum of 5 years (maximum follow-up, 8 years). Participants were recruited from 45 investigative sites in the United States and Canada, enrolled from March 2007 to May 2010, and followed up until September 2013.

The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955).The median follow-up time was 4 years. Using several measures of Parkinson disease progression, the researchers found that treatment with creatine, compared with placebo, did not improve clinical outcomes.

There were no detectable differences in adverse and serious adverse events by body system.

“These findings do not support the use of creatine monohydrate in patients with Parkinson disease,” the authors write.

(doi:10.1001/jama.2015.120; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Financial support for this study was provided by a grant from the National Institute of Neurological Disorders and Stroke. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, FEBRUARY 10, 2015

Media Advisory: To contact Mitesh S. Patel, M.D., M.B.A., M.S., email Anna Duerr at anna.duerr@uphs.upenn.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.17841

Smartphone Applications, Wearable Devices Appear to be Accurate in Tracking Step Counts

The testing of 10 smartphone applications and wearable devices intended to track physical activity found that most were accurate in tracking step counts, according to a study in the February 10 issue of JAMA.

Despite the potential of pedometers to increase physical activity and improve health, there is little evidence of broad adoption by the general population. In contrast, nearly two-thirds of adults in the United States own a smartphone and technology advancements have enabled these devices to track health behaviors such as physical activity and provide convenient feedback. New wearable devices that may have more consumer appeal have also been developed. Even though these devices and applications might better engage individuals in their health, there has been little evaluation of their use, according to background information in the article.

Mitesh S. Patel, M.D., M.B.A., M.S., of the University of Pennsylvania, Philadelphia, and colleagues recruited healthy adults at a university to evaluate the accuracy of smartphone applications and wearable devices compared with direct observation of step counts. Participants walked on a treadmill set at 3.0 mph for 500 and 1,500 steps, each twice. An observer counted steps using a tally counter. At the end of each trial, step counts from each device were recorded.

The participants used applications and devices that were selected from among the top sellers in the U.S.: the Digi-Walker SW-200 pedometer (Yamax); the Zip and One (Fitbit) accelerometers; the wearable devices Flex (Fitbit), the UP24 (Jawbone), and the Fuelband (Nike); an iPhone 5s (Apple) simultaneously running 3 iOS applications, Fitbit (Fitbit), Health Mate (Withings), and Moves (ProtoGeo Oy); and a Galaxy S4 (Samsung Electronics) running 1 Android application, Moves (ProtoGeo Oy).

Across all devices, 552 step count observations were recorded from 14 participants in 56 walking trials. Participants were 71 percent female, with an average age of 28 years. The researchers found that compared with direct observation, the relative difference in average step count ranged from -0.3 percent to 1.0 percent for the pedometer and accelerometers, -22.7 percent to -1.5 percent for the wearable devices, and -6.7 percent to 6.2 percent for smartphone applications. Findings were mostly consistent between the 500 and 1,500 step trials.

“Data from smartphones were only slightly different than observed step counts, but could be higher or lower. Wearable devices differed more and 1 device reported step counts more than 20 percent lower than observed. Step counts are often used to derive other measures of physical activity, such as distance or calories burned. Underlying differences in device accuracy may be compounded in these measures,” the authors write.

“Increased physical activity facilitated by these devices could lead to clinical benefits not realized by low adoption of pedometers. Our findings may help reinforce individuals’ trust in using smartphone applications and wearable devices to track health behaviors, which could have important implications for strategies to improve population health.”

(doi:10.1001/jama.2014.17841; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded in part through a grant from the National Institute on Aging. Dr. Patel was supported by the U.S. Department of Veteran Affairs and the Robert Wood Johnson Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, FEBRUARY 10, 2015

Media Advisory: To contact Joseph E. Kiss, M.D., email Jim Fitzgerald at jfitzgerald@itxm.org.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.119

Iron Supplementation Improves Hemoglobin Recovery Time Following Blood Donation

Among blood donors with normal hemoglobin levels, low­-dose oral iron supplementation, compared with no supplementation, reduced the time to recovery of the postdonation decrease in hemoglobin concentration in donors with low or higher levels of a marker of overall iron storage (ferritin), according to a study in the February 10 issue of JAMA.

It is estimated that 25 percent to 35 percent of blood donors become iron depleted from regular blood donation. Although blood donation is allowed every 8 weeks in the United States, recovery of hemoglobin to the currently accepted standard is frequently delayed, and some donors become anemic. Hemoglobin level and iron status are getting renewed attention as a donor safety issue based on increasing evidence that iron depletion is associated with fatigue, decreased exercise capacity and neurocognitive changes, according to background information in the article.

Joseph E. Kiss, M.D., of the Institute for Transfusion Medicine, Pittsburgh, and colleagues randomly assigned 215 eligible study participants (who had not donated whole blood or red blood cells within 4 months) to receive one tablet of ferrous gluconate (37.5 mg of elemental iron) daily or no iron for 24 weeks after donating a unit of whole blood (500 ml). The study was conducted at four regional blood centers in the United States. The primary outcomes for the study were time to recovery of 80 percent of the postdonation decrease in hemoglobin and recovery of ferritin level (an indicator of the amount of total iron stored in the body).

The researchers found that compared with participants who did not receive iron supplementation, those who did had shortened time to 80 percent hemoglobin recovery in both the low-ferritin (average 32 days vs 158 days) and higher-ferritin groups (average 31 days vs 78 days). Recovery of iron stores in all participants who received supplements took a median of 76 days; for participants not taking iron, median recovery time was longer than 168 days. Without iron supplements, 67 percent of participants did not recover iron stores by 168 days.

“Although the absolute amount of hemoglobin decrease was relatively small and of marginal clinical consequence after a single blood donation, donating blood is an iterative [repeated] process that leads to progressive iron loss and anemia in some frequent blood donors, so it is important that the hemoglobin decrease after blood donation be recovered before the next blood donation,” the authors write.

(doi:10.1001/jama.2015.119; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by the National Heart, Lung, and Blood Institute. Dr. Mast reported having received a grant from Novo Nordisk and honoraria from Siemens. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, FEBRUARY 10, 2015

Media Advisory: To contact Kazem Rahimi, D.M., M.Sc., email Maya Kay at mkay@georgeinstitute.org.au. To contact editorial author Bryan Williams, M.D., email bryan.williams@ucl.ac.uk.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.18574. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.89

For Patients with Type 2 Diabetes, Blood Pressure-Lowering Treatment Linked to Longer Survival, Lower Risk of CVD Events

Blood pressure-lowering treatment among patients with type 2 diabetes is associated with a lower risk of cardiovascular disease (CVD) and heart disease events and improved mortality, according to a study in the February 10 issue of JAMA.

By 2030, it is estimated that there will be at least 400 million individuals with type 2 diabetes mellitus worldwide. Type 2 diabetes is associated with a substantially increased risk of events such as heart attack and stroke. Blood pressure (BP) levels are on average higher among individuals with diabetes and increased BP is a well-established risk factor for people with diabetes. Lowering BP in individuals with diabetes is an area of current controversy, with particular debate surrounding who should be offered therapy and the BP targets to be achieved, according to background information in the article.

Kazem Rahimi, D.M., M.Sc., of the George Institute for Global Health, University of Oxford, Oxford, U.K., and colleagues conducted a review and meta-analysis of large-scale randomized controlled trials of BP-lowering treatment including patients with diabetes, published between January 1966 and October 2014. A search of the medical literature identified 40 trials judged to be of low risk of bias (100,354 participants), and were included in the analysis to examine the associations between BP-lowering treatment and vascular disease in type 2 diabetes.

The researchers found that each 10-mm Hg lower systolic BP was associated with a lower risk of mortality, cardiovascular disease events, coronary heart disease events, stroke, albuminuria (the presence of excessive protein in the urine), and retinopathy (loss of vision related to diabetes). The associations between BP-lowering treatments and outcomes were not significantly different, irrespective of drug class, except for stroke and heart failure.

Although proportional associations of BP­lowering treatment for most outcomes studied were diminished below a systolic BP level of 140 mm Hg, data indicated that further reduction below 130 mm Hg is associated with a lower risk of stroke, retinopathy, and albuminuria, potentially leading to net benefits for many individuals at high risk for those outcomes.

“Among patients with type 2 diabetes, BP lowering was associated with improved mortality and other clinical outcomes. These findings support the use of medications for BP lowering in these patients,” the authors write.

(doi:10.1001/jama.2014.18574; 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: Treating Hypertension in Patients With Diabetes

“These findings are timely, clear, and important and lend support to current guideline recommendations to consider offering patients with type 2 diabetes antihypertensive therapy when their systolic BP is 140 mm Hg or greater, aiming for a target systolic BP toward 130 mm Hg but not usually lower than this,” writes Bryan Williams, M.D., of University College London, in an accompanying editorial.

“However, the findings of the study by Emdin et al suggest that for some patients, these treatment thresholds and targets might be too conservative, especially for optimally reducing the risk of stroke and the development or progression of albuminuria. This conundrum highlights the problems with clinician overreliance on guidelines and guideline overdependence on an often, uncritical adoption of evidence, despite the limitations of the clinical trials. Guidelines are just that, and are necessarily conservative in providing population-based recommendations that physicians must interpret in the context of the individual patient being treated.”

(doi:10.1001/jama.2015.89; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Williams has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reports receipt of funding as a senior investigator for the National Institute for Health Research.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, FEBRUARY 3, 2015

Media Advisory: To contact John B. Holcomb, M.D., email Rob Cahill at Robert.Cahill@uth.tmc.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12.

Study Compares Effectiveness of Different Transfusion Strategies for Severe Trauma

Among patients with severe trauma and major bleeding, those who received a transfusion of a balanced ratio of plasma, platelets, and red blood cells (RBCs) were more likely to have their bleeding stopped and less likely to die due to loss of blood by 24 hours compared to patients who received a transfusion with a higher ratio of RBCs, according to a study in the February 3 issue of JAMA. There was no significant difference in overall death at 24 hours or at 30 days between the two transfusion strategies.

Approximately 20 percent to 40 percent of trauma deaths occurring after hospital admission involve massive hemorrhage from an injury to the trunk of the body and are potentially preventable with rapid hemorrhage control and improved resuscitation techniques. These patients often require massive transfusion. Earlier transfusion with balanced blood product ratios (1:1:1 ratios for plasma, platelets, and red blood cells), defined as “damage control resuscitation”, has been associated with improved outcomes; however, there have been no large multicenter clinical trials, according to background information in the article.

John B. Holcomb, M.D., of the University of Texas Health Science Center at Houston, and colleagues conducted a study in which 680 severely injured patients who arrived at 1 of 12 level I trauma centers and were predicted to require massive transfusion were randomly assigned to receive blood product ratios of 1:1:1 for units of plasma to platelets to red blood cells (a ratio that is the closest approximation to reconstituted whole blood), or 1:1:2, during active resuscitation in addition to all local standard-of-care interventions. Patients were assigned to one these component ratios within 8 minutes of calling the blood bank, allowing the rapid delivery and infusion of the predetermined ratios.

The researchers found no significant differences for the primary outcomes of the study: mortality at 24 hours (12.7 percent in 1:1:1group vs 17.0 percent in 1:1:2 group) or at 30 days (22.4 percent vs 26.1 percent, respectively).  Exsanguination (extensive loss of blood), which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1group (9.2 percent vs 14.6 percent in 1:1:2 group). More patients in the 1:1:1 group achieved hemostasis (the stoppage of bleeding) than in the 1:1:2 group (86 percent vs 78 percent, respectively).

Despite concerns that the 1:1:1 group would experience higher rates of multiple inflammatory-mediated complications such as acute respiratory distress syndrome, multiple organ failure, infection, blood clots, and sepsis, no differences were detected between the two treatment groups.

“Given the lower percentage of deaths from exsanguination and our failure to find differences in safety, clinicians should consider using a 1:1:1 transfusion protocol, starting with the initial units transfused while patients are actively bleeding, and then transitioning to laboratory-guided treatment once hemorrhage control is achieved. Future studies of hemorrhage control products, devices, and interventions should concentrate on the physiologically relevant period of active bleeding after injury and use acute complications and later deaths (24 hours and 30 days) as safety end points,” the authors write.

(doi:10.1001/jama.2015.12; 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: 11 A.M. (ET) TUESDAY, FEBRUARY 3, 2015

Media Advisory: To contact Hemal K. Kanzaria, M.D., M.S.H.P.M., call Enrique Rivero at 310-794-2273 or email ERivero@mednet.ucla.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.17550.

Care of Patients Prior to Making a Diagnosis Rarely Assessed By Quality Measures

An examination of process measures endorsed by the National Quality Forum finds that these measures focus predominantly on management of patients with established diagnoses, and that quality measures for patient presenting symptoms often do not reflect the most common reasons patients seek care, according to a study in the February 3 issue of JAMA.

Health care reform efforts, such as accountable care organizations, focus on improving value partly through controlling use of services, including diagnostic tests. Publicly reported quality measures that evaluate care provided prior to arriving at a diagnosis could prevent financial incentives from producing harm. The National Quality Forum (NQF) currently serves as the consensus-based quality-measure-endorsement entity called for in the Affordable Care Act. Endorsed measures are often adopted by the Centers for Medicare & Medicaid Services in payment and public reporting programs, according to background information in the article.

Hemal K. Kanzaria, M.D., M.S.H.P.M., of the University of California, Los Angeles, and colleagues examined NQF-endorsed process measures that evaluate the prediagnostic (prior to making a diagnosis) care of patients presenting with signs or symptoms. There were 372 process quality measures listed on the NQF website as of June 4, 2014; from these, 385 codings were determined, by categorizing the process quality measures by a system developed by the Institute of Medicine. Approximately two-thirds (n = 267) targeted disease management and 12 percent (n = 46) targeted evaluation/diagnosis. The remaining were evenly distributed among prevention, screening, and follow-up.

Of 313 measures pertaining to evaluation/diagnosis or management, 211 (67 percent) began with an established diagnosis, whereas 14 (4.5 percent) started with a sign/symptom. The sign/symptom-based measures focused on geriatric care (e.g., memory loss, falls, urine leakage) or emergency department care (e.g., chest pain). In contrast, many common reasons for which patients seek care, including fever, cough, headache, shortness of breath, earache, rash, and throat symptoms, were not reflected by the quality measures. The performance of a lab test or medical imaging study was the action required by 59 of 313 (19 percent) endorsed quality measures; many others required actions related to medication prescribing.

“… we believe that using a comprehensive set of endorsed sign/symptom-based measures could help patients receive timely care as payment models are changed and may prevent financial incentives from resulting in underuse of necessary care. Efforts to develop valid sign/symptom-based quality measures will be challenging; however, as cost pressures increase, they may be necessary to maintain and improve the accuracy of patient diagnosis upon which all subsequent care depends,” the authors write.

(doi:10.1001/jama.2014.17550; 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: 11 A.M. (ET) TUESDAY, FEBRUARY 3, 2015

Media Advisory: To contact corresponding author Karl Y. Bilimoria, M.D., M.S., email Bret Coons at bcoons@nm.org. To contact editorial author Lucian L. Leape, M.D., email Todd Datz at tdatz@hsph.harvard.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.18614. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.18666.

 
Hospital Readmissions after Surgery Associated Mostly With Complications Related to Surgical Procedure

In a study that included readmission information from nearly 350 hospitals, readmissions the first 30 days after surgery were associated with new postdischarge complications related to the surgical procedure and not a worsening of any medical conditions the patient already had while hospitalized for surgery, according to a study in the February 3 issue of JAMA.

Readmission as a quality and cost-containment metric is now a major issue for hospitals, clinicians, and policy makers. Financial penalties for readmission have been expanded beyond medical conditions to include surgical procedures. Hospitals are working to reduce readmissions; however, little is known about the reasons for readmission after surgery. Identification of these reasons could help direct future surgical quality improvement efforts and policy decisions designed to reduce surgical readmission rates, according to background information in the article.

Ryan P. Merkow, M.D., M.S., of the American College of Surgeons, Chicago, and colleagues examined the reasons, timing, and factors associated with unplanned postoperative hospital readmissions within 30 days after surgery. The study included data from patients undergoing surgery at one of 346 hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) between January and December 2012. Readmission rates and reasons were assessed for all surgical procedures and for six representative operations: bariatric procedures, colectomy or proctectomy, hysterectomy, total hip or knee arthroplasty, ventral hernia repair, and lower extremity vascular bypass.

The unplanned 30 day readmission rate for 498,875 operations was 5.7 percent. For the individual procedures, the rate of readmission ranged from 3.8 percent after hysterectomy to 14.9 percent after lower extremity vascular bypass. The most common reason for unplanned readmission was surgical site infection (SSI; 19.5 percent), ranging from 11.4 percent after bariatric surgery to 36.4 percent after lower extremity vascular bypass.

The most common reason for readmission after bariatric surgery was ileus (blockage of the intestine) or obstruction (24.5 percent), and ileus or obstruction was the second most common reason for readmission overall (10.3 percent) and for colectomy or proctectomy, ventral hernia repair, and hysterectomy. Other common causes included dehydration or nutritional deficiency, bleeding or anemia, blood clots, and surgical device issues.

When examining early (within 7 days of discharge) and late (more than 7 days after discharge) unplanned readmissions separately, the top 3 reasons for readmission were similar overall (SSI, ileus or obstruction, and bleeding) and when examining each of the 6 procedure groups individually. Only 2.3 percent of patients were readmitted for the same complication they had experienced during their index hospitalization.

“Understanding the underlying reasons for readmission, the timing, and the associated factors should help hospitals to undertake targeted quality improvement initiatives to reduce readmissions. However, surgical readmissions mostly reflect postdischarge complications, and readmission rates may be difficult to reduce until effective strategies are put forth to reduce common complications such as SSI. Efforts should focus on reducing complication rates overall than simply those that occur after discharge, and this will subsequently reduce readmission rates as well. Readmissions after surgery may not be an appropriate measure for pay-for-performance programs but rather better suited as measure for hospitals to track internally,” the authors write.

(doi:10.1001/jama.2014.18614; 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: Hospital Readmissions Following Surgery

In an accompanying editorial, Lucian L. Leape, M.D., of the Harvard School of Public Health, Boston, comments on this study.

“The findings reported by Merkow et al are noteworthy because they are derived from analysis of ACS NSQIP data, widely regarded as among the most reliable measures of quality. These results contrast with most readmission studies that rely on administrative data, which are known to have major deficiencies. In addition, the authors make several useful suggestions as to how these findings could be used to reduce readmissions—but an important question is how can the data be used to reduce the pain and suffering that complications cause for patients? … The findings reported by Merkow et al provide an unprecedented opportunity to apply these lessons to make substantial reductions in surgical complications.”

(doi:10.1001/jama.2014.18666; 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: 11 A.M. (ET) TUESDAY, FEBRUARY 3, 2015

Media Advisory: To contact Nicholas H. Osborne, M.D., M.S., email Kara Gavin at kegavin@umich.edu. To contact David A. Etzioni, M.D., M.S.H.S., email Jim McVeigh at Mcveigh.Jim@mayo.edu. To contact editorial author Donald M. Berwick, M.D., M.P.P., email Madge Kaplan at mkaplan@ihi.org.

To place an electronic embedded link to this study and editorial in your story  This link to the 1^st study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.25. This link to the 2^nd study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.90. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4.

Studies Find No Association Between Participation in Surgical Quality Improvement Program and Improvement in Outcomes, Complications, Risk of Death

Participation by hospitals in the American College of Surgeons National Surgical Quality Improvement Program has not been associated with an improvement in surgical outcomes, serious complications, hospital readmissions, risk of death or lower Medicare payments, according to two studies in the February 3 issue of JAMA.

Increased scrutiny of hospital performance has led to an increase of clinical registries used to benchmark outcomes. One of the most visible national quality reporting programs is the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). The program provides hospitals with reports that include a detailed description of their risk-adjusted outcomes (e.g., mortality, specific complications, and length of stay). These reports allow hospitals to benchmark their performance relative to all other ACS NSQIP hospitals. Participating hospitals are encouraged to focus improvement efforts on areas in which they perform poorly. The extent to which participation in ACS NSQIP improves outcomes is unclear.

In one study, Nicholas H. Osborne, M.D., M.S., of the University of Michigan, Ann Arbor, and colleagues evaluated the association of participation in the ACS NSQIP with surgical outcomes and payments among Medicare patients. The researchers used national Medicare data (2003-2012) for a total of 1,226,479 patients undergoing general and vascular surgery at 263 hospitals participating in ACS NSQIP and 526 nonparticipating (control) hospitals.

The authors found that although there were slight trends toward improved outcomes in ACS NSQIP hospitals before vs after enrollment (year 1, year 2, and year 3), there were similar trends in control hospitals, with no significant improvements in outcomes after enrollment in ACS NSQIP. For example, in analyses comparing outcomes at 3 years after (vs before) enrollment, there were no significant differences in risk-adjusted 30-day mortality (4.3 percent vs 4.5 percent), serious complications (11.1 percent vs 11.0 percent), reoperations (0.49 percent vs 0.45 percent), or readmissions (13.3 percent vs 12.8 percent).

There were also no differences at 3 years after (vs before) enrollment in average total Medicare payments, or payments for the index admission or hospital readmission.

“Enrollment in a national surgical quality reporting program was not associated with improved outcomes or lower payments among Medicare patients. Feedback of outcomes alone may not be sufficient to improve surgical outcomes,” the authors write.

(doi:10.1001/jama.2015.25; Available pre-embargo to the media at https://media.jamanetwork.com)

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

In another study, David A. Etzioni, M.D., M.S.H.S., of Mayo Clinic Arizona, Phoenix, and colleagues compared rates of any complications, serious complications, and death during a hospitalization for elective general/vascular surgery at hospitals that did vs did not participate in the NSQIP.

Data from the University HealthSystem Consortium from January 2009 to July 2013 were used to identify elective hospitalizations representing a broad spectrum of elective general/vascular operations in the United States. The study group included 345,357 hospitalizations occurring in 113 different academic hospitals; 172,882 (50.1 percent) hospitalizations were in NSQIP hospitals. Hospitalized patients were predominantly female (62 percent), with an average age of 56 years. The types of procedures performed most commonly were hernia repairs (15.7 percent), bariatric (10.5 percent), mastectomy (9.7 percent), and cholecystectomy (9.0 percent).

Over the course of the study period, risk-adjusted rates of postoperative complications, serious complications, and mortality decreased for hospitalizations at both NSQIP and non­NSQIP hospitals. After accounting for patient risk, procedure type, underlying hospital performance, and temporal (transient) trends, the researchers found no significant differences over time between NSQIP and non­NSQIP hospitals in terms of likelihood of inpatient complications, serious complications, or risk of death.

The authors suggest that the “failure of this and other studies to demonstrate an association between outcomes-oriented reporting systems and improved surgical outcomes may be related to difficulties translating outcomes reports into evidence-based approaches to quality improvement.”

“This study has implications for hospitals and health care systems considering the role of programs that monitor surgical outcomes. Among hospitals providing care to patients undergoing general and vascular surgical procedures, our findings suggest that a surgical outcomes reporting system does not provide a clear mechanism for quality improvement.”

(doi:10.1001/jama.2015.90; 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: Measuring Surgical Outcomes for Improvement

“The most likely explanation for the findings of these 2 studies is that end-results information, although necessary for improvement, is not sufficient, and that the skills necessary to make effective changes in processes and cultures do not yet pervade U.S. hospitals, to say the least. Both research groups speculate about that as a reason for their results,” writes Donald M. Berwick, M.D., M.P.P., of the Institute for Healthcare Improvement, Cambridge, Mass., in an accompanying editorial.

“ACS NSQIP and its champions and proponents should take these important studies as prompts, not to decrease investment in the careful analysis and reporting of surgical results but rather to link that information more energetically to processes of learning, skill building, and change within participating hospitals. Hospitals not enrolled in ACS NSQIP should not use these studies as an excuse to avoid measuring and investigating their own surgical results systematically, one way or another. But all hospitals should take note that measurement, alone, is not enough for improvement.”

(doi:10.1001/jama.2015.4; 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: 11 A.M. (ET) TUESDAY, JANUARY 27, 2015

Media Advisory: To contact Tom Tomlinson, Ph.D., email Sarina Gleason at Sarina.Gleason@cabs.msu.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.16363.

Survey Indicates Willingness of General Population to Donate Tissue Samples to Biobank for Research

A survey of nearly 1,600 individuals found that the majority were willing to donate tissue samples and medical information to a biobank for research and that most were willing to donate using a blanket consent, according to a study in the January 27 issue of JAMA.

Research biobanks are increasing in number and importance, with great potential for advancing knowledge of human health, disease, and treatment. Recruitment of donors is vital to their success and relies largely on blanket consent, in which donors give one-time permission for any future research uses of their coded specimen. Previous studies suggest that donors may have moral, religious, and cultural concerns about the use to which their specimens are put, which may affect their willingness to give blanket consent. These earlier studies, however, surveyed groups that were not representative of the U.S. population, according to background information in the article.

Tom Tomlinson, Ph.D., of Michigan State University, East Lansing, and colleagues used the GfK KnowledgePanel (a probability-based online panel of adults, designed to represent the U.S. population) to field a survey examining associations between moral concerns and the willingness to donate to a biobank. Respondents read an introductory description of a fictional biobank and then used a 6-point scale—from strongly agree to strongly disagree—to indicate their willingness to donate, first using blanket consent and then “even if” their samples might be used in each of 7 potential research scenarios presenting moral concerns. The researchers then gave respondents short descriptions of the benefits and consequences of 5 methods of gaining consent and asked them to indicate which were the acceptable, best, and worst options.

The final analysis included 1,599 of 2,654 participants. Respondents were older (51 years vs 45 years for nonrespondents), were more commonly white, and had higher levels of education and household income. Using blanket consent, 68 percent were willing to donate. In all but 1 scenario, moral concerns were associated with a significant reduction in willingness to donate.

When asked about different approaches to gaining consent, 43.6 percent of respondents found the blanket consent method to be unacceptable. Specific consent, in which donors are asked to consent to each study using their specimen, was considered the worst option by 45.0 percent. These findings suggest “that an adequate approach for dealing with donors’ moral concerns may lie between these 2 extremes,” the authors write.

“As recruitment of donors becomes more widespread, such concerns [as raised in this study] may need to be addressed to moderate possible effects on donation rates.”

(doi:10.1001/jama.2014.16363; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The work was supported by a grant from the National Human Genome Research Institute. 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: 11 A.M. (ET) TUESDAY, JANUARY 27, 2015

Media Advisory: To contact Peter A. Pinto, M.D., email the NCI Press Office at ncipressofficers@mail.nih.gov. To contact editorial co-author Ethan Basch, M.D., email Katy Jones at katy_jones@med.unc.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.17942.  This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.17943.

Targeted Biopsy Technique Associated With Increased Detection of High-Risk Prostate Cancer, Decreased Detection of Low-Risk Cancer

Among men undergoing biopsy for suspected prostate cancer, targeted magnetic resonance/ultrasound fusion biopsy, compared with a standard biopsy technique, was associated with increased detection of high-risk prostate cancer and decreased detection of low-risk prostate cancer, according to a study in the January 27 issue of JAMA.

The current diagnostic procedure for men suspected of prostate cancer is a standard extended-sextant biopsy (i.e., standard biopsy). Advances in imaging have led to the development of targeted magnetic resonance (MR)/ultrasound fusion biopsy (i.e., targeted biopsy), which has been shown to detect prostate cancer. The implications of targeted biopsy alone vs standard biopsy or the 2 methods combined are not well understood, according to background information in the article.

Peter A. Pinto, M.D., and M. Minhaj Siddiqui, M.D., of the National Cancer Institute, National Institutes of Health, Bethesda, Md., and colleagues examined the outcomes of 1,003 men who underwent an imaging procedure to identify regions of prostate cancer suspicion followed by targeted biopsy and concurrent standard biopsy from 2007 through 2014 at the National Cancer Institute. Patients were referred for elevated level of prostate-specific antigen (PSA) or abnormal digital rectal examination results, often with prior negative biopsy results.

Targeted biopsy diagnosed a similar number of cancer cases (461 patients) to standard biopsy (469 patients). There was exact agreement between targeted and standard biopsy in 690 men (69 percent) undergoing biopsy. However, the 2 approaches differed in that targeted biopsy diagnosed 30 percent more high-risk cancers vs standard biopsy (173 vs 122 cases) and 17 percent fewer low-risk cancers (213 vs 258 cases).

Adding standard biopsy to targeted biopsy lead to 103 more cases of cancer (22 percent); however, of these, 83 percent were low risk while only 5 percent were high risk; 12 percent were intermediate risk. Thus, the usefulness of combining these methods was found to be limited, with the number needed to biopsy by standard biopsy in addition to targeted biopsy to diagnose 1 additional high-risk tumor was 200 men.

The predictive ability of targeted biopsy for differentiating low-risk from intermediate- and high-risk disease in 170 men with whole-gland pathology after prostatectomy (surgical removal of the prostate gland) was greater than that of standard biopsy or the 2 approaches combined.

“This study demonstrated that targeted biopsy could significantly change the distribution of risk in men newly diagnosed with prostate cancer toward diagnosis of more high­risk disease. Although these improvements in risk stratification could translate into substantial clinical benefits, it is important to recognize that this study is preliminary with regard to clinical end points such as recurrence of disease and prostate cancer-specific mortality. These findings provide a strong rationale for the conduct of randomized clinical trials to determine the effect of targeted biopsy on clinical outcomes,” the authors write.

(doi:10.1001/jama.2014.17942; 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: MR/Ultrasound Fusion-Guided Biopsy in Prostate Cancer

“Decisions to adopt new technologies such as this one that occupy a largely unregulated space ultimately rely on clinicians and payers, based on available data,” write Lawrence H. Schwartz, M.D., of the Columbia University College of Physicians and Surgeons, New York, and Ethan Basch, M.D., of the University of North Carolina, Chapel Hill, and Associate Editor, JAMA, in an accompanying editorial.

“Any test that can inform decision making and potentially spare patients harm is immediately appealing, even if the effect on clinical outcomes is unknown. Nonetheless, a new test should not be widely adopted in the absence of direct evidence showing benefits on quality of life, life expectancy, or ideally both. Therefore, the scientific community has the responsibility to ensure through clinical research that promising new technologies such as MR/ultrasound fusion imaging-guided biopsies bring value to patients.”

(doi:10.1001/jama.2014.17943; 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: 5:15 P.M. (ET) TUESDAY, JANUARY 20, 2015

Media Advisory: To contact Michael J. Noto, M.D., Ph.D., email Craig Boerner at craig.boerner@Vanderbilt.Edu. To contact editorial co-author Didier Pittet, M.D., M.S., email didier.pittet@hcuge.ch.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.18400. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.18482.

Findings Do Not Support Chlorhexidine Bathing in ICUs

Once daily bathing with disposable cloths with the topical antimicrobial agent chlorhexidine of critically ill patients did not reduce the incidence of health care-associated infections, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the Society of Critical Care Medicine’s 44th Critical Care Congress.

Infections acquired during hospitalization (health care associated infections) are associated with increased hospital length of stay, rates of death, and increased costs. The skin of hospitalized patients is a reservoir for infectious pathogens. Subsequent invasion by skin flora is thought to be a mechanism contributing to health care-associated infections. Chlorhexidine is a broad-spectrum topical antimicrobial agent that, when used to bathe the skin, may decrease the bacterial burden, thereby reducing infections. Chlorhexidine bathing is incorporated into some expert guidelines, according to background information in the article.

Michael J. Noto, M.D., Ph.D., of Vanderbilt University, Nashville, Tenn., and colleagues conducted a study in which five adult intensive care units in Nashville performed once-daily bathing of all patients (n = 9,340) with disposable cloths impregnated with 2 percent chlorhexidine or nonantimicrobial cloths as a control. Bathing treatments were performed for a 10-week period followed by a 2-week washout period (a period allowed in order to eliminate the effect of the first intervention before starting a new intervention), during which patients were bathed with nonantimicrobial disposable cloths, before crossover (switching) to the alternate bathing treatment for another 10 weeks.

A total of 55 infections occurred during the chlorhexidine bathing period (4 central line-associated bloodstream infections [CLABSIs], 21 catheter-associated urinary tract infections [CAUTIs], 17 ventilator-associated pneumonia [VAP], and 13 Clostridium difficile) and 60 infections during the control bathing periods (4 CLABSI, 32 CAUTI, 8 VAP, and 16 C difficile infections). After adjusting for various factors, no significant difference between groups in the rate of the primary outcome (composite of these infections) was detected.

Other infection-related secondary outcomes, including health care-associated bloodstream infections, blood culture contamination, and clinical cultures positive for multi-drug resistant organisms were also not improved by chlorhexidine.

“The finding that chlorhexidine bathing did not reduce infections in this study suggests that such bathing may not be necessary, resulting in cost saving and avoidance of unnecessary [antimicrobial] exposure without adversely affecting clinical outcome,” the authors write.

(doi:10.1001/jama.2014.18400; 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: Daily Chlorhexidine Bathing for Critically Ill Patients

In an accompanying editorial, Didier Pittet, M.D., M.S., of the University of Geneva Hospitals, Geneva, Switzerland, and Derek C. Angus, M.D., M.P.H., of the University of Pittsburgh School of Medicine, and Associate Editor, JAMA, write that “widespread treatment of patients with antimicrobials – whether antibiotics, antivirals, antifungals, or biocides – has never been a good idea.”

“Issues around chlorhexidine use include allergy, costs, resistance, and even safety. Although chlorhexidine bathing was found previously to reduce health care-acquired infection, the largest benefit appears to be in settings where the baseline prevalence of multidrug-resistant organisms is high. In these settings, the same benefits potentially could be gained through other approaches, such as improved hand hygiene, which may be safer and less likely to affect the ecology of bacterial resistance in the ICU. The current study by Noto et al suggests that widespread adoption of daily chlorhexidine bathing is not indicated at this point, a position also articulated in the 2014 Society for Healthcare Epidemiology of America guidelines. Rather, for institutions with infection rates similar to those reported in the current study, a simpler, less expensive approach that focuses on basic hygiene practices seems best.”

(doi:10.1001/jama.2014.18482; 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: 11 A.M. (ET) TUESDAY, JANUARY 20, 2015

Media Advisory: To contact corresponding author Juliane E. Kämmer, Ph.D., email kaemmer@mpib-berlin.mpg.de.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15770.

Working Collaboratively May Help Reduce Medical Errors

Medical students who worked in pairs were more accurate in diagnosing simulated patient cases compared to students who worked alone, according to a study in the January 20 issue of JAMA.

Diagnostic errors contribute substantially to preventable medical error. Cognitive error is among the leading causes of diagnostic errors and mostly results from faulty data synthesis, according to background information in the article.

Wolf E. Hautz, M.D., M.M.E., of the Charite Campus Mitte and Campus Virchow Klinikum, Berlin, Germany, and colleagues investigated the effect of working in pairs as opposed to alone on diagnostic performance among fourth-year medical students. Participants were randomly assigned to work individually or in pairs. Their main task was to evaluate six simulated cases of difficult breathing on a computer. Each case started with a video presentation of a prototypical patient. Thereafter, participants could select, in any order, from 30 diagnostic tests and as many as desired, but were instructed to be as fast and accurate as possible.  Results were presented as real-world clinical information (heart sounds or x-ray images).  To complete a case, participants had to select 1 of 20 diagnoses and indicate their confidence in the answer.

Of 88 students recruited, 28 worked individually and 60 in pairs. Pairs of students were more accurate than individuals in selecting a correct diagnosis (68 percent vs 50 percent) despite having comparable knowledge about the topic and selecting an equal number of diagnostic tests. Pairs needed longer time than individuals to reach a diagnosis, but the tests they selected would have taken less time in a real clinical setting. Pairs were more confident with their selected diagnoses than individuals.

“Similar to other studies, collaboration may have helped correct errors, fill knowledge gaps, and counteract reasoning flaws,” the authors write.

(doi:10.1001/jama.2014.15770; 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: 5:15 P.M. (ET) TUESDAY, JANUARY 20, 2015

Media Advisory: To contact Martha A.Q. Curley, R.N., Ph.D., email Christine Coleman at chrcol@nursing.upenn.edu. To contact editorial author Sangeeta Mehta, M.D., F.R.C.P.C., email Sally Szuster at sszuster@mtsinai.on.ca.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.18399.  This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1.

Use of Sedation Protocol Does Not Reduce Time on Ventilator for Children With Respiratory Failure

Among children undergoing mechanical ventilation for acute respiratory failure, the use of a nurse-implemented, goal­directed sedation protocol compared with usual care did not reduce the duration of mechanical ventilation, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the Society of Critical Care Medicine’s 44th Critical Care Congress.

Although sedation therapy benefits critically ill infants and children, it is also associated with adverse effects. Numerous studies in adult critical care support a minimal yet effective approach to sedation management. In contrast, few data inform sedation practices in pediatric critical care. Knowledge generated in adult critical care may not translate to the care of critically ill children, according to background information in the article.

Martha A.Q. Curley, R.N., Ph.D., of the University of Pennsylvania, Philadelphia, and colleagues studied 2,449 children (average age, 4.7 years) mechanically ventilated for acute respiratory failure in pediatric intensive care units (PICUs) to a sedation intervention (17 sites; n = 1,225 patients) or sedation with usual care (14 sites; n = 1,224 patients). The intervention PICUs used a protocol that included targeted sedation, arousal assessments, extubation (removal of breathing tube) readiness testing, sedation adjustment every 8 hours, and sedation weaning. Patients were followed up until 72 hours after opioids were discontinued, 28 days, or hospital discharge.  The study (RESTORE) was conducted from 2009-2013.

The duration of mechanical ventilation, the primary outcome for the study, was not different between the 2 groups (intervention: median, 6.5 days vs control: median, 6.5 days).  There were no group differences in the time to recovery from acute respiratory failure, duration of weaning from mechanical ventilation, PICU and hospital lengths of stay or 28- or 90-day in-hospital mortality. There were no significant differences in sedation-related adverse events including inadequate pain management, inadequate sedation management, extubation failure, ventilator-associated pneumonia, catheter-associated bloodstream infection, or new tracheostomy. Intervention patients experienced more postextubation stridor (an abnormal sound made when the breathing passages are narrowed; 7 percent vs 4 percent) and fewer stage 2 or worse immobility-related pressure ulcers (<1 percent vs 2 percent).

“Exploratory analyses of several secondary outcomes indicated that the sedation protocol was associated with a difference in patients’ sedation experience; patients in the intervention group were able to be safely managed in a more awake and calm state while intubated, receiving fewer days of opioid exposure and fewer sedative classes without an increase in inadequate pain or sedation management or clinically significant iatrogenic [consequence of treatment] withdrawal compared with patients receiving usual care, but they experienced more days with reported pain and agitation, suggesting a complex relationship among wakefulness, pain, and agitation,” the authors write.

The researchers add that although this study focused on the process of how sedatives are administered, future studies should compare the best sedative agent for varied lengths of critical illness. “Outcomes of interest include efficacy as well as an evaluation of the immediate risk-benefit ratio and an evaluation of the long-term effect of sedatives on neurocognitive development and posttraumatic stress.”

(doi:10.1001/jama.2014.18399; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Protocolized Sedation in Critically Ill Children

“Curley and colleagues answered the call for the conduct of a large clinical trial in children and have contributed valuable data to help advance approaches to sedation management in critically ill children,” writes Sangeeta Mehta, M.D., F.R.C.P.C., of Mount Sinai Hospital and the University of Toronto, in an accompanying editorial.

“While it is disappointing that this trial showed no advantage of a complex sedation management strategy, it is reassuring that the overall clinical outcomes related to ‘usual care’ in the 14 control PICUs were not significantly different than protocolized sedation in the intervention PICUs. It is imperative that high-quality research in this field continues, not only to learn more about the short- and long-term effects of sedation strategies but, more importantly, to improve clinical care and outcomes for these vulnerable patients.”

(doi:10.1001/jama.2015.1; 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: 11 A.M. (ET) TUESDAY, JANUARY 20, 2015

Media Advisory: To contact Sheree L. Boulet, Dr.P.H., M.P.H., call Brittany Behm at 404-639-3286 or email media@cdc.gov.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.17985.

Use of IVF Procedure for Male Infertility Has Doubled, Although Not Associated With Improved Outcomes

The use of an assisted reproduction technique known as intracytoplasmic sperm injection (ICSI) doubled between 1996 and 2012, although compared with conventional in vitro fertilization (IVF), use of ICSI was not associated with improved reproductive outcomes, according to a study in the January 20 issue of JAMA.

Intracytoplasmic sperm injection is an IVF procedure in which a single sperm is injected directly into an egg. The introduction of ICSI in 1992 revolutionized the treatment of couples with male factor infertility (infertility due to abnormal semen characteristics, abnormal sperm function, or surgical sterilization), and made paternity possible for a large proportion of men with no measurable sperm count. In contrast to conventional IVF, ICSI bypasses natural barriers to fertilization, thereby increasing the possibility of the transmission of genetic defects compared to conventional IVF. In addition, the procedure is also considerably more expensive than conventional IVF and adds to financial burdens already experienced by many couples undergoing fertility treatment, according to background information in the article.

Sheree L. Boulet, Dr.P.H., M.P.H., of the Centers for Disease Control and Prevention, Atlanta, and colleagues assessed national trends and reproductive outcomes of fresh IVF cycles (embryos transferred without being frozen) associated with the use of ICSI compared with conventional IVF. The researchers used data on fresh IVF and ICSI cycles reported to the U.S. National Assisted Reproductive Technology Surveillance System during 1996-2012.

Of the 1,395,634 fresh IVF cycles from 1996 through 2012, 908,767 (65.1 percent) used ICSI and 499,135 (35.8 percent) reported male factor infertility. Among cycles with male factor infertility, ICSI use increased from 76.3 percent to 93.3 percent; for those without male factor infertility, ICSI use increased from 15.4 percent to 66.9 percent.

During 2008-2012, male factor infertility was reported for 35.7 percent (176,911/494,907) of fresh cycles. In the absence of male factor infertility, ICSI use was associated with small but statistically significant decreases in implantation, pregnancy, live birth, multiple live birth, and low birth weight rates compared with conventional IVF.

“Although such differences may be a function of the large sample size and thus not clinically relevant, our findings suggest that use of ICSI may improve fertilization rates but not implantation or pregnancy rates in the setting of unexplained infertility, advanced maternal age, and low oocyte [a cell from which an egg develops] yield,” the authors write.

(doi:10.1001/jama.2014.17985; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 20, 2015

Media Advisory: To contact Richard K. Burt, M.D., call Bret Coons at 312-926-2955 or email bcoons@nm.org. To contact editorial author Stephen L. Hauser, M.D., call Pete Farley at 415- 502-4608 or email peter.farley@ucsf.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.17986. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.18150.

Stem Cell Transplantation Shows Potential for Reducing Disability in Patients with MS

Results from a preliminary study indicate that among patients with relapsing-remitting multiple sclerosis (MS), treatment with nonmyeloablative hematopoietic stem cell transplantation (low intensity stem cell transplantation) was associated with improvement in measures of disability and quality of life, according to a study in the January 20 issue of JAMA.

Fifty percent of patients with MS are unable to continue employment by 10 years from diagnosis or are unable to walk by 25 years. Despite an annual cost of approximately $47,000 per patient to treat MS, no therapy approved by the U.S. Food and Drug Administration has been shown to significantly reverse neurological disability or improve quality of life, according to background information in the article.

Multiple sclerosis is thought to be an immune­mediated disorder of the central nervous system. Autologous (the use of one’s own cells) hematopoietic (blood) stem cell transplantation (HSCT) is a form of immune suppression but unlike standard immune-based drugs, autologous HSCT is designed to reset rather than suppress the immune system. Richard K. Burt, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, and colleagues studied the association of nonmyeloablative HSCT with neurological disability and other clinical outcomes in patients with relapsing-remitting MS (defined as acute relapses followed by partial or complete recovery and stable clinical manifestations between relapses; n = 123) or secondary-progressive MS (defined as a gradual progression of disability with or without superimposed relapses; n = 28) treated between 2003 and 2014.

Outcome analysis was available for 145 patients with an average follow-up of 2.5 years. On a measure of disability (Expanded Disability Status Scale [EDSS] score), there was significant improvement in 41 patients (50 percent of patients tested at 2 years) and in 23 patients (64 percent of patients tested at 4 years). “To our knowledge, this is the first report of significant and sustained improvement in the EDSS score following any treatment for MS,” the authors write.

Receipt of HSCT was also associated with improvement in physical function, cognitive function and quality of life. There was also a reduction on another measure of clinical disease severity, volume of brain lesions associated with MS seen on magnetic resonance imaging (MRI). Four-year relapse-free survival was 80 percent and progression-free survival was 87 percent.

Patient selection is important in determining outcome, the researchers write. “In the post hoc analysis, the EDSS score did not improve in patients with secondary-progressive MS or in those with disease duration longer than 10 years.”

The authors note the results are limited because this was an observational study without a control group. “Definitive conclusions will require a randomized trial; however, this analysis provides the rationale, appropriate patient selection, and therapeutic approach for a randomized study.”

(doi:10.1001/jama.2014.17986; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was made possible by financial support from the Danhakl family, the Cumming Foundation, the Zakat Foundation, the McNamara Purcell Foundation, and Morgan Stanley and Company. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Hematopoietic Stem Cell Transplantation for MS

Stephen L. Hauser, M.D., of the University of California, San Francisco, writes in an accompanying editorial that the study by Burt et al, taken together with other available evidence, enables several conclusions to be made with reasonable confidence.

“First, autologous HSCT does not appear to be effective against established progressive forms of MS and, absent new data, additional trials of these protocols are probably not indicated for patients with progressive MS. Second, immunosuppressive regimens that include HSCT appear to be effective against the relapsing-remitting form of MS, at least over several years of observation. However, it is by no means clear that the beneficial effects result from the infusion of stem cells rather than from the conditioning regimen. Given the availability of highly effective FDA-approved therapies against relapsing-remitting MS, it would seem reasonable to use these proven monotherapies in the clinical setting before considering complex HSCT regimens.”

“Third, the mechanism of action of autologous HSCT in MS needs to be clarified. … Fourth, it is important to remember that MS is a chronic disease, usually arising in young adults and lasting throughout the lifespan. Many important disability-related outcomes take many years or decades to develop. To understand the role of any therapy for MS, and especially an intensive regimen with uncertain long-term risk, very long follow-up periods are required to meaningfully assess if the disease has indeed been rebooted over the long-term, and also to increase confidence that these therapies have not caused undue harm.”

(doi:10.1001/jama.2014.18150; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Hauser has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported serving on scientific advisory boards for Symbiotix, Annexon, and Bionure.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 20, 2015

Media Advisory: To contact corresponding author Sachin Yende, M.D., M.S., email Richard Pietzak at pietzakr@upmc.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.18229.

Hospitalization for Pneumonia Associated with Increased Risk of Cardiovascular Disease

Hospitalization with pneumonia in older adults was associated with an increased short-term and long-term risk of cardiovascular disease (CVD), suggesting that pneumonia may be an important risk factor for CVD, according to a study in the January 20 issue of JAMA.

Cardiovascular disease is the principal cause of illness and death worldwide. Characterizing the risk factors for CVD is important to design optimal preventive strategies. Several studies that examined the association between infection and subsequent long­term risk of CVD have had conflicting results. Characterizing the short-term and long-term risk of CVD after infection is important because it could suggest that infection is a risk factor for CVD, according to background information in the article.

Vicente F. Corrales-Medina, M.D., M.Sc., of the University of Ottawa, Ottawa Ontario, Canada, and colleagues examined whether hospitalization for pneumonia is associated with an increased short-term and long-term risk of CVD. The researchers chose pneumonia because respiratory tract infections have been consistently associated with increased risk of CVD, pneumonia is a well-characterized infectious syndrome that affects 1.2 percent of the population in the northern hemisphere each year, and it is the most common medical diagnosis responsible for hospitalizations in the United States.

The study included two community-based groups: the Cardiovascular Health Study (CHS, n = 5,888; enrollment age, 65 years or older; enrollment period, 1989-1994) and the Atherosclerosis Risk in Communities study (ARIC, n = 15,792; enrollment age, 45-64 years of age; enrollment period, 1987-1989). Participants hospitalized with pneumonia were matched to two controls. Pneumonia cases and controls were followed for occurrence of CVD over 10 years after matching.

Of 591 pneumonia cases in CHS, 206 had CVD events (heart attack, stroke, and fatal coronary heart disease) over 10 years after pneumonia hospitalization. In ARIC, of 680 pneumonia cases, 112 had CVD events over 10 years after hospitalization.  Analysis indicated that hospitalization with pneumonia was associated with a subsequent increase in the risk of CVD. The risk was highest (4-fold) in the first 30 days after pneumonia, and although it progressively declined during the first year, it remained approximately 1.5-fold higher in subsequent years. This association persisted after adjusting for demographics, the burden of cardiovascular risk factors, crude measures of frailty, and was observed across a range of infection severity.

“Moreover, in our analyses, the magnitude of risk for CVD associated with pneumonia was similar or higher compared with the risk of CVD associated with traditional risk factors, such as smoking, diabetes, and hypertension. Thus, our results suggest that pneumonia is an important risk factor for CVD,” the authors write.

(doi:10.1001/jama.2014.18229; 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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