EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 9, 2014

Media Advisory: To contact Sunny Smith, M.D., call Jacqueline Carr at 619-543-6427 or email jcarr@ucsd.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.2014.16066.

Number of Medical Schools with Student-Run Free Clinics Has More Than Doubled

There has been a doubling during the last decade in the number of U.S. medical schools that have student-run free clinics, with more than half of medical students involved with these clinics, according to a study in the December 10 issue of JAMA, a theme issue on medical education.

Sunny Smith, M.D., of the University of California, San Diego, and colleagues conducted a study to assess whether there has been growth of student-run free clinics (SRFCs) in medical schools and describe the characteristics of these clinics. The first national study of SRFCs conducted in 2005 described 111 SRFCs at 49 Association of American Medical Colleges (AAMC) member institutions. The researchers developed a 39 item survey with yes/no, multiple-choice, and open-ended responses. SRFCs and their medical student leaders were identified through the Society of Student-Run Free Clinics.

The authors identified SRFCs at 106 of 141 (75.2 percent) U.S. AAMC member institutions. The survey response rate was 81.1 percent (86/106). The 86 responding institutions reported 208 SRFC sites. More than half of medical students were reported to be involved in SRFCs, including first- through fourth­ year students. Fifty-three percent of institutions reportedly offered no academic credit for participation.

The most common core services provided by the SRFCs were outpatient adult medicine, health care maintenance, chronic disease management, language interpreters and social work. The most common diseases treated were diabetes and hypertension.

In open-ended responses, students identified the greatest strengths of SRFCs as serving the underserved and student education. The biggest challenges were obtaining sufficient faculty staffing and funding.

“Despite the lack of academic credit at many institutions, most medical students are volunteering in this setting. Given the ubiquity of SRFCs in the education of future physicians, further research is needed to assess their educational and clinical outcomes,” the authors write.

“The lack of funding and sufficient faculty supervisors identified as the biggest challenges in SRFCs are actionable items because institutional support could help stabilize and improve these educational opportunities for years to come.”

(doi:10.1001/jama.2014.16066; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 9, 2014

Media Advisory: To contact Bradley M. Gray, Ph.D., call Lorie Slass at 215-399-4005 or email lslass@abim.org. To contact John Hayes, M.D., email Gary Kunich at gary.kunich@va.gov. To contact editorial author Thomas H. Lee, M.D., M.Sc., email Kristen Berry at kberry@ariamarketing.com.

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.2014.12716. This link to the 2nd study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13992. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13566.

Studies Examine Effect on Patient Care and Costs of Requirements for Maintaining Board Certification

Two studies in the December 10 issue of JAMA, a theme issue on medical education, evaluate the effect of the requirement of maintaining board certification on hospitalizations, health care costs and quality of patient care.

One of the largest changes in physician accreditation policy was the initiation of a 10-year Maintenance of Certification (MOC) requirement in 1990 by the American Board of Internal Medicine (ABIM). This change was also adopted by 24 certifying boards of the American Board of Medical Specialties, affecting 85 percent of all U.S. physicians. Despite the importance of this change, there has been limited research examining associations between the MOC requirement and patient outcomes.

In one study, Bradley M. Gray, Ph.D., of the American Board of Internal Medicine, Philadelphia, and colleagues examined outcomes of care for Medicare beneficiaries treated in 2001 by two groups of ABIM-certified internal medicine physicians (general internists). One group (n = 956), initially certified in 1991, was required to fulfill the MOC program in 2001 (MOC-required) and treated 84,215 beneficiaries in the sample; the other group (n = 974), initially certified in 1989, was grandfathered out of the MOC requirement (MOC-grandfathered) and treated 69,830 similar beneficiaries in the sample. The primary outcome measured was ambulatory care-sensitive hospitalizations (ACSHs), which are hospitalizations triggered by conditions (such as diabetes and asthma) thought to be potentially preventable through better access to and quality of outpatient care.  Other outcomes included health care cost measures (adjusted to 2013 dollars).

Annual incidence of ACSHs (per 1,000 beneficiaries) increased from the pre-MOC period (37.9 for MOC-required beneficiaries vs 37.0 for MOC-grandfathered beneficiaries) to the post-MOC period (61.8 for MOC-required beneficiaries vs 61.4 for MOC-grandfathered beneficiaries) for both groups, as did annual per-beneficiary health care costs (pre-MOC period, $5,157 for MOC-required beneficiaries vs $5,133 for MOC-grandfathered beneficiaries; post-MOC period, $7,633 for MOC-required beneficiaries vs $7,793 for MOC-grandfathered beneficiaries). The MOC requirement was not statistically associated with group differences in the growth of the annual ACSH rate.

The researchers found that the MOC requirement was associated with a decreased growth in costs related to laboratory tests, imaging, and specialty visits.

“Imposition of the MOC requirement was not associated with a difference in the increase in ACSHs but was associated with a small reduction in the growth differences of costs for a cohort of Medicare beneficiaries,” the authors write.

The authors note that this research should be replicated for the current MOC program using more robust measures of care quality, across other patient populations as well as across internal medicine subspecialties, and for other certification boards’ MOC requirements.

(doi:10.1001/jama.2014.12716; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Financial and material support was provided by the American Board of Internal Medicine. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

In an another study in the December 10 issue of JAMA, John Hayes, M.D., of the Clement J. Zablocki VA Medical Center, Milwaukee, Wisc., and colleagues examined whether there are differences in the quality of primary care provided between internists with time-limited board certification and those with time-unlimited certification. Before 1990, board certification was time-unlimited. Since 1990, to maintain certification internists must pass an examination every 10 years.

American Board of Internal Medicine initiatives encourage internists with time-unlimited certificates to recertify. However, there are limited data evaluating differences in performance between internists with time-limited or time-unlimited board certification, according to background information in the article.

The study consisted of an analysis of data for 10 primary care performance measures (such as blood pressure control, colorectal cancer screening) from 1 year (2012-2013) at four Veterans Affairs (VA) medical centers. Participants were internists with time-limited (n = 71) or time-unlimited (n = 34) ABIM certification providing primary care to 68,213 patients.

After adjustment for various factors, the researchers found no significant differences in outcomes for patients cared for by internists with time-limited or time-unlimited certification for any of the performance measures. “To whatever extent a goal of MOC is to improve the quality of patient care, these findings raise a question of whether that goal is being achieved, at least among internists at these VA hospitals.”

“Additional research to examine the difference in patient outcomes among holders of time-unlimited and time-limited certificates in VA and nonacademic settings and the association with other ABIM goals may help clarify the potential benefit of MOC participation,” the authors conclude.

(doi:10.1001/jama.2014.13992; 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: Certifying the Good Physician – A Work in Progress

Physicians should work constructively to help MOC improve, much as physicians should work continuously to improve how they collaborate with colleagues and with patients, writes Thomas H. Lee, M.D., M.Sc., of Press Ganey, Brigham and Women’s Hospital, Harvard Medical School, Boston, in an editorial in this issue of JAMA.

“In addition, physicians must make the commitment to lifelong, meaningful learning to ensure that their knowledge and skills remain current and relevant. Patients would be disappointed by anything less. The medical profession may never fully understand the effect of MOC, but that does not mean that physicians should give up or stop trying to make it better. The MOC program is a work in progress, as are all good physicians.”

(doi:10.1001/jama.2014.13566; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 9, 2014

Media Advisory: To contact Lisa Diamond, M.D., M.P.H., call Courtney DeNicola Nowak at 212-639-3573 or email denicolc@mskcc.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.2014.15444.

Gap Exists Between Languages Spoken by Medical Residency Applicants and U.S. Patients with Limited English Proficiency

An analysis of the non-English-language skills of U.S. medical residency applicants finds that although they are linguistically diverse, most of their languages do not match the languages spoken by the U.S. population with limited English proficiency, according to a study in the December 10 issue of JAMA, a theme issue on medical education.

More than 25 million U.S. residents have limited English proficiency, an 80 percent increase from 1990 to 2010. Limited English proficiency (LEP) may impede participation in the English­language-dominant health care system. Little is known about the non-English-language skills of physicians in training, according to background information in the article.

Lisa Diamond, M.D., M.P.H., of Memorial Sloan Kettering Cancer Center, New York, and colleagues conducted a study to characterize the language diversity of all U.S. residency applicants through the Electronic Residency Application Service and contrast applicant language skills with the predominant languages of the U.S. population with LEP. Applicants were asked to self-report proficiency in all languages spoken. The five response options were: native/functionally native; advanced; good; fair; and basic. The applicants’ linguistic diversity was contrasted with the U.S. LEP population. The top 25 LEP languages spoken were obtained from the U.S. Census Bureau for individuals 5 years and older between 2007 and 2011.

Most (84.4 percent) of the 52,982 applicants for 2013 reported some proficiency in at least 1 non-English language. The most common languages were Spanish (53.2 percent), Hindi (20.5 percent), French (15.6 percent), Urdu (10.1 percent), and Arabic (9.8 percent). Only 21 percent of applicants reported advanced Spanish proficiency.

Among the 25.1million U.S. LEP speakers, 16.4 million speak Spanish. For every 100,000 U.S. LEP speakers, there were 105 applicants who reported at least advanced proficiency in a non­English language. Relative to this rate, there was an over-representation of Hindi-speaking applicants, and an under-representation of Spanish, Vietnamese, Korean, and Tagalog, which are 4 of the top 5 U.S. LEP languages.

“Further research is needed on whether increasing the number of bilingual residents, educating trainees on language services, or implementing medical Spanish courses as a supplement to (not a substitute for) interpreter use would improve care for LEP patients,” the authors write.

(doi:10.1001/jama.2014.15444; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Diamond was supported by Memorial Sloan Kettering Cancer Center, Department of Psychiatry and Behavioral Sciences, Immigrant Health and Cancer Disparities Service. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 9, 2014

Media Advisory: To contact co-author Fitzhugh Mullan, M.D., call Kathy Fackelmann at 202-994-8354 or email kfackelmann@gwu.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.2014.15973.

Region of Medical Residency Training May Affect Future Spending Patterns of Physician

Among primary care physicians, the spending patterns in the regions in which their residency program was located were associated with expenditures for subsequent care they provided as practicing physicians, with those trained in lower-spending regions continuing to practice in a less costly manner, even when they moved to higher-spending regions, and vice versa, according to a study in the December 10 issue of JAMA, a theme issue on medical education.

Regional and system-level variations in Medicare spending and overall intensity of medical services delivered to patients represent the collective practice decisions of clinicians in these different systems. Some research suggests that the nature of residency training influences the nature of physician practice, which raises the question of whether exposure to different practice and spending patterns during residency influences physicians’ practice patterns and cost of care after training, according to background information in the article.

Candice Chen, M.D., M.P.H., of George Washington University, Washington, D.C., and colleagues examined the relationship between spending patterns in the region of a physician’s graduate medical education training and individual physician practice spending patterns after training. The study consisted of an analysis of 2011 Medicare claims data (Part A hospital and Part B physician) for a random, nationally representative sample of family medicine and internal medicine physicians completing residency between 1992 and 2010 with Medicare patient panels of 40 or more patients (2,851 physicians providing care to 491,948 Medicare beneficiaries). Locations of practice and residency training were matched with Dartmouth Atlas Hospital Referral Region (HRR) files. Training and practice HRRs were categorized into low-, average-, and high-spending groups, with approximately equal distribution of beneficiary numbers.

For physicians practicing in high-spending regions, those trained in high-spending regions had an average spending per Medicare beneficiary per year $1,926 higher than those trained in low-spending regions. For practice in average-spending HRRs, average spending per beneficiary was $897 higher for physicians trained in high- vs low-spending regions. For practice in low-spending HRRs, the difference across training HRR levels was not significant ($533).

Overall, there was approximately a 7 percent difference in spending between physicians trained in the highest and lowest training HRR spending groups, corresponding to an estimated $522 difference between low- and high-spending training regions.

For physicians 1 to 7 years in practice, there was a 29 percent difference in spending between those trained in low- and high-spending regions; however, after 16 to 19 years, there was no significant difference.

“These observations suggest an imprinting of care-related spending behaviors that may take place during residency. Decay of the effect over time would be consistent with a training imprint that wanes because of practice environment. These findings are notable for the initial size and continuation of the association of training with physician spending patterns for up to 15 years after training. This potential imprinting has implications for physician training and potentially for hiring, particularly because major efforts are under way to reduce health care spending,” the authors write.

(doi:10.1001/jama.2014.15973; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 9, 2014

Media Advisory: To contact Mitesh S. Patel, M.D., M.B.A., M.S., call Anna Duerr at 215-349-8369 or email anna.duerr@uphs.upenn.edu. To contact the corresponding author for the 2^nd study, Karl Y. Bilimoria, M.D., M.S., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu. To contact editorial co-author James A. Arrighi, M.D., call David Orenstein at 401-863-1862 or email david_orenstein@brown.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.2014.15273. This link to the 2nd study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15277. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15580.

Resident Duty Hour Reforms Do Not Appear to Have Had Significant Effect on Patient Outcomes or on Resident Board Examination Scores

An examination of the effect of resident duty hour reforms in 2011 finds no significant change in mortality or readmission rates for hospitalized patients or outcomes for general surgery patients, according to two studies in the December 10 issue of JAMA, a theme issue on medical education.

In 2011, the Accreditation Council for Graduate Medical Education (ACGME) implemented new duty hour reforms for all ACGME-accredited residency programs. The revisions maintain the weekly limit of 80 hours set forth by the 2003 duty hour reforms but reduced the work hour limit from 30 consecutive hours to 16 hours for first­year residents (interns) and 24 hours for upper-year residents (with an additional 4 hours to perform transitions of care and participate in educational activities). Initial duty hour reforms in 2003 were prompted by wide­spread concern about the effects of resident fatigue. There has been concern that the 2011 duty hour reforms may adversely affect the quality of resident education, increase handoffs in care, and put both patient safety and outcomes at risk.

In one study, Mitesh S. Patel, M.D., M.B.A., M.S., of the Veterans Administration Hospital and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues evaluated the association of the 2011 ACGME duty hour reforms with mortality and readmissions among hospitalized Medicare patients during the first year after the reforms. The study analyzed Medicare patient admissions (6,384,273 admissions from 2,790,356 patients) to short-term, acute care hospitals (n = 3,104) with principal medical diagnoses of heart attack, stroke, gastrointestinal bleeding, or congestive heart failure or a classification of general, orthopedic, or vascular surgery.

After an analysis of the number of hospital admissions, deaths and readmissions in the two years before duty hour reforms compared with these figures in the first year after the reforms, the researchers found no significant positive or negative associations of duty hour reforms with 30-day mortality for any of the medical conditions or surgical categories in this study, and no significant positive or negative associations of these reforms with 30-day all-cause readmissions for combined medical conditions or combined surgical categories.

The authors write that their findings suggest that in the first year after the 2011 duty hour reforms, the goals of improving the quality and safety of patient care, as measured by decreased 30-day mortality and all-cause readmissions rates “were not being achieved. Conversely, concerns that outcomes might actually worsen because of decreased continuity of care have not been borne out.”

(doi:10.1001/jama.2014.15273; 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.

In an another study in the December 10 issue of JAMA, Ravi Rajaram, M.D., of the American College of Surgeons, Chicago, and colleagues conducted a study to determine if the 2011 ACGME duty hour reform was associated with a change in general surgery patient outcomes or in resident examination performance.

The study examined general surgery patient outcomes two years before (academic years 2009-2010) and after (academic years 2012-2013) the 2011 duty hour reform. Patients were those undergoing surgery at hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program. General surgery resident performance on the annual in-training, written board, and oral board examinations was assessed for this same period.

In the main analysis, 204,641 patients were identified from 23 teaching (n = 102,525) and 31 nonteaching (n = 102,116) hospitals. In adjusted analyses, the researchers found that the duty hour reform was not associated with a significant change in death or serious illness in either post-reform year 1 or post-reform year 2 or when both post-reform years were combined. There was also no association between duty hour reform and any other postoperative adverse outcome.

Average in-training examination scores did not significantly change from 2010 to 2013 for first-year residents, for residents from other postgraduate years, or for first-time examinees taking the written or oral board examinations during this period.

The authors write that the study findings could be interpreted in at least two ways. “First, there is no evidence of worsened patient care or resident education, and given assumed improvements to resident well-being, this could indicate that current policies should continue forward as they are. Conversely, the potential harm from poor continuity of care, increased handoffs, trainees feeling unprepared to practice, and concern regarding residents developing a shift-work mentality engendered by these policies could suggest that the duty hour reform may require significant revision  or reconsideration. Although many of these concerns have not been substantiated by consistent evidence, they reflect the intense interest duty hour reform has generated from the clinical and educational community.”

“The implications of these findings should be considered when evaluating the merit of the 2011 ACGME duty hour reform and revising related policies in the future.”

(doi:10.1001/jama.2014.15277; 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: Duty Hour Requirements – Time for a New Approach?

“How should the studies in this issue of JAMA and other literature on duty hour restrictions be interpreted,” asks James A. Arrighi, M.D., of the Warren Alpert Medical School of Brown University and the Lifespan Cardiovascular Institute, Providence, R.I., and James C. Hebert, M.D., of the University of Vermont College of Medicine and Fletcher Allen Healthcare, Burlington, Vt., in an accompanying editorial.

“First, with regard to potential short-term policy decisions on duty hour requirements, is it important to decide whether a null association with safety and education metrics is a positive or negative finding? In our roles as residency review committee chairs, we think this is the wrong question to ask because there was no justification for making the rules more complex or restrictive, as occurred in 2011.”

“Second, in the absence of improvement in patient outcomes in these 2 studies, how should the 2011 duty hour revisions be judged? … Many program directors have expressed great concern about the potential negative effects of this second set of changes, including effects on resident education, preparedness for senior roles, patient safety, and continuity of care. Thus, in the absence of clear data demonstrating benefit, the concerns of the educational community should be given credence and not be dismissed as mere perceptions.”

“Third, although high-quality observational studies such as these are very helpful, randomized data are lacking. Recognizing this gap in research, the educational community has proposed 2 randomized trials on duty hour requirements in medical and surgical residents that may provide more definitive information.”

(doi:10.1001/jama.2014.15580; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, DECEMBER 2, 2014

Media Advisory: To contact corresponding author Shabbir M. H. Alibhai, M.D., M.Sc., call Jane Finlayson at 416-946-2846 or email jane.finlayson@uhn.ca.

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.2014.14038

Prescriptions for Drugs to Strengthen Bones Remains Low Despite Recommended Use for Men Receiving Androgen Deprivation Therapy

Although some guidelines recommend use of bisphosphonates (a class of drugs used to strengthen bone) for men on androgen deprivation therapy, an analysis finds that prescriptions for these drugs remains low, even for those men at high risk of subsequent fractures, according to a study in the December 3 issue of JAMA.

Androgen deprivation therapy (ADT) is an effective, widely used therapy for men with prostate cancer. Adverse effects include bone loss and increased fracture risk. Canadian guidelines recommended bisphosphonate use in men with osteoporosis or fragility fracture as early as 2002 and in men on ADT in 2006. Bisphosphonate prescribing patterns are relatively unknown and may have changed over time because of increasing awareness of bone effects of ADT and evidence of bisphosphonate efficacy, according to background information in the article.

Using administrative databases at the Institute for Clinical Evaluative Sciences and the Ontario Cancer Registry, Husayn Gulamhusein, B.H.Sc., of the University Health Network, Toronto, and colleagues examined rates of bisphosphonate prescriptions in men initiating ADT in Ontario between 1995 and 2012. The study group included men 66 years of age or older starting ADT for prostate cancer, who had undergone surgical removal of one or both testicles or received at least 6 months of continuous medical ADT and survived at least 1 year after ADT initiation. Any bisphosphonate claim within 12 months of ADT initiation was captured through drug database claims. Bisphosphonate prescription over time was examined for three groups: all nonusers of bisphosphonates, those with prior osteoporosis, and those with prior fragility fracture.

A total of 35,487 men with prostate cancer who began ADT during the study period were identified. Bisphosphonate claims among all nonusers increased from 0.35 per 100 persons in 1995-1997 to 3.40 per 100 persons in 2010-2012. Even among those with prior osteoporosis or fragility fracture, rates remained low. Among all 3 groups, peak bisphosphonate claims occurred in 2007-2009, with a high of 11.89 per 100 persons in those with prior osteoporosis.

As the most widely used class of prescription drugs for osteoporosis, the authors write that these findings suggest “limited awareness among clinicians regarding optimal bone health management.”

The researchers speculate that the decrease in bisphosphonate prescriptions after 2009 may be partly due to recent negative media regarding the association of bisphosphonates with rare osteonecrosis (bone death) of the jaw and atypical femoral fractures. “This is appropriate for groups at low risk for fractures, but the decrease in use for high-risk patients is concerning.”

“Although the optimal rate of bisphosphonate use in men on ADT is unknown, it is reasonable that most men with prior osteoporosis or fracture should be taking a bisphosphonate or other effective bone medication.”

(doi:10.1001/jama.2014.14038; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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

Media Advisory: To contact corresponding author Lisa M. Schwartz, M.D., M.S., call Annmarie Christensen at 603-653-0897 or email Annmarie.Christensen@dartmouth.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.2014.13329.

Study Examines FDA Influence on Design of Pivotal Drug Studies

An examination of the potential interaction between pharmaceutical companies and the U.S. Food and Drug Administration (FDA) to discuss future studies finds that one-quarter of recent new drug approvals occurred without any meeting, and when such meetings occurred, pharmaceutical companies did not comply with one-quarter of the recommendations made by the FDA regarding study design or primary outcome, according to a study in the November 26 issue of JAMA.

To enhance protocol quality, federal regulations encourage but do not require meetings between pharmaceutical companies and the FDA during the design phase of pivotal studies assessing drug efficacy and safety for the proposed indication. These meetings often generate FDA recommendations for improving research, although companies are not bound to follow them, according to background information in the article.

Steven Woloshin, M.D., M.S., of the Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, N.H., and colleagues reviewed and analyzed approximated 200 FDA documents (memos; meeting minutes; filing checklists; and medical, statistical, and summary reviews) for 35 new drugs approved between February 1, 2011, and February 29, 2012. The researchers identified all FDA comments and analyzed recommendations about pivotal study design or primary outcomes and characterized the effect of recommendations on study quality.

Of 35 new drug approvals, companies met with the FDA to discuss pivotal studies for 28. The FDA made 53 recommendations about design (e.g., controls, doses, study length) or primary outcome for 21 approvals. Fifty-one recommendations were judged as increasing study quality (e.g., adding controls, blinding, or specific measures and frequency for toxicity assessments, lengthening studies to assess outcome durability) and two as having an uncertain effect. Companies complied with 40 of the 53 recommendations. Examples of non-compliance include a request for randomized trials of brentuximab and crizotinib, but the companies conducted uncontrolled studies. Other cases included primary outcome choice (e.g., progression­free instead of overall survival) and drug (active comparator) doses tested.

Companies can also request FDA review of pivotal trial protocols.  If FDA endorses the protocol it agrees not to object to any study design issues when reviewing the drug for approval.  Companies requested protocol review for only 21 of the 35 new drug approvals – and FDA endorsed the protocol for 12.

The authors write that instituting mandatory FDA review of pivotal trial protocols with the power to issue binding recommendations could be an effective way to optimize study quality.  They believe that such review may be even more important with increasingly flexible approval pathways. “An independent FDA-commissioned report suggested that stronger early FDA involvement could avoid deficiencies that delay approval of effective drugs and more clearly identify ineffective or harmful ones.”

(doi:10.1001/jama.2014.13329; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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

Media Advisory: To contact Arthur J. Reynolds, Ph.D., call Andrea Cournoyer at 612-625-9436 or email acournoy@umn.edu. To contact editorial author Lawrence J. Schweinhart, Ph.D., email schweinhart@att.net.

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.2014.15376. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15124.

Full-Day Preschool Associated With Increased School Readiness, Reduced Absences, Compared with Part-Day

Children who attended a full-day preschool program had higher scores on measures of school readiness skills (language, math, socio-emotional development, and physical health), increased attendance, and reduced chronic absences compared to children who attended part-day preschool, according to a study in the November 26 issue of JAMA.

Participation in high-quality early childhood programs at ages 3 and 4 years is associated with greater school readiness and achievement, higher rates of educational attainment and socioeconomic status, and lower rates of crime. Although publicly funded preschool such as Head Start and state prekindergarten serve an estimated 42 percent of U.S. 4-year­ olds, most provide only part-day services, and only 15 percent of 3-year-olds enroll. These rates plus differences in quality may account for only about half of entering kindergartners having mastered skills needed for school success. One approach for enhancing effectiveness is increasing from a part-day to a full-day schedule; whether this improves outcomes is unknown, according to background information in the article.

Arthur J. Reynolds, Ph.D., of the University of Minnesota, Minneapolis, and colleagues investigated whether full-day preschool was associated with higher levels of school readiness, attendance, and parent involvement compared with part-day participation. The study consisted of an end-of-preschool follow-up of a group of predominantly low-income, ethnic minority children enrolled in the Child-Parent Centers (CPC) for the full day (7 hours; n = 409) or part day (3 hours on average; n = 573) in the 2012-2013 school year in 11 schools in Chicago.

Implemented in the Chicago Public Schools since 1967, the Midwest CPC Education Program provides comprehensive education and family services beginning in preschool. A scale-up of the CPC program began in 2012 in more diverse communities. The model was revised to incorporate advances in teaching practices and family services and included the opening of full-day preschool classrooms in some sites.

At the end of preschool, the researchers evaluated school readiness skills (in several domains) of the children, attendance and chronic absences, and parental involvement. They found that full-day preschool participants had higher scores than part-day peers on measures of socio-emotional development (58.6 vs 54.5), language (39.9 vs 37.3), math (40.0 vs 36.4), and physical health (35.5 vs 33.6). Scores for literacy (64.5 vs 58.6) and cognitive development (59.7 vs 57.7) were not significantly different.

Full-day preschool graduates also had higher rates of attendance (85.9 percent vs 80.4 percent) and lower rates of chronic absences (10 percent or greater days missed; 53.0 percent vs 71.6 percent; 20 percent or greater days missed; 21.2 percent vs 38.8 percent), but no differences in parental involvement.

“Full-day preschool appears to be a promising strategy for school readiness. The size and breadth of associations go beyond previous studies. The positive association of full-day preschool also suggests that increasing access to early childhood programs should consider the optimal dosage of services. In addition to increased educational enrichment, full-day preschool benefits parents by providing children with a continually enriched environment throughout the day, thereby freeing parental time to pursue career and educational opportunities. By offering another service option, full-day preschool also can increase access for families who may not otherwise enroll,” the authors write.

They add that these findings need to be replicated in other programs and contexts.

(doi:10.1001/jama.2014.15376; 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: The Value of High-Quality Full-Day Preschool

In an accompanying editorial, Lawrence J. Schweinhart, Ph.D., of the HighScope Educational Research Foundation, Ann Arbor, Mich., writes that although the associations found in this study were statistically significant, “they may not be substantial enough to justify the larger expense of full-day preschool, essentially twice that of part-day preschool.”

“This must be debated and discussed by parents, educators, and policy makers and the longer-term effects and economic returns studied. But the findings are large enough to assure parents and the rest of the public that the positive benefits found for high-quality part-day preschool were found in high-quality full-day preschool to an even greater extent.”

“In part, the importance of the study by Reynolds and colleagues is that it represents a contemporary sample of children and their families. As the demand for preschool programs shifts from part-day to full-day, it is important to know whether this shift is educationally valuable as well. The study by Reynolds and colleagues provides evidence that high­quality, full-day programs are educationally more valuable than part-day programs.”

(doi:10.1001/jama.2014.15124; 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: 10:45 A.M. (CT) MONDAY, NOVEMBER 17, 2014
Media Advisory: To contact Joseph B. Muhlestein, M.D., email Jess Gomez at Jess.Gomez@imail.org. To contact editorial author Raymond J. Gibbons, M.D., call Traci Klein at 507-990-1182 or email Klein.Traci@mayo.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.2014.15825. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15958.

Findings Do Not Support Routine Screening of Patients with Diabetes for Coronary Artery Disease with CT Angiography

Joseph B. Muhlestein, M.D., of the Intermountain Medical Center Heart Institute, Murray, Utah, and colleagues examined whether screening patients with diabetes deemed to be at high cardiac risk with coronary computed tomographic angiography (CCTA) would result in a significant long­term reduction in death, heart attack, or hospitalization for unstable angina. The study appears in JAMA and is being released to coincide with its presentation at the American Heart Association’s Scientific Sessions 2014.

Diabetes mellitus is the most important coronary artery disease (CAD) risk factor; patients with diabetes often develop severe but asymptomatic CAD. The combination of aggressive, asymptomatic CAD has made it the most common cause of death in patients with diabetes. The development of cardiac imaging with high-resolution CCTA now provides the opportunity to evaluate the actual coronary anatomy noninvasively and ascertain the overall extent and severity of coronary atherosclerosis. However, whether routine CCTA screening in high-risk populations can effect changes in treatment (such as preemptive coronary revascularization or more aggressive medical therapy), leading to a reduction in cardiac events, remains unproven, according to background information in the article.

The trial randomly assigned 900 patients with types 1 or 2 diabetes of at least 3 to 5 years’ duration and without symptoms of CAD to CAD screening with CCTA (n = 452) or to standard national guidelines-based optimal diabetic care (n = 448). Patients were recruited from 45 clinics and practices of a single health system (Intermountain Healthcare, Utah). Standard or aggressive therapy (for treating abnormal lipid, blood pressure and glucose levels) was recommended based on CCTA findings.

At an average follow-up time of 4 years, the primary outcome event rates (composite of all-cause death, nonfatal heart attack, or unstable angina requiring hospitalization) were not significantly different between the CCTA and the control groups (6.2 percent [28 events] vs 7.6 percent [34 events]). The incidence of the composite secondary end point of ischemic major adverse cardiac events (CAD death, nonfatal heart attack, or unstable angina) also did not differ between groups (4.4 percent [20 events] vs 3.8 percent [17 events]).

“Coronary computed tomographic angiography involves significant expense and radiation exposure, so that justification of routine screening requires demonstration of net benefit in an appropriately high-risk population,” the authors write. “These findings do not support CCTA screening in this population.”
(doi:10.1001/jama.2014.15825; 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: Optimal Medical Therapy vs CT Angiography Screening for Patients with Diabetes

“What are the take-home messages from this randomized trial,” asks Raymond J. Gibbons, M.D., of the Mayo Clinic, Rochester, Minn., in an accompanying editorial.

“Although studies like this are often characterized as ‘negative,’ there are several important messages. As suggested by the authors, future randomized trials of cardiac imaging in asymptomatic patients with diabetes should be larger and focused on an enriched study population at higher risk. Such a strategy would certainly enhance the chances of success. A more important and more currently applicable message is that guideline-directed medical therapy for hypertension and hyperlipidemia is effective in asymptomatic patients with diabetes and should be implemented more consistently. The data in this study suggest that Intermountain Healthcare has set a new published standard for what is achievable in patients with diabetes with respect to blood pressure control and lipid-lowering therapy and that, when therapy is applied this effectively, patients with diabetes are no longer at high risk for major cardiovascular events.”
(doi:10.1001/jama.2014.15958; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported serving as a consultant for Lantheus Medical Imaging.

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EMBARGOED FOR RELEASE: 10:45 A.M. (CT) MONDAY, NOVEMBER 17, 2014
Media Advisory: To contact Yasuo Ikeda, M.D., email yikeda@aoni.waseda.jp. To contact editorial co-author J. Michael Gaziano, M.D., M.P.H., call Jessica Caragher at 617-525-6373 or email jcaragher@partners.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.2014.15690. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.16047.

Once-Daily, Low-Dose Aspirin Does Not Reduce Risk of CV Death and Other Adverse Outcomes in Older Patients with Certain Risk Factors

Yasuo Ikeda, M.D., of Waseda University, Tokyo, Japan, and colleagues examined whether once-daily, low-dose aspirin would reduce the total number of cardiovascular (CV) events (death from CV causes, nonfatal heart attack or stroke) compared with no aspirin in Japanese patients 60 years or older with hypertension, diabetes, or poor cholesterol or triglyceride levels. The study appears in JAMA and is being released to coincide with its presentation at the American Heart Association’s Scientific Sessions 2014.

The World Health Organization estimates that annual global mortality due to cardiovascular diseases (including heart attack and stroke) will approach 25 million by 2030. A recent study of trends in cardiovascular disease in Japan indicated that there has been, from 1960 to 2000, a steep increase in the prevalence of glucose intolerance, hypercholesterolemia, and obesity, probably due to the adoption of Western diets and lifestyles. By 2030, it is estimated that 32 percent of the Japanese population will be 65 years or older. Prevention of atherosclerotic cardiovascular diseases is an important public health priority in Japan due to an aging population, according to background information in the article.

This study included 14,464 patients (60 to 85 years of age) with hypertension, dyslipidemia (poor cholesterol or triglyceride levels), or diabetes mellitus who were randomized to aspirin (100 mg/d) or no aspirin in addition to ongoing medications. The patients were recruited by primary care physicians at 1,007 clinics in Japan. The study was terminated early by the data monitoring committee after a median follow-up of 5.02 years based on likely futility.

The researchers found that there was no statistically significant difference between the two groups in time to the primary end point (a composite of death from cardiovascular causes, nonfatal stroke, and nonfatal heart attack). At 5 years after randomization, the cumulative primary event rate was similar in participants in the aspirin group (2.77 percent) and those in the no aspirin group (2.96 percent).

Aspirin significantly reduced incidence of nonfatal heart attack and transient ischemic attack, and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization.

The authors write that despite inconsistent evidence for the benefit of aspirin in primary prevention of cardiovascular events, the benefits in secondary prevention are well documented, including in Japanese patients. “There is also a growing body of evidence to suggest benefits for aspirin in the prevention of colorectal and other cancers, and the prevention of cancer recurrence, including in the Japanese population. Reduction in the incidence of colorectal cancer may influence the overall benefit­risk profile of aspirin. Further analyses of [this] study data are planned, including analysis of deaths associated with cancers, to allow more precise identification of the patients for whom aspirin treatment may be most beneficial.”
(doi:10.1001/jama.2014.15690; 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: When Should Aspirin Be Used for Prevention of Cardiovascular Events?

J. Michael Gaziano, M.D., M.P.H., of the Veterans Affairs Boston Healthcare System, Brigham and Women’s Hospital, Harvard Medical School, Boston, and Associate Editor, JAMA, and Philip Greenland, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, and Senior Editor, JAMA, write in an accompanying editorial that the findings from this study adds to the body of evidence that helps refine the answer to the question of when aspirin should be used to prevent vascular events.

“Decision making involves an assessment of individual risk-to-benefit that should be discussed between clinician and patient. However, at present the choice of aspirin remains clear in several situations. Aspirin is indicated for patients at high short-term risk due to an acute vascular event and those undergoing certain vascular procedures; patients with any evidence of vascular disease should be given daily aspirin. On the other hand, patients at very low risk of vascular events should not take aspirin for prevention of vascular events, even at low dose.”

“However, some individuals who do not have overt vascular disease will have risk levels that approach those of patients with CVD (such as patients with multiple risk factors). It remains likely that there is some level of risk of CVD events that would result in a positive trade-off of benefit and risk for the use of aspirin, but the precise level of risk is uncertain.”
(doi:10.1001/jama.2014.16047; 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: 7 A.M. (CT) MONDAY, NOVEMBER 17, 2014
Media Advisory: To contact Mikhail Kosiborod, M.D., call Laurel Gifford at 816-502-8532 or email lgifford@saint-lukes.org. To contact editorial author Bradley S. Dixon, M.D., call Tom Moore at 319-356-3945 or email thomas-moore@uiowa.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.2014.15688. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15736

Drug Helps Lower High Potassium Levels Associated With Potentially Lethal Cardiac Arrhythmias

Mikhail Kosiborod, M.D., of Saint Luke’s Mid America Heart Institute, Kansas City, and colleagues evaluated the efficacy and safety of the drug zirconium cyclosilicate in patients with hyperkalemia (higher than normal potassium levels). The study appears in JAMA and is being released to coincide with its presentation at the American Heart Association’s Scientific Sessions 2014.

Hyperkalemia is a common electrolyte disorder which can cause potentially life-threatening cardiac arrhythmias and is associated with chronic kidney disease, heart failure, and diabetes mellitus. There is a lack of effective and safe therapies for the management of this disorder in the outpatient setting. Sodium zirconium cyclosilicate (zirconium cyclosilicate) is an agent designed to entrap potassium in the intestine, according to background information in the article. In previous studies, this drug was well tolerated and effective in lowering potassium within 48 hours of administration; for this study, outcomes for 28 days were evaluated.

In this phase 3 trial, ambulatory patients with hyperkalemia (n = 258) received zirconium cyclosilicate three times daily in the initial 48-hour open-label phase. Patients (n = 237) achieving normal potassium levels were then randomized to receive zirconium cyclosilicate, 5 g (n = 45 patients), 10 g (n = 51), or 15 g (n = 56), or placebo (n = 85) daily for 28 days. Patients were recruited from 44 sites in the United States, Australia, and South Africa.

The researchers found that zirconium cyclosilicate was effective both in rapidly lowering potassium to normal range and maintaining normal potassium levels for up to 4 weeks in patients with various degrees of hyperkalemia. The potassium-lowering effect of zirconium cyclosilicate was consistent across all patient subgroups and observed immediately (after 1 hour of the first dose), and normal levels of potassium was achieved in 84 percent of the patients within 24 hours and 98 percent within 48 hours of treatment initiation. Compared with placebo, all three doses of zirconium cyclosilicate resulted in significantly higher proportions of patients with normal potassium levels for up to 28 days. These outcomes occurred with a tolerability profile that was comparable with that of placebo.

“Further studies are needed to evaluate the efficacy and safety of zirconium cyclosilicate beyond 4 weeks and to assess long-term clinical outcomes,” the authors write.
(doi:10.1001/jama.2014.15688; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Zirconium Cyclosilicate for Treatment of Hyperkalemia

Bradley S. Dixon, M.D., of the Veterans Administration Medical Center and the University of Iowa, Iowa City, comments on the findings of this study in an accompanying editorial.

“The findings reported by Kosiborod et al suggest that zirconium cyclosilicate may represent a promising new therapy for the acute and short-term (i.e., 28-day) treatment of outpatients with mild hyperkalemia. However, longer-term studies are needed to assess the clinical benefits and risks that may be related to more extended use of this product, especially among hospitalized patients, as well as those with more severe hyperkalemia, other medical conditions, and other medications that affect potassium [levels].”
(doi:10.1001/jama.2014.15736; 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: 8:30 A.M. (CT) SATURDAY, NOVEMBER 15, 2014
Media Advisory: To contact corresponding author John S. Gill, M.D., M.S., email Dave Lefebvre at dlefebvre@providencehealth.bc.ca.

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.2014.14721.

Administration of Antibiotic Following Kidney Transplantation Does Not Prevent Virus Infection

Among kidney transplant recipients, a 3-month course of the antibiotic levofloxacin following transplantation did not prevent the major complication known as BK virus from appearing in the urine. The intervention was associated with an increased risk of adverse events such as bacterial resistance, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the American Society of Nephrology’s annual Kidney Week meeting.

Kidney transplantation is the preferred treatment for end­stage renal disease. The development of potent immunosuppressant medications has reduced the incidence of acute rejection to less than 10 percent; however, immunosuppression can lead to reactivation of the BK virus, a polyomavirus which has a prevalence of 60 percent to 80 percent in the general population. BK virus infection progresses through discrete stages, appearing first in the urine (BK viruria), which is associated with a high risk of transplant failure. There are currently no therapies to prevent or treat BK virus infection. Quinolone antibiotics have antiviral properties against BK virus but efficacy at preventing this infection has not been shown in prospective controlled studies, according to background information in the article.

Greg A. Knoll, M.D., of the Ottawa Hospital Research Institute and University of Ottawa, Ontario, Canada, and colleagues randomly assigned 154 patients who received a living or deceased donor kidney-only transplant in 7 Canadian transplant centers to receive a 3-month course of levofloxacin (n = 76) or placebo (n = 78) starting within 5 days after transplantation. Patients were tested for occurrence of BK viruria within the first year after transplantation.

The overall average follow-up time was 46.5 weeks in the levofloxacin group and 46.3 weeks in the placebo group; 27 patients had follow-up terminated before end of the planned follow-up period or development of viruria because the trial was stopped early because of lack of funding. BK viruria occurred in 22 patients (29 percent) in the levofloxacin group and in 26 patients (33.3 percent) in the placebo group.

Analysis of other virologic measures including occurrence of BK viremia (virus in the blood), peak urine and blood viral loads, and time to sustained viruria showed that such measures were not significantly different between groups. There was an increased risk of resistant infection associated with isolates usually sensitive to quinolones in the levofloxacin group (58 percent vs 33 percent) and also a nonsignificant increase in suspected tendinitis (8 percent vs. 1 percent).

“These findings do not support the use of levofloxacin to prevent posttransplantation BK virus infection,” the authors conclude.
(doi:10.1001/jama.2014.14721; 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: 8:30 A.M. (CT) SATURDAY, NOVEMBER 15, 2014
Media Advisory: To contact Amit X. Garg, M.D., Ph.D., email Crystal Mackay at crystal.mackay@schulich.uwo.ca. To contact editorial co-author Wolfgang C. Winkelmayer, M.D., M.P.H., Sc.D., email Julia Parsons at Julia.Parsons@bcm.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.2014.15284. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14548.

Use of Aspirin or Blood Pressure Medication Before and After Surgery Does Not Reduce Risk of Kidney Injury

In patients undergoing noncardiac surgery, neither aspirin nor clonidine (a medication primarily used to treat high blood pressure) taken before and after surgery reduced the risk of acute kidney injury, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the American Society of Nephrology’s annual Kidney Week meeting.

About 10 percent of the 200 million adults estimated to undergo major noncardiac surgery each year develop acute kidney injury (a sudden loss of kidney function). Perioperative (around the time of surgery) acute kidney injury is associated with poor outcomes, a long hospital stay, and high health care costs. Some studies suggest aspirin or clonidine administered during the perioperative period reduces the risk of acute kidney injury; however these effects are uncertain and each intervention has the potential for harm (bleeding with aspirin and abnormally low blood pressure with clonidine), which could increase the risk of acute kidney injury, according to background information in the article.

Amit X. Garg, M.D., Ph.D., of the London Health Sciences Centre and Western University, London, Ontario, Canada, and colleagues randomly assigned 6,905 patients undergoing noncardiac surgery from 88 centers in 22 countries to take aspirin (200 mg) or placebo 2 to 4 hours before surgery and then aspirin (100 mg) or placebo daily up to 30 days after surgery; oral clonidine (0.2 mg) or placebo 2 to 4 hours before surgery, and then a transdermal clonidine patch (applied to the skin) or placebo patch that remained until 72 hours after surgery. Acute kidney injury was primarily defined as a certain increase in serum creatinine concentration (a substance commonly found in blood, urine, and muscle tissue and used as an indicator of kidney function).

The researchers found that neither aspirin nor clonidine reduced the risk of acute kidney injury. The percentage of patients in each study group who experienced acute kidney injury: aspirin 13.4 percent vs 12.3 percent (placebo); clonidine 13.0 percent vs 12.7 percent (placebo).

Aspirin increased the risk of major bleeding. In turn, major bleeding was associated with a greater risk of subsequent acute kidney injury (23.3 percent when bleeding was present vs 12.3 percent when bleeding was absent). Similarly, clonidine increased the risk of clinically important hypotension (abnormally low blood pressure). Such hypotension was associated with a greater risk of subsequent acute kidney injury (14.3 percent when hypotension was present vs 11.8 percent when hypotension was absent).

The authors write that future large trials to prevent acute kidney injury in the surgical setting should focus on interventions that target pathways other than inhibiting platelet aggregation and alpha 2-adrenergic agonism. “Interventions that prevent perioperative bleeding and perioperative hypotension may prove useful.”
(doi:10.1001/jama.2014.15284; 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: Prevention of Acute Kidney Injury Using Vasoactive or Antiplatelet Treatment

Wolfgang C. Winkelmayer, M.D., M.P.H., Sc.D., of the Baylor College of Medicine, Houston, and Associate Editor, JAMA, and Kevin W. Finkel, M.D., of the University of Texas Medical School, Houston, comment on this study in an accompanying editorial.

“In their contribution, Garg and colleagues once again have embarked on a promising mechanism to generate evidence for kidney outcomes, which involved partnering with investigators of large cardiovascular trials and proposing (and then executing) ancillary studies of kidney-relevant end points. Given the disproportionate paucity of randomized trials in nephrology, this is a useful and economical approach, especially in light of the many risk factors that cardiovascular disease and both acute and chronic kidney disease share. It is almost unfathomable that funding agencies would have funded a stand-alone trial of interventions for the primary prevention of acute kidney injury of the size and scope of [this study].”
(doi:10.1001/jama.2014.14548; 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: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact Stefanie Schulz-Schupke, M.D., email schulzs@dhm.mhn.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.2014.15305

Comparison of Outcomes, Complications For Methods to Achieve Artery Closure Following Coronary Angiography

Stefanie Schulz-Schupke, M.D., of the Deutsches Herzzentrum Munchen, Technische Universitat, Munich, Germany and colleagues assessed whether vascular closure devices are noninferior (not worse than) to manual compression in terms of access site-related vascular complications in patients undergoing diagnostic coronary angiography. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Percutaneous (through the skin) coronary angiography and interventions have become a cornerstone in the diagnosis and treatment of coronary artery disease. A substantial proportion of the adverse effects associated with these procedures is related to access-site complications. The common femoral artery (a large artery in the groin) is still the most frequently used access site. After the procedure, closure of the artery access site is usually achieved by manual compression. Since the mid-1990s, however, vascular closure devices (VCDs) have been introduced into clinical practice with the aim of improving efficacy and safety. Different types of VCDs have been developed, including intravascular and extravascular. However, concern exists about the safety of VCDs in comparison with manual compression, according to background information in the article.

For this study, conducted at four centers in Germany, 4,524 patients undergoing coronary angiography via the common femoral artery were randomly assigned to receive an intravascular VCD (n = 1,509), extravascular VCD (n = 1,506), or manual compression (n = 1,509) to achieve hemostasis (defined as no bleeding or only light superficial bleeding and no expanding hematoma [a localized swelling filled with blood]). Before hospital discharge, imaging of the access site was performed in 4,231 (94 percent) patients.

The primary end point (the composite of access site-related vascular complications at 30 days after randomization with a two percent noninferiority margin) was observed in 208 patients (6.9 percent) assigned to receive a VCD and 119 patients (7.9 percent) assigned to manual compression (difference, -1.0 percent). In addition, the time to hemostasis was significantly shorter with VCD compared with manual compression; time to hemostasis was shorter with intravascular VCD vs extravascular VCD; and device failures were less frequent with intravascular VCD vs extravascular VCD.

The authors write that the results of this trial may represent an important development for the clinical use of these devices. “Overall, the increase in efficacy of VCD use, with no trade-off in safety, provides a sound rationale for the use of VCD over manual compression in daily routine.”
(doi:10.1001/jama.2014.15305; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was funded by the Deutsches Herzzentrum Munchen, Munich, Germany. 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: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact Giulio Conte, M.D., email giulioconte.cardio@gmail.com.

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.2014.13752

Follow-up Testing Indicated After Initial Negative Test for Inherited Cardiac Syndrome That Can Cause Sudden Death

Giulio Conte, M.D., of the Heart Rhythm Management Centre, UZ Brussel-VUB, Brussels, Belgium and colleagues investigated the clinical significance of repeat testing after puberty in asymptomatic children with a family history of Brugada syndrome who had an initial negative test earlier in childhood. Brugada syndrome is a genetic disease that is characterized by abnormal electrocardiogram findings without structural heart disease and an increased risk of sudden cardiac death. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Brugada syndrome can present within the first months of life, although more typically in the fourth or fifth decade. Testing using ajmaline (an alkaloid) challenge is recommended, as it is an antiarrhythmic agent that can bring out the diagnostic electrocardiogram (ECG) pattern typical in patients suspected of having Brugada syndrome. Although screening of first-degree relatives is common, no evidence-based guidelines exist, particularly for children with normal ECGs, according to background information in the article.

The study included 53 asymptomatic individuals with a first-degree relative with Brugada syndrome and negative ajmaline test performed before 16 years of age between 1992 and 2010 who were seen at the university hospital of Brussels, Belgium (UZ Brussel­ VUB) and had an ECG repeated annually and were scheduled to repeat the test after puberty. Nine individuals were younger than 16 years and 1 presented with spontaneous Brugada type 1 ECG at age 16 years. The remaining 43 individuals repeated the ajmaline test, which unmasked type 1 ECG in 10 patients (23 percent).

“The ECG phenotype does not appear during childhood in most cases, but may develop later in response to hormonal, autonomic, or genetic factors,” the authors write.

“Screening of asymptomatic first-degree relatives of patients with Brugada syndrome is advisable, although the ideal timing is unknown. Relatives developing symptoms should always be investigated with ajmaline challenge even if they had a negative drug test performed before puberty. These findings support the need for repeat monitoring of family members of patients with Brugada syndrome, including those initially considered at low risk because of young age.”
(doi:10.1001/jama.2014.13752; 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: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact corresponding author Manesh R. Patel, M.D., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.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.2014.15095

Study Examines Prevalence, Risk of Death of Type of Coronary Artery Disease in Heart Attack Patients

Duk-Woo Park, M.D., of the University of Ulsan College of Medicine, Seoul, Korea, and Manesh R. Patel, M.D., of the Duke Clinical Research Institute, Durham, N.C., and colleagues investigated the incidence, extent, and location of obstructive non-infarct-related artery (IRA) disease and compared 30-day mortality according to the presence of non-IRA disease in patients with ST-segment elevation myocardial infarction (STEMI; a certain pattern on an electrocardiogram following a heart attack). Obstructive non-IRA disease is blockage in arteries not believed to be the cause of a heart attack. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Acute STEMI is the leading cause of sudden cardiac death and typically arises from the blockage of a coronary artery. Because the presence of significant non-IRA disease in patients with STEMI has been found to be associated with recurrent angina, repeat revascularization, and worse prognosis, a comprehensive estimation of the extent and location of obstructive non-IRA disease may be clinically important information for physicians in the development of optimal treatment strategies, according to background information in the article.

The study included a sample of patients from eight international, randomized STEMI clinical trials published between 1993 and 2007. Among 68,765 patients enrolled in the trials, 28,282 patients with valid angiographic information were included in this analysis. Follow-up varied from 1 month to 1 year. To assess the generalizability of trial-based results, external validation was performed using observational data for patients with STEMI from the Korea Acute Myocardial Infarction Registry (KAMIR; n = 18,217) and the Duke Cardiovascular Databank (n = 1,812).

The researchers found that 53 percent of patients (n = 14,929) had non-IRA disease and there were no substantial differences in the extent and location of non-IRA disease according to the IRA territory (muscle or area served by the suspected heart attack artery with the blockage). The presence of non-IRA disease was significantly associated with increased 30-day mortality, compared to patients without non-IRA disease (3.3 percent vs 1.9 percent). The overall prevalence and association of non-IRA disease with 30-day mortality was consistent with findings from the KAMIR registry, but not with the Duke database.

“These findings require confirmation in prospectively designed studies, but raise questions about the appropriateness and timing of non­IRA revascularization in patients with STEMI,” the authors write.
(doi:10.1001/jama.2014.15095; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported in part by the John Bush Simson Fund. The statistical portion of the manuscript was funded by the Duke Clinical Research Institute. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact Lars H. Lund, M.D., Ph.D., email lars.lund@alumni.duke.edu. To contact editorial co-author Marc A. Pfeffer, M.D., Ph.D., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.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.2014.15241. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.15358

Use of Beta-Blockers by Patients with Certain Type of Heart Failure Associated With Improved Rate of Survival

Lars H. Lund, M.D., Ph.D., of the Karolinska Institutet, Stockholm, Sweden, and colleagues conducted a study to examine whether beta-blockers are associated with reduced mortality in heart failure patients with preserved ejection fraction (a measure of how well the left ventricle of the heart pumps with each contraction).The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Up to half of patients with heart failure have normal or near-normal ejection fraction, termed heart failure with preserved ejection fraction (HFPEF). The risk of death in HFPEF may be as high as in heart failure with reduced ejection fraction (HFREF), but there is no proven therapy. Beta-blockers improve outcomes in HFREF and may be beneficial in HFPEF, but data are sparse and inconclusive, and beta-blockers are currently not indicated for treating HFPEF, according to background information in the article.

The researchers used data from the Swedish Heart Failure Registry, which includes 67 hospitals with inpatient and outpatient units and 95 outpatient primary care clinics in Sweden. This analysis included 41,976 patients, 19,083 patients with HFPEF. Of these, 8,244 were matched 2:1 based on age and beta-blocker use, yielding 5,496 treated and 2,748 untreated patients with HFPEF. Another analysis involved 22,893 patients with HFREF, of whom 6,081were matched, yielding 4,054 treated with beta-blockers and 2,027 untreated patients.

In the matched HFPEF cohort, 5-year survival was 45 percent vs 42 percent for treated vs untreated patients, with 2,279 (41 percent) vs 1,244 (45 percent) total deaths, and a seven percent reduction in the risk of death. Beta-blockers were not associated with reduced combined mortality or heart failure hospitalizations: 3,368 (61 percent) vs 1,753 (64 percent) total for first events. In the matched HFREF cohort, beta-blockers were associated with reduced mortality and also with reduced combined mortality or heart failure hospitalization.

“In patients with HFPEF, use of beta-blockers was associated with lower all-cause mortality but not with lower combined all­cause mortality or heart failure hospitalization,” the authors write. “Beta-blockers in HFPEF should be examined in a large randomized clinical trial.”
(doi:10.1001/jama.2014.15241; 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: Searching for Treatments of Heart Failure with Preserved Ejection Fraction – Matching the Data to the Question

In an accompanying editorial, Susan Cheng, M.D., M.P.H., and Marc A. Pfeffer, M.D., Ph.D., of Brigham and Women’s Hospital, Boston, write that by design, administrative databases, such as the one used in this study, offer limited ability to provide complete information about potentially important confounders.

“Thus, an attempt to use administrative data to probe the potential efficacy of a therapy is a mismatch of the data to the question. However, for most questions in medicine, only incomplete data are available to guide diagnostic and therapeutic decisions, and observational studies may have a role in assisting with treatment options. As the authors also conclude, more definitive information about whether beta-blocker therapy is effective for preventing important outcomes in HFPEF requires well-designed and well­ conducted randomized clinical trials.”
(doi:10.1001/jama.2014.15358; 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: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact Vivek Y. Reddy, M.D., call Lauren Woods at 646-634-0869 or email Lauren.Woods@mountsinai.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.2014.15192

Implanted Device Shows Potential as Alternative to Warfarin for Stroke Prevention in Patients with Atrial Fibrillation

Vivek Y. Reddy, M.D., of the Icahn School of Medicine at Mount Sinai, New York, and colleagues examined the long-term efficacy and safety, compared to warfarin, of a device to achieve left atrial appendage closure in patients with atrial fibrillation. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

The left atrial appendage (LAA) is a pouch-like appendix located in the upper left chamber of the heart. Studies have suggested that the LAA is the major source of clots that block blood vessels in patients with atrial fibrillation (AF). This has led to the development of mechanical approaches (via percutaneous catheters) to close the LAA. Oral anticoagulation with warfarin has been the mainstay of treatment for prevention of cardioembolic stroke in AF. Although effective, warfarin is limited by a need for lifelong coagulation monitoring and multiple medication and food interactions, according to background information in the article.

This study included 707 patients with nonvalvular AF and at least 1 additional stroke risk factor who were randomly assigned to LAA closure with a device (WATCHMAN; Boston Scientific) (n = 463) or warfarin (n = 244). The study was conducted at 59 hospitals in the U.S. and Europe.

At an average follow-up of 3.8 years, there were 39 events (stroke, systemic embolism [blood clot], and cardiovascular death) among 463 patients (8.4 percent) in the device group, compared with 34 events among 244 patients (13.9 percent) in the warfarin group, with the difference in the event rate indicating that LAA closure met prespecified criteria for both noninferiority (not worse than) and superiority compared with warfarin. LAA closure reduced the relative risk of a composite of these events by 40 percent (1.5 percent absolute reduction) compared with warfarin anticoagulation.

Patients in the device group demonstrated lower rates of both cardiovascular death (3.7 percent vs 9.0 percent of patients) and all-cause death (12.3 percent vs 18.0 percent of patients), with the device-based strategy associated with a 60 percent relative risk reduction (1.4 percent absolute reduction) of cardiovascular death and 34 percent relative reduction (5.7 percent absolute reduction) in all-cause death. The authors note that these mortality end points are secondary end points, and due to multiplicity of data analysis, there is some uncertainty in the confidence of this conclusion.

Although the device implantation procedure was associated with early complications, the accumulation of complications related to chronic anticoagulation resulted in similar safety profiles for the two groups.
(doi:10.1001/jama.2014.15192; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by the manufacturer of the device, Atritech (now owned by Boston Scientific) which provided the LAA closure device used in this trial. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact Matthew D. Ritchey, D.P.T., call Kate Grusich at 770-488-3337 or email yhb3@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.2014.11344

Overall Death Rate from Heart Disease Declines, Although Increase Seen for Certain Subtypes

Matthew D. Ritchey, D.P.T., of the Centers for Disease Control and Prevention (CDC), Atlanta, and colleagues examined the contributions of heart disease subtypes to overall heart disease mortality trends during 2000-2010. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Despite considerable information on overall heart disease (HD) and coronary HD (CHD) mortality trends, less is known about trends for other HD subtypes. The researchers analyzed mortality data from the CDC WONDER database, which contains death certificate information from every U.S. state and the District of Columbia. Deaths were included that occurred during 2000-2010 among U.S. residents 35 years or older with an underlying cause of death coded as CHD, heart failure, hypertensive HD (HHD), valvular HD, arrhythmia, pulmonary HD, or other HD.

During 2000-2010, there were 7,102,778 HD deaths. The mortality rates declined annually for total HD (-3.8 percent) and CHD (-5.1 percent). Mortality increased annually for HHD (1.3 percent) and arrhythmia (1.0 percent) and declined for most other subtypes. Although the HHD rate increased among non-Hispanic whites and was unchanged among non-Hispanic blacks, it remained much higher among non-Hispanic blacks in 2010. In 2010, excluding CHD and other HD, the leading cause of HD-related death was HHD among adults 35 to 54 years of age (12.1 percent) and those 55 to 74 years of age (6.7 percent); among those 75 years or older, it was heart failure (12.2 percent).

The authors write that although the proportions of HD deaths attributable to HHD and arrhythmia are relatively small, their mortality rate increases are notable. “Uncontrolled blood pressure and obesity among younger adults, especially non-Hispanic blacks, may be putting them at risk for developing HHD at an early age. … These increases might be linked to an aging population, the sequelae of persons living longer with heart failure, increases in chronic kidney disease and HHD prevalence, and possible changes in how arrhythmias are diagnosed and reported on death certificates.”

“Despite a continued decrease in overall HD mortality, considerable burden still exists. Public health and clinical communities should continue to develop and rigorously apply evidence-based interventions to prevent and treat CHD as well as other HD subtypes such as HHD and arrhythmia,” the authors conclude.
(doi:10.1001/jama.2014.11344; 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: 10 A.M. (CT) SUNDAY, NOVEMBER 16, 2014
Media Advisory: To contact corresponding author George A. Stouffer, M.D., call Tom Hughes at 984-974-1151 or email Tom.Hughes@unchealth.unc.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.2014.15236

Risk of Death May Be Higher if Heart Attack Occurs in a Hospital

Prashant Kaul, M.D., of the University of North Carolina, Chapel Hill, and colleagues conducted a study to define the incidence and treatment and outcomes of patients who experience a certain type of heart attack during hospitalization for conditions other than acute coronary syndromes. The study appears in the November 19 issue of JAMA, a cardiovascular disease theme issue.

Early restoration of blood flow with percutaneous coronary intervention (PCI; a procedure such as stent placement used to open narrowed coronary arteries) or administration of medication to dissolve a clot remains the primary goal in the initial treatment of eligible patients presenting to a hospital with ST-elevation myocardial infarction (STEMI; a certain pattern on an electrocardiogram following a heart attack). Over the last decade, recognition that this strategy is of critical importance has prompted the development of a number of regional and national initiatives to facilitate and improve systems of care for STEMI. These initiatives have focused exclusively on patients who develop STEMI outside of a hospital setting (outpatient-onset STEMI), and little is known about the incidence and outcomes of STEMI in patients hospitalized for non-acute coronary syndrome (ACS) conditions (inpatient­onset STEMI), according to background information in the article.

This study included an analysis of STEMIs occurring between 2008 and 2011 as identified in the California State Inpatient Database. Models were used to evaluate associations among location of onset of STEMI, resource utilization and outcomes. A total of 62,021 STEMIs were identified in 303 hospitals, of which 3,068 (4.9 percent) occurred in patients hospitalized for non-ACS indications.

The researchers found that patients developing inpatient-onset STEMI had more than 3-fold greater in-hospital mortality than those with outpatient-onset STEMI (33.6 percent vs 9.2 percent). Patients with inpatient-onset STEMI were less likely to be discharged home (33.7 percent vs 69.4 percent), and were less likely to undergo cardiac catheterization (33.8 percent vs 77.8 percent) or PCI (21.6 percent vs 65 percent). Average length of stay (13 days vs 5 days) and inpatient charges ($245,000 vs $129,000) were higher for inpatient-onset STEMI. Patients with inpatient-onset STEMI were older and more frequently female.

“The question of how to improve outcomes and define optimum treatment in hospitalized patients who experience a STEMI is an area that merits more attention and concern. Although there have been improvements in treatment times and clinical outcomes in outpatients who have onset of STEMI, few initiatives have focused on optimizing care of hospitalized patients with onset of STEMI after admission,” the authors write.
(doi:10.1001/jama.2014.15236; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3:30 P.M. (CT) THURSDAY, NOVEMBER 13, 2014
Media Advisory: To contact co-author Alexander P. Reiner, M.D., call Kristen Lidke Woodward at 206-972-4333 or email kwoodwar@fredhutch.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.2014.15063

Sickle Cell Trait Among African Americans Associated With Increased Risk of Chronic Kidney Disease

In a study that included nearly 16,000 African Americans, those with sickle cell trait had an associated increased risk of chronic kidney disease and measures linked to poorer kidney function, according to a study appearing in JAMA. Sickle cell trait is a condition in which a person has only one copy of the gene for sickle cell but does not have sickle cell disease (which requires two copies of this gene). The study is being released to coincide with its presentation at the American Society of Nephrology’s annual Kidney Week meeting.

It is estimated that sickle cell trait (SCT) affects 1 in 12 African Americans and nearly 300 million people worldwide. The relationship of SCT to long-term functional impairment of the kidney has not been firmly established, according to background information in the article.

Using five large, U.S. population-based studies, Rakhi P. Naik, M.D., of Johns Hopkins University, Baltimore, and Vimal K. Derebail, M.D., of the University of North Carolina at Chapel Hill, and colleagues evaluated 15,975 self-identified African Americans (1,248 patients with SCT [SCT carriers] and 14,727 patients without SCT [noncarriers]) to examine the relationship between SCT and chronic kidney disease (CKD) and albuminuria (the presence of excessive protein in the urine, often a symptom of a kidney disorder). The studies included in the analysis were the Atherosclerosis Risk in Communities Study (ARIC); Jackson Heart Study (JHS); Coronary Artery Risk Development in Young Adults (CARDIA); Multi-Ethnic Study of Atherosclerosis (MESA); and the Women’s Health Initiative (WHI).

Chronic kidney disease (defined as a certain measure of estimated glomerular filtration rate [eGFR; the flow rate of filtered fluid through the kidney]) was present in 2,233 individuals (239 of 1,247 SCT carriers [19.2 percent) vs 1,994 of 14,722 noncarriers [13.5 percent]). A total of 20.7 percent of SCT carriers vs 13.7 percent of noncarriers experienced incident CKD. Sickle cell trait was significantly associated with a faster decline in eGFR; 22.6 percent of SCT carriers vs 19.0 percent of noncarriers from the 5 cohorts experienced eGFR decline; 31.8 percent of SCT carriers had albuminuria vs 19.6 percent of noncarriers.

“Our findings show an association of SCT with the development of CKD in African Americans,” the authors write.

The researchers add that the associations found in this study may offer an additional genetic explanation for the increased risk of CKD observed among African Americans compared with other racial groups. “Our study also highlights the need for further research into the renal complications of SCT. Because screening for SCT is already being widely performed, accurate characterization of disease associations with SCT is critical to inform policy and treatment recommendations.”
(doi:10.1001/jama.2014.15063; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 11, 2014
Media Advisory: To contact Adriaan J. van der Meer, M.D., Ph.D., email a.vandermeer@erasmusmc.nl.

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.2014.12627

Study Examines Life Expectancy Among Patients With Chronic Hepatitis C Virus Infection and Cirrhosis

Patients with chronic hepatitis C virus infection and advanced fibrosis or cirrhosis who attained sustained virological response (SVR) had survival comparable with that of the general population, whereas patients who did not attain SVR had reduced survival, according to a study in the November 12 issue of JAMA.

Almost three million people in the United States are chronically infected with the hepatitis C virus (HCV). The life expectancy of patients with chronic HCV infection is reduced compared with the general population, largely attributable to the development of cirrhosis, liver failure and cancer. Studies have shown that the risk of all-cause death is lower among patients with chronic HCV infection and advanced hepatic (liver) fibrosis (development of excess fibrous connective tissue) if sustained virological response (SVR) is attained, but comparisons have been limited to those without SVR, according to background information in the article.

Adriaan J. van der Meer, M.D., Ph.D., of the Erasmus MC University Medical Center Rotterdam, the Netherlands, and colleagues compared overall survival of patients with chronic HCV infection and advanced fibrosis or cirrhosis before therapy (with and without SVR) with that of the general population. The researchers used data on patients from Europe and Canada with chronic HCV and advanced hepatic fibrosis from a previous study. Follow-up started 24 weeks after cessation of antiviral treatment, at which time achievement of SVR (defined as HCV RNA negativity in a blood sample) was determined. For each virological response group, the observed overall survival was compared with the expected survival from matched age-, sex- and calendar time–specific death rates of the general population in the Netherlands.

In total, 530 patients were followed for a median of 8.4 years; follow-up was complete in 454 patients (86 percent), 192 of whom attained SVR. Thirteen patients with SVR died, resulting in a cumulative 10-year overall survival of 91.1 percent, which did not differ significantly from the age- and sex-matched general population. In contrast, 100 patients without SVR died. The cumulative 10-year survival was 74.0 percent, which was significantly lower compared with the matched general population.

“The excellent survival among patients with advanced liver disease and SVR might be explained by the associations between SVR and regression of hepatic inflammation and fibrosis, reduced hepatic venous pressure gradient, reduced occurrence of hepatocellular carcinoma and liver failure, as well as reduced occurrence of diabetes mellitus, end-stage renal disease, and cardiovascular events. Even though patients with cirrhosis and SVR remain at risk for hepatocellular carcinoma, the annual hepatocellular carcinoma incidence is low and survival is substantially better compared with those without SVR,” the authors write.
(doi:10.1001/jama.2014.12627; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 11, 2014
Media Advisory: To contact Ziad Obermeyer, M.D., M.Phil., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org. To contact editorial co-author Joan M. Teno, M.D., M.S., call David Orenstein at 401-863-1862 or email david_orenstein@brown.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.2014.14950. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.14949

Use of Hospice Care by Medicare Patients Associated With Lower Rate of Hospitalization, ICU Admission, Invasive Procedures and Costs

Medicare patients with poor­ prognosis cancers who received hospice care had significantly lower rates of hospitalization, intensive care unit (ICU) admissions and invasive procedures at the end of life, along with significantly lower health care expenditures during the last year of life, according to a study in the November 12 issue of JAMA.

Multiple studies have documented the high intensity of medical care at the end of life, and there is increasing consensus that such care can produce poor outcomes and conflict with patient preferences. The Institute of Medicine report Dying in America has drawn attention to the difficulties of promoting palliative care, including Medicare’s hospice program, the largest palliative care intervention in the United States, which covers all comfort­oriented care related to terminal illnesses from medications to home care to hospitalizations. More patients with cancer use hospice currently than ever before, but there are indications that care intensity outside of hospice is increasing, and length of hospice stay decreasing. Uncertainties regarding how hospice affects health care utilization and costs have hampered efforts to promote it, according to background information in the article.

Using data from Medicare beneficiaries with poor-prognosis cancers (e.g., brain, pancreatic, metastatic malignancies), Ziad Obermeyer, M.D., M.Phil., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues matched those enrolled in hospice before death to those who died without hospice care and compared utilization and costs at the end of life. The study included a nationally representative 20 percent sample of Medicare fee-for-service beneficiaries who died in 2011.

Among 86,851 patients with poor-prognosis cancers, 51,924 (60 percent) entered hospice before death. Matching patients based on various criteria produced a hospice and nonhospice group, each with 18,165 patients. Median hospice duration was 11 days.

The researchers found that nonhospice beneficiaries had significantly greater health care utilization, largely for acute conditions not directly related to cancer and higher overall costs. Rates of hospitalizations (65 percent vs 42 percent), ICU admissions (36 percent vs 15 percent), invasive procedures (51 percent vs 27 percent), and death in a hospital or nursing facility (74 percent vs 14 percent) were higher for nonhospice beneficiaries compared to hospice patients. Overall, costs during the last year of life were $62,819 for hospice beneficiaries and $71,517 for nonhospice beneficiaries.

“Our findings highlight the potential importance of frank discussions between physicians and patients about the realities of care at the end of life, an issue of particular importance as the Medicare administration weighs decisions around reimbursing physicians for advance care planning,” the authors write.
(doi:10.1001/jama.2014.14950; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by grants from the National Institutes of Health, National Cancer Institute, and Agency for Healthcare Research and Quality. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

There will be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, November 11 at this link.

Editorial: Quality and Costs of End-of-Life Care

Joan M. Teno, M.D., M.S., and Pedro L. Gozalo, Ph.D., of the Brown University School of Public Health, Providence, R.I., comment on end-of-life care in an accompanying editorial.

“As financial incentives change in the U.S. health care system, valid measures of care quality are increasingly important for ensuring transparency and accountability. Obermeyer and colleagues assessed hospitalization rates, intensive care admissions, and invasive procedures, but additional measures must have evidence of their ability to discriminate the quality of care and must be responsive to change, easy to understand, and actionable. This will involve investing public dollars in the ‘quality’ of quality measures and their dissemination. If quality of care is not front and center, the momentum to improve end-of-life care in the United States could face a serious setback.”
(doi:10.1001/jama.2014.14949; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Teno is the recipient of a Robert Wood Johnson Foundation Health Policy Investigators Award grant. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 11, 2014
Media Advisory: To contact Elyse O. Kharbanda, M.D., M.P.H., email Patricia Lund at Patricia.A.Lund@healthpartners.com.

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.2014.14825

Administration of Tdap Vaccine During Pregnancy Not Associated With Increased Risk of Preterm Delivery, Small Birth Size

Among approximately 26,000 women, receipt of the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine during pregnancy was not associated with increased risk of preterm delivery or small-for-gestational-age birth or with hypertensive disorders of pregnancy, although a small increased risk of being diagnosed with chorioamnionitis (an inflammation of the membranes that surround the fetus) was observed, according to a study in the November 12 issue of JAMA.

The Tdap vaccine was licensed in 2005 for use in nonpregnant adolescents and adults. Initially, postpartum administration of Tdap to parents and other caregivers was encouraged to prevent the transmission of pertussis to newborns. However, recent outbreaks, including infant deaths, have led to changing Tdap vaccine recommendations. In 2010, California became the first state to recommend Tdap be routinely administered during pregnancy. Tdap is now recommended by the Advisory Committee on Immunization Practices for all pregnant women, preferably between 27 and 36 weeks’ gestation. To date, there have been limited specific data on whether vaccination with Tdap during pregnancy adversely affects the health of mothers or their offspring, according to background information in the article.

Elyse O. Kharbanda, M.D., M.P.H., of the HealthPartners Institute for Education and Research, Minneapolis, and colleagues used administrative health care databases from 2 California Vaccine Safety Datalink sites to examine whether receipt of Tdap during pregnancy was associated with increased risks of selected adverse obstetric or birth outcomes. Included in the analysis were 123,494 women with pregnancies ending in a live birth between January 1, 2010 and November 15, 2012; 26,229 (21 percent) received Tdap during pregnancy and 97,265 did not.

The researchers found that receipt of Tdap during pregnancy was not associated with increased risk of preterm (<37 weeks’ gestation) or small-for-gestational-age (SGA) births. Among all pregnancies, 8.4 percent of those who received Tdap during pregnancy and 8.3 percent who were unexposed to the vaccine had an SGA birth. The rate of preterm delivery among women receiving Tdap during pregnancy at 36 weeks’ gestation or earlier was 6.3 percent, whereas the rate for unexposed women was 7.8 percent. Receipt of Tdap was not associated with increased risk of hypertensive disorders of pregnancy. Among women who received Tdap at any time during pregnancy, 6.1 percent were diagnosed with chorioamnionitis compared with 5.5 percent of unexposed women. In the subset of women vaccinated between 27 and 36 weeks’ gestation, this risk was still increased but less so. The authors note that these results should be interpreted with caution because the magnitude of the risk was small. “Given limited prior safety data, continued widespread pertussis transmission, and current recommendations to routinely vaccinate during pregnancy, our study provides important information on the safety of Tdap vaccination during pregnancy,” the authors write. (doi:10.1001/jama.2014.14825; Available pre-embargo to the media at https://media.jamanetwork.com) Editor’s Note: This study was funded through a contract from the CDC. Additional funding for chart reviews came from contracts from the CDC Vaccine Safety Datalink infrastructure task order. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc. [ama_toc_item id="29146"] # # #

Long-term Risks and Benefits of Bariatric Surgery
(For Immediate Release)

Bruce M. Wolfe, M.D., of the Oregon Health and Science University, Portland and Steven H. Belle, Ph.D., of the University of Pittsburgh Graduate School of Public Health, discuss the research challenges presented for determining long-term outcomes of bariatric surgery. They write that “metabolic/bariatric surgery offers the potential to address the morbidity and mortality of the obesity epidemic, but important research questions remain unresolved. No single study or research model will successfully address all of these questions. The substantial resources required for a clinical trial large enough with enough follow-up to address important research questions may be impractical, so extending follow-up of well-characterized and established cohorts, potentially with linkage to other data resources, may be the best hope to obtain the information needed to address long-term risks and benefits of bariatric surgery.”
(doi:10.1001/jama.2014.12966)

Behavioral Treatment of Obesity in Patients Encountered in Primary Care Settings
(Embargoed for Release: 3 p.m. CT Tuesday, November 4, 2014)

Thomas A. Wadden, Ph.D., of the University of Pennsylvania Perelman School of Medicine, Philadelphia, and colleagues conducted a systematic review of behavioral counseling for overweight and obese patients recruited from primary care, as delivered by primary care practitioners working alone or with trained interventionists (eg, medical assistants, registered dietitians), or by trained interventionists working independently. The researchers found that intensive behavioral counseling can induce clinically meaningful weight loss, but there is little research on primary care practitioners providing such care. They add that the “findings suggest that a range of trained interventionists, who deliver counseling in person or by telephone, could be considered for treating overweight or obesity in patients encountered in primary care settings.”
(doi:10.1001/jama.2014.14173)

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 4, 2014
Media Advisory: To contact Tsontcho Ianchulev, M.D., M.P.H., call Scott Maier at 415-476-3595 or email scott.maier@ucsf.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.2014.13754

Study Finds Google Glasses May Partially Obstruct Peripheral Vision

Testing of study participants who wore head-mounted display systems (Google glasses) found that the glasses created a partial peripheral vision obstruction, according to a study in the November 5 issue of JAMA.

Interest in wearable head-mounted display systems for general consumers is increasing, with multiple models in production. However, their effect on vision is largely unknown. Peripheral visual field is a main component of vision and essential for daily activities such as driving, pedestrian safety, and sports. Conventional spectacle frames can reduce visual field, sometimes causing absolute blind spots, and head­ mounted devices have even more pronounced frames, according to background information in the article.

Tsontcho Ianchulev, M.D., M.P.H., of the University of California, San Francisco, and colleagues compared performance on visual field tests with a head-mounted device vs regular eyewear to quantify their effect on visual function. Three healthy individuals with 20/20 best-corrected visual acuity and normal baseline visual fields were tested in April 2014. Participants used a wearable device (Google Glass, Google Inc.), following manufacturer’s instructions, for a 60-minute acclimation period. Perimetric visual testing (a measurement of the field of vision) was conducted first with the device, followed by a control frame (regular eyewear) of similar color and temple width.

In addition, to assess how the devices are worn by general consumers, photographs of people wearing the product and facing the camera, obtained from an Internet search, were analyzed. Photographs were assessed for prism position relative to the pupil.

Visual field testing demonstrated significant scotomas (blind spots) in all 3 participants while wearing the device, creating a clinically meaningful visual field obstruction in the upper right quadrant. Defects were induced by the Google Glass frame hardware design only and were not related to a distracting effect of software-related interference.

An analysis of 132 images indicated that many people wear the device near or overlapping their pupillary axis (a line perpendicular to the surface of the cornea, passing through the center of the pupil), which may induce scotomas and interfere with daily function.

The authors note that the study is limited by the small number of participants, who may not be representative of all users, and that a larger sample is needed to identify factors that influence scotoma size and depth.

“Additional studies are needed to understand the effects of these devices on visual function, particularly as their use becomes increasingly common,” the authors conclude.
(doi:10.1001/jama.2014.13754; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 4, 2014
Media Advisory: To contact F. Stephen Hodi, M.D., call Teresa Herbert at 617-632-5653 or email teresa_herbert@dfci.harvard.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.2014.13943

Combination Treatment for Metastatic Melanoma Results in Longer Overall Survival

Among patients with metastatic melanoma, treatment with a combination of the drugs sargramostim plus ipilimumab, compared with ipilimumab alone, resulted in longer overall survival and lower toxicity, but no difference in progression-free survival, according to a study in the November 5 issue of JAMA.

F. Stephen Hodi, M.D., of the Dana-Farber Cancer Institute, Boston, and colleagues conducted a phase 2 clinical trial in which 245 patients with unresectable (unable to be removed by surgery) stage Ill or IV melanoma were randomly assigned to receive ipilimumab (intravenously) on day 1 plus sargramostim (injected beneath the skin) on days 1 to 14 of a 21-day cycle (n = 123) or ipilimumab alone (n = 122). The researchers compared the effect of these treatments on length of overall survival, progression-free survival, response rate, safety, and tolerability.

Median follow-up was 13.3 months. The overall survival was significantly improved with the addition of sargramostim to ipilimumab. The median overall survival was 17.5 months for the ipilimumab plus sargramostim group and 12.7 months for the ipilimumab-only group. The 1-year overall survival was 68.9 percent for the combination treatment group and 52.9 percent for the ipilimumab-only group. There was no difference in progression-free survival. Adverse events were more common in the ipilimumab-only group. Toxicity was significantly lower in the ipilimumab plus sargramostim group than in the ipilimumab­only group.

“This randomized phase 2 study supports the evidence that the addition of sargramostim to ipilimumab therapy improved overall survival in patients with metastatic melanoma,” the authors write. “These findings require confirmation in larger sample sizes and with longer follow-up.”
(doi:10.1001/jama.2014.13943; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, NOVEMBER 4, 2014
Media Advisory: To contact Thomas M. Maddox, M.D., M.Sc., call Daniel Warvi at 303-393-5205 or email Daniel.Warvi@va.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.2014.14681

Nonobstructive Coronary Artery Disease Associated With Increased Risk of Heart Attack, Death

In a study that included nearly 38,000 patients, those diagnosed with nonobstructive coronary artery disease (CAD) had a significantly increased risk of heart attack or death one year after diagnosis, according to a study in the November 5 issue of JAMA.

Nonobstructive coronary artery disease (CAD) is atherosclerotic plaque that would not be expected to obstruct blood flow or result in anginal symptoms (such as chest pain). Although such lesions are relatively common, occurring in 10 percent to 25 percent of patients undergoing coronary angiography, their presence has been characterized as “insignificant” or “no significant CAD” in the medical literature. However, this perception of nonobstructive CAD may be incorrect, because prior studies have noted that the majority of plaque ruptures and resultant myocardial infarctions (MIs; heart attacks) arise from nonobstructive plaques. Despite the prevalence of nonobstructive CAD identified by coronary angiography, little is known about its risk of adverse outcomes, according to background information in the article.

Thomas M. Maddox, M.D., M.Sc., of the VA Eastern Colorado Health Care System, Denver, and colleagues compared heart attack and mortality rates among patients with nonobstructive CAD, obstructive CAD, and no apparent CAD. The patients included in the study were all U.S. veterans who underwent elective coronary angiography for CAD between October 2007 and September 2012 in the Veterans Affairs health care system. Patients with prior CAD events were excluded. CAD extent was defined by degree of vessel narrowing and distribution (1, 2, or 3 vessel).

During the study period, 37,674 patients underwent elective coronary angiography for indications related to CAD; of those, 22.3 percent had nonobstructive CAD and 55.4 percent had obstructive CAD. Within 1 year, 845 patients died and 385 were rehospitalized for MI. The researchers found that the 1-year MI risk progressively increased by the extent of CAD, rather than abruptly increasing between nonobstructive and obstructive CAD. Patients with nonobstructive CAD had an associated risk of MI that was 2-to 4.5-fold greater than among those with no apparent CAD. Similar observations were seen with 1-year mortality and the combined outcome of 1-year MI and death.

“These findings highlight a need to recognize that nonobstructive CAD is associated with significantly increased risk for MI, consistent with prior biologic studies indicating that a majority of MIs are related to nonobstructive stenosis [narrowing of an artery]. Correspondingly, these results reveal the limitations of a dichotomous [divided into two parts] characterization of angiographic CAD into ‘obstructive’ and ‘nonobstructive’ to predict MI and highlight the importance of preventive strategies such as pharmacotherapy treatments and lifestyle modifications to mitigate these risks,” the authors write.
(doi:10.1001/jama.2014.14681; 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: 11:30 A.M. (CT) SATURDAY, NOVEMBER 1, 2014
Media Advisory: To contact Robert A. Fowler, M.D.C.M., M.S., call Laura Bristow at 416-480-4040 or email laura.bristow@sunnybrook.ca.

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.2014.15101

Low-Molecular-Weight Heparin More Cost-Effective than Unfractionated Heparin for Preventing Blood Clots in Critically Ill Patients

From a health care payer perspective, prevention of venous thromboembolism (blood clot in a vein) with low-molecular-weight heparin dalteparin in critically ill patients was more effective and had similar or lower costs than the use of unfractionated heparin, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the Critical Care Canada Forum.

A recent randomized trial (PROTECT) comparing the effectiveness of the two most common strategies using drugs to prevent venous thromboembolism (VTE), the anticoagulants low-molecular-weight heparin (LMWH) dalteparin and unfractionated heparin (UFH), found no difference regarding deep-vein thrombosis but reduced rates of pulmonary embolus (clot) and heparin-induced thrombocytopenia (low platelet count) in the patients who received LMWH dalteparin. Drug acquisition costs have historically been higher for LMWH than for UFH. However, if the effects of these drugs on outcomes important to patients differs substantially, paying more may be worth it, which highlights the need for comparative economic and clinical effectiveness research to inform practice, according to background information in the article. Cost is cited as the most important barrier to using LWMH in a recent North American survey.

Robert A. Fowler, M.D.C.M., M.S., of the Sunnybrook Health Sciences Centre, University of Toronto, and colleagues evaluated the comparative cost-effectiveness of LMWH vs UFH for prevention against VTE in critically ill patients. The researchers conducted an economic evaluation concurrent with the PROTECT trial (May 2006 to June 2010), including measured costs among 2,344 patients in 23 centers in 5 countries and applied these costs to measured resource use and effects of all enrolled patients.

The researchers found that the median postrandomization hospital costs of care for patients who received UFH was greater ($40,805) compared with $39,508 for patients who received dalteparin, but the difference was not statistically significant. For 7 of 8 prespecified subgroups, using conventional cost metrics to prevent specific VTE-related events indicated that dalteparin was the most effective and least costly strategy to prevent all thrombotic events, pulmonary embolus, deep-vein thrombosis, major bleeding, and heparin-induced thrombocytopenia, given its lower cost combined with better effects.

Additional analyses indicated that a strategy using LMWH was most effective, least costly 78 percent of the time, and remained least costly unless the drug acquisition cost of dalteparin was to increase by more than 20-fold. There was no threshold in which lowering the acquisition cost of UFH favored prevention with UFH.

“These findings are important for the care of critically ill patients because they provide a cost-minimization rationale that complements clinical effectiveness knowledge from PROTECT. For example, if an ICU with 1,000 medical-surgical admissions per year uses UFH instead of LMWH for prevention of VTE, the annual incremental cost may be between $1,000,000 to $1,500,000 with similar or worse clinical outcomes, despite the individual drug cost of UFH being $4 to $5 less per day,” the researchers write.

The authors note that these findings were driven by lower rates of pulmonary embolus and heparin-induced thrombocytopenia and corresponding lower overall use of resources with LMWH.
(doi:10.1001/jama.2014.15101; 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: 2:30 P.M. (CT) SUNDAY, OCTOBER 26, 2014
Media Advisory: To contact corresponding author George Thanassoulis, M.D., email Julie Robert at julie.robert@muhc.mcgill.ca or Jane-Diane Fraser at JFraser@hsf.ca.

Genetic Predisposition to Elevated LDL-C Associated With Narrowing of the Aortic Valve

In an analysis that included approximately 35,000 participants, genetic predisposition to elevated low-density lipoprotein cholesterol (LDL-C) was associated with aortic valve calcium and narrowing of the aortic valve, findings that support a causal association between LDL-C and aortic valve disease, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the Canadian Cardiovascular Congress.

Aortic valve disease remains the most common form of heart valve disease in Europe and North America and is the most common indication for valve replacement. Despite the heavy disease burden, no medical treatments are known to stop or slow disease progression. Plasma LDL-C has been associated with aortic stenosis (narrowing) in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. If LDL-C plays a causal role in the earlier stages of aortic valve disease, this could have important implications for prevention, according to background information on the article.

Because of the random allocation of genetic information that occurs at conception, genetic variation can be used as an effective tool to distinguish potentially causal from noncausal biomarkers. Termed “Mendelian randomization,” this approach has been successfully applied to assess for causality of several biomarkers with various clinical end points. Using this approach, J. Gustav Smith, M.D., of Lund University, Lund, Sweden, and colleagues, evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, were associated with aortic valve disease. The researchers included community-based cohorts participating in the CHARGE consortium (n = 6,942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1,295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2,527), Age Gene/Environment Study–Reykjavik (2000-2012; n = 3,120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28,461).

Aortic valve calcium was quantified by computed tomography; prevalent and new diagnoses of aortic stenosis and aortic valve replacement were identified by record linkage with nationwide registers on hospitalizations and causes of death.

The researchers found that in the subgroup of the MDCS where lipid fractions were measured (n = 5,269), baseline LDL-C, but not high-density lipoprotein cholesterol (HDL-C) or triglycerides (TG) levels, was significantly associated with new aortic stenosis. Also, the LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE and with new aortic stenosis in MDCS.

“Our findings link a genetically mediated increase in plasma LDL-C with early subclinical valve disease, as measured by aortic valve calcium, and incident clinical aortic stenosis, providing supportive evidence for a causal role of LDL-C in the development of aortic stenosis,” the authors write. “These data suggest that, in addition to the established risks for myocardial infarction and other vascular diseases, increases in LDL-C are also associated with increased risk for aortic stenosis.”

“Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.”
(doi:10.1001/jama.2014.13959; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 21, 2014
Media Advisory: To contact Pieter A. Cohen, M.D., call David Cecere at 617-591-4044 or email dcecere@challiance.org.

Study Finds High Percentage of Recalled Dietary Supplements Still Have Banned Ingredients

About two-thirds of FDA recalled dietary supplements analyzed still contained banned drugs at least 6 months after being recalled, according to a study in the October 22/29 issue of JAMA.

The U.S. Food and Drug Administration (FDA) initiates class I drug recalls when products have the reasonable possibility of causing serious adverse health consequences or death. Recently, the FDA has used class I drug recalls in an effort to remove dietary supplements adulterated with pharmaceutical ingredients from U.S. markets. Prior research has found that even after FDA recalls, dietary supplements remain available on store shelves. However, it has not been known if the supplements on sale after FDA recalls are free of the adulterants, according to background information in the article.

Pieter A. Cohen, M.D., of Harvard Medical School, Boston, and colleagues conducted a study to determine if banned drugs were still present in dietary supplements purchased at least six months after a recall. The FDA recalled 274 dietary supplements between January 2009 and December 2012. Twenty-seven of the 274 recalled supplements (9.9 percent) met inclusion criteria for the study and were analyzed using the same methods at the FDA’s laboratories (e.g., gas chromatography/mass spectrometry). Supplements were purchased an average of 34.3 months (range 8-52 months) after the FDA recall. Seventy-four percent of supplements (20/27) were produced by U.S. manufacturers.

The researchers found that one or more pharmaceutical adulterant was identified in 66.7 percent of recalled supplements still available for purchase (18/27). Supplements remained adulterated in 85 percent (11/13) of those for sports enhancement, 67 percent (6/9) for weight loss, and 20 percent (1/5) for sexual enhancement. Of the subset of supplements produced by U.S. manufacturers, 65 percent (13/20) remained adulterated with banned ingredients.

Sixty-three percent of analyzed supplements contained the same adulterant identified by the FDA. Six (22.2 percent) supplements contained 1 or more additional banned ingredients not identified by the FDA. Some supplements contained both the previously identified adulterant as well as additional pharmaceutical ingredients.

Banned substances identified in recalled supplements included sibutramine, sibutramine analogs, sildenafil, fluoxetine, phenolphthalein, aromatase inhibitor, and various anabolic steroids.

“To our knowledge, this is the first study to determine if adulterants remain in supplements sold after FDA recalls,” the authors write.

“Action by the FDA has not been completely effective in eliminating all potentially dangerous adulterated supplements from the U.S. marketplace. More aggressive enforcement of the law, changes to the law to increase the FDA’s enforcement powers, or both will be required if sales of these products are to be prevented in the future.”
(doi:10.1001/jama.2014.10308; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 21, 2014
Media Advisory: To contact James C. Robinson, Ph.D., M.P.H., call Sarah Yang at 510- 643-7741 or email scyang@berkeley.edu.

Study Examines Differences Between Types of Physician Practice Ownership and Expenditures

From the perspective of the insurers and patients, between 2009 and 2012, hospital-owned physician organizations in California incurred higher expenditures for commercial health maintenance organization enrollees for professional, hospital, laboratory, pharmaceutical and ancillary services than did physician-owned organizations, according to a study in the October 22/29 issue of JAMA.

Hospitals and multihospital systems are acquiring medical groups and physician practices as part of a strategy to build integrated delivery systems capable of providing the full range of professional, facility, laboratory, and pharmaceutical services to affiliated patients. This consolidation may foster cooperation and thereby reduce expenditures, but also may lead to higher expenditures through greater use of hospital-based ambulatory services and through greater hospital pricing leverage against health insurers. The policy debate about consolidation has gained new policy attention due to the financial incentives provided by the Affordable Care Act for physicians to join hospital-affiliated accountable care organizations, according to background information in the article.

James C. Robinson, Ph.D., M.P.H., of the University of California, School of Public Health, Berkeley, and Kelly Miller, B.A., of the Integrated Healthcare Association, Oakland, conducted a study to determine whether total expenditures per patient were higher in physician organizations owned by local hospitals or multihospital systems compared with physician organizations owned by participating physicians. Data were obtained on total expenditures for the care provided to 4.5 million patients treated by integrated medical groups and independent practice associations in California between 2009 and 2012.The patients were covered by commercial health maintenance organization (HMO) insurance and the data did not include patients covered by commercial preferred provider organization (PPO) insurance, Medicare, or Medicaid.

Of the 158 organizations, 118 physician organizations (75 percent) were physician-owned and provided care for 3,065,551 patients, 19 organizations (12 percent) were owned by local hospitals and provided care for 728,608 patients and 21organizations (13 percent) were owned by multihospital systems and provided care for 693,254 patients. The researchers found that the average expenditure per patient across all physician organizations increased by 16.5 percent between 2009 and 2012, from $2,954 to $3,443. By 2012, expenditures per patient had increased to an average of $3,066 in physician-owned organizations, $4,312 in local hospital-owned organizations, and $4,776 in multihospital system-owned organizations. These represent a 40.6 percent relative difference in expenditures per patient associated with hospital ownership and 55.8 percent relative difference associated with ownership by a multihospital system compared with ownership by member physicians.

After adjusting for patient severity and other factors over the period, local hospital-owned physician organizations incurred expenditures per patient 10.3 percent higher than did physician-owned organizations. Organizations owned by multihospital systems incurred expenditures 19.8 percent higher than physician-owned organizations. The largest physician organizations incurred expenditures per patient 9.2 percent higher than the smallest organizations.

“These findings are in contrast to the hope and expectation that organizational consolidation of physicians with hospitals would result in greater coordination, and hence lower expenditures. Policymakers must strive to ensure that hospital acquisition of medical groups and physician practices does not lead to higher expenditures. Antitrust law and policy need to find the appropriate balance between permitting hospital acquisitions that improve efficiency, on the one hand, and preventing acquisitions that increase expenditures, on the other. Reform of payment methods by Medicare and private insurers should focus on the total expenditures made on behalf of patients by the physicians and facilities involved in their care to promote coordination but also to create incentives for efficiency and price reductions,” the authors write.
(doi:10.1001/jama.2014.14072; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Support for this research was obtained from 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: 3 P.M. (CT) TUESDAY, OCTOBER 21, 2014
Media Advisory: To contact Laurence C. Baker, Ph.D., call Becky Bach at 530-415-0507 or email retrout@stanford.edu.

More Competition Among Physicians Related to Lower Prices Paid By Private PPOs For Office Visits

An examination of the relationship between physician competition and prices paid by private preferred provider organizations (PPOs) for common office visits finds that more competition is associated with lower prices paid to physicians in 10 large specialties, according to a study in the October 22/29 issue of JAMA.

Physicians are increasingly moving away from solo and smaller practices toward larger organizations. These changes may be beneficial if larger practices with more resources are better able to coordinate care, adopt process improvements, increase use of information technology, or take other actions that improve quality of care. At the same time, a trend toward fewer and larger groups could increase what economists refer to as “market concentration,” resulting in fewer practices facing less competition and with greater economic power. This in turn could lead health plans to pay higher prices for physician services. However, there is little evidence on the relationship between competition and prices paid for physician services, according to background information in the study.

Laurence C. Baker, Ph.D., of the Stanford University School of Medicine, Stanford, Calif., and colleagues conducted a study that included data from 1,058 U.S. counties in urbanized areas, representing all 50 states. The researchers determined the average price paid by county to physicians in 10 specialties by private PPOs for office visits with established patients and a price index measuring the county-weighted average price for 10 types of office visits with new and established patients relative to national average prices. The specialties were internal medicine, family practice, cardiology, dermatology, gastroenterology, neurology, general surgery, orthopedics, urology, and otolaryngology.

The researchers found that less competition among physician practices was associated with higher prices paid by private PPOs to physicians for office visits. Across 10 types of office visits, the difference in the Hirschman-Herfindahl Index (HHI; an economic competition measure) was associated with average prices for office visits 8.3 percent to 16.1 percent higher. In a more conservative model, this difference in the HHI was associated with 3.5 percent to 5.4 percent higher average prices. “This is consistent with the hypothesis that greater market power allows physicians to bargain for higher prices from private insurance companies.”

Examining changes in prices between 2003 and 2010, prices increased more rapidly in areas where practices were initially less competitive than in other areas. In some specialties, declining competition was also associated with larger increases in prices in areas that were initially more competitive. “This pattern suggests the possibility that the results we observe in 2010 may be related to the ability of practices in low-competition areas to negotiate larger price increases over time as well as related to changes in competition over time. This suggests that a lack of competition could have long­lasting effects, continuing to drive future price increases even without further changes in Hirschman-Herfindahl Index,” the authors write.

“An association between competition and prices may have important implications for health policy, as pressures to increase practice size persist or even increase in the future. We saw substantial amounts of concentration in the markets we studied, which raises concerns about potentially harmful implications for consumers. Higher health care spending due to increased prices paid to physicians without accompanying improvements in quality, satisfaction, or outcomes would generate inefficiency in the health care system.”

“These results may inform the development or adaptation of policies that influence practice competition,” the authors conclude.
(doi:10.1001/jama.2014.10921; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The National Institute for Health Care Management provided funding to support this work. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 21, 2014
Media Advisory: To contact Karen E. Joynt, M.D., M.P.H., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu. To contact editorial author David M. Cutler, Ph.D., email Peter Reuell at preuell@fas.harvard.edu.

Hospital Switch to For-Profit Status Associated With Improvements in Financial Health, But Not With Differences in Quality of Care, Mortality Rates

Hospital conversion from nonprofit to for-profit status in the 2000s was associated with better subsequent financial health but had no relationship to the quality of care delivered, mortality rates, or the proportion of poor or minority patients receiving care, according to a study in the October 22/29 issue of JAMA.

During the past decade, there has been increasing attention to the growing number of nonprofit or public hospitals that have become for-profit. These conversions are controversial. Advocates argue that for-profit organizations bring needed resources and experienced management to struggling institutions, improving the quality an d efficiency of the care that these hospitals provide. Critics are concerned that once hospitals become “for­profit” they will focus on financial metrics such as improving payer mix and increasing volume, shunning disadvantaged patients and providing less attention to the provision of high­ quality care. There is little contemporary empirical evidence on what happens to patient care or to patient mix when hospitals convert, according to background information in the article.

Karen E. Joynt, M.D., M.P.H., of the Harvard School of Public Health, Boston, and colleagues examined characteristics of U.S. acute care hospitals associated with conversion to for-profit status and changes following conversion. The study included 237 converting hospitals and 631 matched control hospitals. Participants were 1,843,764 Medicare fee-for-service beneficiaries at converting hospitals and 4,828,138 patients at control hospitals.

The researchers found that converting hospitals improved their total margins (ratio of net income to net revenue plus other income) more than controls (2.2 percent vs 0.4 percent improvement). Hospitals that converted had similar performance on process quality indicators for heart attack, congestive heart failure, and pneumonia compared with controls at baseline (84.3 percent vs 85.5 percent). Both groups improved their process quality metrics (6.0 percent vs 5.6 percent).

Mortality rates did not change at converting hospitals relative to controls for Medicare patients overall or for dual-eligible (Medicare and Medicaid eligible) or disabled patients. There was also no change in converting hospitals relative to controls in annual Medicare volume, the proportion of patients with Medicaid, or the proportion of patients who were black or Hispanic.

“We found no evidence that conversion was associated with worsening care, as measured by processes of care, nurse staffing, or outcomes. On the other hand, for-profit hospitals have often argued that conversion will provide resources that will lead to better care, and our study failed to find any evidence to support this notion, either. In fact, our findings suggest that as regulators and policy makers consider for-profit conversions, the likely changes that could be anticipated will primarily be in the financial health of the institution, with little relationship, either positive or negative, to the quality of care provided or the institution’s mortality rates. Although there may be individual instances in which quality or outcomes improve or decline after a conversion, we did not find any consistent pattern during the past decade,” the authors write.
(doi:10.1001/jama.2014.13336; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Who Benefits From Health System Change?

In an accompanying editorial, David M. Cutler, Ph.D., of Harvard University, Cambridge, Mass., comments on the three studies in this issue of JAMA that examine the effect of hospital conversions, physician competition, and physician practice ownership.

“The data from the 3 studies reported in this issue of JAMA are all from the period when payments were largely on a fee-for-service basis and patient cost sharing was relatively low. These findings may not necessarily translate to the current rapidly changing environment, in which payments are increasingly rewarded on a value basis, not a volume basis, and in which patients have significant cost sharing for services received. Such a payment system could lead to more systematic cost savings.”

“The experience so far is that consolidation has been good for many health care organizations and entities and for many clinicians and practitioner groups, with little clarity on how it has affected patients. Understanding how consolidation is related to resource use and quality of care, and how consolidated institutions will change in a changing health care system, will be fundamental in measuring the winners and losers in the new organization of care.”
(doi:10.1001/jama.2014.13491; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 21, 2014
Media Advisory: To contact Neeraj Sood, Ph.D., call Robert Perkins at 213-740-9226 or email perkinsr@usc.edu. To contact editorial author Uwe E. Reinhardt, Ph.D., email B. Rose Huber at brhuber@Princeton.EDU.

Making Health Services Prices Available Linked to Lower Total Claims Payments

Searching a health service pricing website before using the service was associated with lower payments for clinical services such as advanced imaging and laboratory tests, according to a study in the October 22/29 issue of JAMA.

Recent changes in the health care insurance market have resulted in commercially insured patients bearing a greater proportion of their health care costs. As patients have an increasing responsibility to pay for their care, they will likely demand access to prices charged for that care. Several state-administered initiatives have increased price transparency by reporting hospital charges or average reimbursement rates. Pricing information made available to patients reflects actual out-of-pocket costs for each individual patient by accounting for billed charge discounts, health benefit design, and deductibles, according to background information in the article.

Neeraj Sood, Ph.D., of the University of Southern California, Los Angeles, Christopher Whaley, B.A., of the University of California, Berkeley, and colleagues examined the association between the availability of health service prices to patients and the total claims payments (the total amount paid by patient and insurer) for these services (laboratory tests, advanced imaging services and clinician office visits). Payments for clinical services provided were compared between patients who searched a pricing website before using the service with patients who had not researched prior to receiving this service. The study included medical claims from 2010-2013 of 502,949 patients who were insured in the United States by 18 employers who provided a price transparency platform to their employees.

The researchers found that patients who searched the platform 14 days before receiving care had lower claim payments than those who did not. Adjusted payments were approximately 14 percent lower for laboratory tests, 13 percent lower for advanced imaging, and 1 percent lower for clinician office visits, with the relative differences translating into lower absolute dollar payments of $3.45 for laboratory tests, $124.74 for advanced imaging, and $1.18 for clinician office visits.

In the period before either group had access to the price transparency platform, payments for searchers were about 4 percent higher for laboratory tests and 6 percent higher for advanced imaging but were 0.26 percent lower for clinician office visits than for nonsearchers.

The authors write that tools such as this price transparency platform may affect use of care. “For example, knowing that some prices are very high, some patients may forego care. Conversely, cost savings from price shopping might enable patients to increase use, which may lead to improved adherence to recommended treatments but also to overuse of services. For this reason, our study cannot determine whether the price transparency technology reduces overall health care spending. Future research should extend this analysis to services beyond the three used in this study. It should also examine how use is affected to better understand the broader effect of price transparency on health care spending and population health.”
(doi:10.1001/jama.2014.13373; 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: Health Care Price Transparency and Economic Theory

“The findings reported by Whaley et al indicate that price transparency works as economists would expect it would,” writes Uwe E. Reinhardt, Ph.D., of Princeton University, Princeton, N.J., in an accompanying editorial.

“However, one important caveat on price transparency must be registered. As Brand et al of the Federal Trade Commission properly have noted, greater transparency about prices and quality in health care are not helpful if the relevant market for health care is monopolized. Transparency can promote savings and encourage better quality only if there are enough competing entities that provide health care in a market. It is a point that is sometimes overlooked but is an essential ingredient for patients to benefit from knowing the price and quality of the health care services they purchase.”
(doi:10.1001/jama.2014.14276; 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: 10 A.M. (CT) SATURDAY, OCTOBER 18, 2014
Media Advisory: To contact corresponding author Christine M. Eng, M.D., call Glenna Picton at 713-798-7973 or email picton@bcm.edu.

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Whole-Exome Sequencing Shows Potential as Diagnostic Tool

Among a group of 2,000 patients referred for evaluation of suspected genetic conditions, whole-exome sequencing provided a potential molecular diagnosis for 25 percent, including detection of a number of rare genetic events and new mutations contributing to disease, according to a study appearing in JAMA. The study is being released to coincide with the American Society of Human Genetics annual meeting.

Whole-exome sequencing analyzes the exons or coding regions of thousands of genes simultaneously using next-generation sequencing techniques. By sequencing the exome of a patient and comparing it with a normal reference sequence, variations in an individual’s DNA sequence can be identified and related back to the individual’s medical concerns in an effort to discover the genetic cause of the medical disorder, according to background information in the article.

Yaping Yang, Ph.D., and Christine M. Eng, M.D., of the Baylor College of Medicine, Houston, and colleagues, had previously conducted a pilot study of whole-exome sequencing that included 250 patients. This current study included 2,000 patients (primarily pediatric, 88 percent), with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Tests were ordered by the patient’s physician for suspected genetic conditions. Peripheral blood, tissue, or extracted DNA samples were collected from patients or their parents. The majority of the patients had neurological disorders or developmental delay (87.8 percent; neurological, neurological plus other organ systems, and specific neurological groups) and 12.2 percent of patients had nonneurological disorders (nonneurological group).

A molecular diagnosis was reported for 504 patients (25.2 percent) with 58 percent of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic (physical manifestations) category were 143/526 (27.2 percent) for the neurological group, 282/1,147 (24.6 percent) for the neurological plus other organ systems group, 30/83 (36.1 percent) for the specific neurological group, and 49/244 (20.1 percent) for the nonneurological group.

In the 2,000 cases, 95 medically actionable incidental findings were reported in 92 patients (4.6 percent). Three patients had more than 1 such finding. In 59 patients (3 percent), the incidental findings occurred in genes included in the American College of Medical Genetics and Genomics list of 56 genes recommended to be disclosed. The remaining 33 patients (1.7 percent) had mutations in genes reported based on the researcher’s local criteria for reporting of medically actionable results.

“A molecular diagnosis rate of 25 percent was observed in our pilot study of 250 cases and has remained consistent in this larger series of predominantly pediatric patients with diverse clinical presentations most notable for intellectual disability and neurological phenotypes,” the authors write.

They add that approximately 30 percent of positive cases reported herein harbored presumptive causative mutations in disease genes discovered since 2011, reflecting the benefits of an accelerating pace of disease gene discovery. “Whole-exome sequencing testing is a platform suitable for timely incorporation of new disease genes because it interrogates entire coding regions, making it possible to automate the updating of disease gene annotation for clinical reporting, even after the initial analysis is completed.”

The researchers conclude that the “observed flexibility and yield of whole-exome sequencing may offer advantages over traditional molecular diagnosis approaches in certain patients.”
(doi:10.1001/jama.2014.14601; 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: 10 A.M. (CT) SATURDAY, OCTOBER 18, 2014
Media Advisory: To contact corresponding author Stanley F. Nelson, M.D., call Elaine Schmidt at 310-794-2272 or email ESchmidt@mednet.ucla.edu. To contact editorial co-author Jonathan S. Berg, M.D., Ph.D., call Katy Jones at 919-962-3405 or email katy_jones@med.unc.edu.

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Type of Exome Sequencing Associated With Higher Molecular Diagnostic Yield than Certain Other Diagnostic Methods

In a sample of patients with undiagnosed, suspected genetic conditions, a certain type of exome sequencing method was associated with a higher molecular diagnostic yield than traditional molecular diagnostic methods, according to a study appearing in JAMA. The study is being released to coincide with the American Society of Human Genetics annual meeting.

Exome sequencing, which sequences the protein­coding region of the genome (the complete set of genes or genetic material present in a cell or organism), has been rapidly applied in research settings and recent increases in accuracy have enabled the development of clinical exome sequencing (CES) for mutation identification in patients with suspected genetic diseases. Early in 2012, the Clinical Genomics Center at the University of California, Los Angeles, launched a CES program with the goal of delivering a more comprehensive method for determining a molecular diagnosis for patients with presumed rare Mendelian disorders (a genetic disease showing a certain pattern of inheritance) that have remained undiagnosed despite exhaustive genetic, biochemical, and radiological testing. Researchers at this center have introduced a new test, called trio-CES, in which the whole exome of the affected proband (first identified individual affected with the disorder among other family members) and both parents are sequenced, according to background information in the article.

Hane Lee, Ph.D., of the University of California, Los Angeles, and colleagues report the results of clinical exome sequencing performed on 814 patients with undiagnosed, suspected genetic conditions at the Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) or as proband-CES (only the affected individual sequenced) when parental samples were not available.

Overall, a molecular diagnosis (with the causative variant(s) identified in a well-established clinical gene) was provided for 213 of the 814 total cases (26 percent). There was a significantly higher molecular diagnostic yield from cases performed as trio-CES (127 of 410 cases; 31 percent) relative to proband-CES (74 of 338 cases; 22 percent) in the overall group of cases.

In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41 percent (45 of 109) for trio-CES cases and 9 percent (2 of 23) for proband-CES cases. “In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted. Clinical implications of these findings need to be better understood before CES should be routinely adopted,” the authors conclude. (doi:10.1001/jama.2014.14604; Available pre-embargo to the media at https://media.jamanetwork.com) Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. [ama_toc_item id="28506"] Editorial: Genome-Scale Sequencing in Clinical Care In an accompanying editorial, Jonathan S. Berg, M.D., Ph.D., of the University of North Carolina at Chapel Hill, comments on the two JAMA studies that examined exome sequencing. “Ultimately, it will be essential to know who will benefit from clinical genomic sequencing, including the role of sequencing in a variety of settings, such as oncology, prenatal diagnosis, newborn screening, or population screening in healthy adults. The National Institutes of Health and other funding agencies are supporting a broad portfolio of research projects investigating these and other questions about genomic medicine. In the meantime, physicians should be judicious in considering when to obtain clinical exome sequencing; should effectively communicate the risks, benefits, and limitations of such testing; should be able to clearly communicate the results to patients and their families; and should avoid unnecessarily burdening patients with the cost of such testing if not covered by insurance. The application of genomic sequencing will ultimately contribute to progress in clinical care, from molecular diagnosis to improved outcomes, but there is much to learn before it can be applied more universally.” (doi:10.1001/jama.2014.14665; 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. [ama_toc_item id="28502"] # # #

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 14, 2014
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Study Shows Increase in Use of Emergency Departments by Children and Teens, Regardless of Insurance Type, Status

In contrast to previous research that documented decreases or no change in children’s rates of emergency department (ED) use in the 1990s and the early 2000s, an analysis of ED visits by children, adolescents, and young adults in California by insurance status from 2005-2010 found that rates increased across all insurance groups and the uninsured, according to a study in the October 15 issue of JAMA.

Concerns regarding cost, continuity of care, and crowding continue to bring ED use under nationwide scrutiny. Although many hope that increasing insurance coverage through the Affordable Care Act will lead to decreases in ED visits, recent evidence in adults suggests that increasing access to specifically Medicaid insurance may actually be associated with increased ED use. Most prior research on trends in ED use in children, adolescents, and young adults predates the recent economic downturn and associated changes in insurance coverage, according to background information in the article.

Renee Y. Hsia, M.D., M.Sc., of the University of California, San Francisco, and colleagues analyzed data of ED visits by youths (children, adolescents, and young adults 18 years of age and younger) to acute care hospitals across California between 2005 and 2010. ED visits were grouped into 4 categories: Medicaid, private insurance, uninsured, and other.

The number of visits to California EDs by youths increased from 2.5 million in 2005 to 2.8 million in 2010, a change of 11 percent. Children covered by Medicaid accounted for 44 percent of all ED visits. The distribution of visits across payer groups changed significantly between 2005 and 2010, with Medicaid accounting for a larger share over time. After adjusting for population (given a 3 percent decrease in the pediatric population during the study period) to obtain ED visit rates, the rate of ED use increased across all insurance groups.

Uninsured youths living in California exhibited the fastest increase in ED visit rates, followed by those privately insured. The rate of ED use among youths covered by Medicaid exhibited the slowest growth, but remained the highest in absolute terms.

The authors write that even though Medicaid patients have the fastest-growing rates of ED use among adults, the largest increases in ED visit rates for youths are not among Medicaid beneficiaries but rather among those individuals who are privately insured or uninsured. “Shifts in insurance (from private and no insurance to Medicaid) during the recession (December 2007-June 2009) likely influenced the trends during this time.”

“These findings suggest that the drivers for ED use differ significantly between youths and adults and that policies regarding insurance expansion may also have varying effects. The divergence from older trends in ED use among youths may also reflect the increasingly central role of the ED in the U.S. health care system, especially during a period of severe economic recession, and could signal an overall deterioration in access to primary care across payer groups, or that even privately insured youths with greater access to primary care physicians are being directed to the ED for care.”
(doi:10.1001/jama.2014.9905; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 14, 2014
Media Advisory: To contact Mark D. Neuman, M.D., M.Sc., email Lee-Ann Donegan at Leeann.Donegan@uphs.upenn.edu. To contact editorial co-author Elizabeth A. McGlynn, Ph.D., call Albert Martinez at 510-625-2124 or email albert.martinez@kp.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.2014.13513. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.12819.

Better Performance on Quality Measures for Skilled Nursing Facilities May Not Result in Better Outcomes for Patients

Among fee-for-service Medicare beneficiaries who received care at a skilled nursing facility following hospital discharge, better performance on various measures of quality of care was not consistently associated with a lower risk of hospital readmission or death at 30 days, according to a study in the October 15 issue of JAMA.

One in five Medicare beneficiaries is readmitted to the hospital within 30 days of discharge. These readmissions are costly and potentially preventable. Skilled nursing facilities (SNFs) represent the most common setting for postacute care in the United States. Little is known about the association between available SNF performance measures and the risk of hospital readmission, according to background information in the article.

Mark D. Neuman, M.D., M.Sc., of the University of Pennsylvania, Philadelphia, and colleagues used national Medicare data on fee-for-service beneficiaries discharged to a SNF after an acute care hospitalization to examine the association between SNF performance on publicly available metrics and the risk of readmission or death 30 days after discharge to a SNF. The metrics were SNF staffing intensity, health deficiencies identified through site inspections, and the percentages of SNF patients with delirium, moderate to severe pain, and new or worsening pressure ulcers.

Of 1,530,824 discharges to SNFs, 321,709 were followed by readmission within 30 days (21.0 percent), and 72,472 were followed by a death within 30 days (4.7 percent). The overall rate of 30-day readmission or death was 23.3 percent. Although better performance on several available SNF performance measures (including better staffing ratings and better facility inspection ratings) was associated with improved outcomes in unadjusted analyses, these associations were diminished substantially after adjustment for patient factors, the discharging hospital, and SNF facility characteristics.

In fully adjusted models, SNFs with better facility inspection ratings demonstrated a slightly lower adjusted risk of readmission or death; however, adjusted outcomes did not vary meaningfully across SNFs that differed in terms of staffing ratings or their performance on clinical measures related to pain or delirium. Other measures did not predict clinically meaningful differences in the adjusted risk of readmission or death.

“Our results provide new information to inform the efforts of hospitals, health systems, and insurers to reduce rates of hospital readmission through more effective use of postacute care. Ultimately, although SNF performance measurement plays an important role in promoting transparency and accountability in the U.S. health care system, our findings suggest that in their current form they are unlikely to serve as a sole basis for large-scale reductions in readmissions unless accompanied by other strategies,” the authors write.
(doi:10.1001/jama.2014.13513; 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: What Makes a Good Quality Measure?

In an accompanying editorial, Elizabeth A. McGlynn, Ph.D., and John L. Adams, Ph.D., of the Kasier Permanente Center for Effectiveness and Safety Research, Pasadena, Calif., comment on the two JAMA studies that examined quality indicators.

“Neither study looked at other processes as potential predictors of the outcomes of interest (readmission, death, childbirth outcomes) and therefore missed an opportunity to identify areas for future measure development. Further, careful consideration of the ultimate goal of a quality measure must be made. The information required for consumers to choose among nursing homes or hospitals may be different than the information required to improve clinical outcomes. Measures that work for one purpose and not another are still valuable. Future studies of quality measures should establish a clear framework and expectations for the intended goals of quality measures. Both reports make it clear that a great deal of additional work is needed to achieve the quality measures necessary for a more complete characterization of system performance and potential improvement opportunities.”
(doi:10.1001/jama.2014.12819; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, OCTOBER 14, 2014
Media Advisory: To contact Elizabeth A. Howell, M.D., M.P.P., call Sid Dinsay at 212-241-9200 or email Sid.Dinsay@mountsinai.org.

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Study Indicates Need for More Obstetric Quality of Care Measures at Hospitals

In an analysis of data on more than 100,000 deliveries and term newborns from New York City hospitals, rates for certain quality indicators and complications for mothers and newborns varied substantially between hospitals and were not correlated with performance measures designed to assess hospital-level obstetric quality of care, according to a study in the October 15 issue of JAMA.

Severe maternal complications occurs in about 60,000 women (1.6 per 100 deliveries) annually in the United States, and 1 in 10 term infants experience neonatal complications. In an effort to improve the quality of care, several obstetric-specific quality measures are now monitored and publicly reported. The extent to which these measures are associated with maternal and neonatal complications has not been known, according to background information in the article.

Elizabeth A. Howell, M.D., M.P.P., of the Icahn School of Medicine at Mount Sinai, New York, and colleagues used New York City discharge and birth certificate data sets from 2010 to determine whether two Joint Commission obstetric quality indicators (elective, nonmedically indicated deliveries performed at 37 weeks or more of gestation and prior to 39 weeks and cesarean deliveries performed in low-risk women) were associated with severe maternal or neonatal complications. Published algorithms were used to identify severe maternal complications (delivery associated with a life-threatening complication or performance of a lifesaving procedure) and complications in term newborns without birth defects (births associated with complications such as birth trauma, hypoxia [a lower-than-normal concentration of oxygen in arterial blood], and prolonged length of stay).

Severe maternal complications occurred among 2,372 of 115,742 deliveries (2.4 percent), and neonatal complications occurred among 8,057 of 103,416 term newborns without birth defects (7.8 percent). Rates for elective deliveries performed before 39 weeks of gestation ranged from 15.5 to 41.9 per 100 deliveries among 41 hospitals. There were 11.7 to 39.3 cesarean deliveries per 100 deliveries performed in low-risk mothers. Severe maternal complication rates varied 4- to 5-fold between hospitals, and there was a 7-fold variation in neonatal complications at term between hospitals.

The maternal quality indicators of elective delivery before 39 weeks of gestation and cesarean delivery performed in low-risk mothers were not associated with severe maternal or neonatal complications.

“Current quality indicators may not be sufficiently comprehensive for guiding quality improvement in obstetric care,” the authors conclude.
(doi:10.1001/jama.2014.13381; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, October 14 at this link.

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EMBARGOED FOR RELEASE: 2 P.M. (CT) SATURDAY, OCTOBER 11, 2014
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Study Shows Feasibility of Treating Clostridium difficile Infection With Oral Administration of Frozen Encapsulated Fecal Material

A preliminary study has shown the potential of treating recurrent Clostridium difficile infection (a bacterium that is one of the most common causes of infection of the colon) with oral administration of frozen encapsulated fecal material from unrelated donors, which resulted in an overall rate of resolution of diarrhea of 90 percent, according to a study published in JAMA. The study is being released early online to coincide with its presentation at IDWeek 2014.

Recurrent Clostridium difficile infection (CDI) is a major cause of illness and death, with a recent increase in the number of adult and pediatric patients affected globally. Standard treatment with oral administration of the antibiotics metronidazole or vancomycin is increasingly associated with treatment failures. Fecal microbiota transplantation (FMT)—i.e., reconstitution of normal flora (gut bacteria) by a stool transplant from a healthy individual—has been shown to be effective in treating relapsing CDI. The majority of reported FMT procedures have been performed with fresh stool suspensions from related donors; however practical barriers and safety concerns have prevented its widespread use, according to background information from the article.

To address these barriers, the use of frozen fecal matter from carefully screened healthy donors has been used for FMT; nasogastric tube (a tube that is passed through the nasal passages and into the stomach) administration of the frozen product was comparable with colonoscopic delivery. Building on this work, the researchers generated a capsulized version of the frozen inoculum that can be administered orally and obviates the need for any gastrointestinal procedures.

Ilan Youngster, M.D., M.M.Sc., of Massachusetts General Hospital, Boston, and colleagues conducted a study to evaluate the safety and rate of diarrhea resolution associated with oral administration of frozen FMT capsules for patients with recurrent CDI. The study included 20 patients with at least three episodes of mild to moderate CDI and failure of a 6- to 8-week taper with oral vancomycin or at least 2 episodes of severe CDI requiring hospitalization. Healthy volunteers were screened as potential donors and FMT capsules were generated and frozen. Patients received 15 capsules on 2 consecutive days and were followed up for symptom resolution and adverse events for up to 6 months.

Among the 20 patients, 14 had clinical resolution of diarrhea after the first administration of capsules (70 percent) and remained symptom free at 8 weeks. All 6 non­responders were retreated at an average 7 days after the first procedure; 4 obtained resolution of diarrhea, resulting in an overall 90 percent rate of clinical resolution of diarrhea.

Daily number of bowel movements decreased from a median of 5 the day prior to administration to 2 at day 3 and 1 at 8 weeks. Self-reported health rating using a standardized questionnaire scale of l to 10 improved significantly over the study period, from a median of 5 for overall health and 4.5 for gastrointestinal health the day prior to FMT, to 8 for both ratings at 8 weeks after the administration.

No serious adverse events attributed to FMT were observed.

“If reproduced in future studies with active controls, these results may help make FMT accessible to a wider population of patients, in addition to potentially making the procedure safer. The use of frozen inocula allows for screening of donors in advance. Furthermore, storage of frozen material allows retesting of donors for possible incubating viral infections prior to administration. The use of capsules obviates the need for invasive procedures for administration, further increasing the safety of FMT by avoiding procedure-associated complications and significantly reducing cost,” the authors write.

“Larger studies are needed to confirm these results and to evaluate long-term safety and effectiveness.”
(doi:10.1001/jama.2014.13875; 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: 8:45 A.M. (CT) FRIDAY, OCTOBER 10, 2014
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After Discontinuation of Audit and Feedback, Initial Benefits of Intervention to Reduce Unnecessary Antibiotic Prescriptions Lost

The initial benefits of an outpatient antimicrobial stewardship intervention designed to reduce the rate of inappropriate antibiotic prescriptions were lost after discontinuation of audit and feedback to clinicians, according to a study published in JAMA. The study is being released early online to coincide with the IDWeek 2014 meeting.

Antibiotics are the most frequently prescribed medications for children; most are prescribed for outpatient acute respiratory tract infections. Because antibiotic prescribing is often inappropriate, Jeffrey S. Gerber, M.D., Ph.D., of Children’s Hospital of Philadelphia, and colleagues recently conducted a randomized trial of an outpatient antimicrobial stewardship intervention that found a nearly 50 percent relative reduction in prescribing rates for broad-spectrum antibiotics, according to background information in the article.

To assess the durability of this intervention, the researchers followed antibiotic prescribing across intervention and control sites after termination of audit and feedback. The randomized trial was conducted within 18 community-based pediatric primary care practices using a common electronic health record. The intervention included clinician education, comprising a 1-hour review of current prescribing guidelines for the targeted conditions; and audit and feedback of antibiotic prescribing. Nine practices received the intervention and 9 practices received no intervention. Twelve months after initiating the study, the researchers stopped providing antibiotic prescribing audit and feedback to clinicians in the intervention group. As planned prior to the end of the intervention, the observation period was extended by an additional 18 months, bringing the total observation time to 50 months.

As previously reported, following the 12-month intervention of prescribing audit and feedback, broad-spectrum antibiotic prescribing decreased from 26.8 percent to 14.3 percent among intervention practices vs 28.4 percent to 22.6 percent in controls. Following termination of audit and feedback, however, prescribing of broad-spectrum antibiotics increased over time, reverting to above-baseline levels. After restandardization of the data set for the additional 18 months of data, antibiotic prescribing increased from 16.7 percent at the end of intervention to 27.9 percent at the end of observation in the intervention group and from 25.4 percent to 30.2 percent in controls.

“These data suggest that audit and feedback was a vital element of this intervention and that antimicrobial stewardship requires continued, active efforts to sustain initial improvements in prescribing. Our findings suggest that extending antimicrobial stewardship to the ambulatory setting can be effective but should include continued feedback to clinicians,” the authors write.
(doi:10.1001/jama.2014.14042; 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: 10 A.M. (CT) THURSDAY, OCTOBER 9, 2014
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Study Examines Effect of Different Levels of Antibiotic Susceptibility on Risk of Death Among Patients With Staphylococcus aureus Bloodstream Infection

In an analysis of more than 8,000 episodes of Staphylococcus aureus bloodstream infections, there were no significant differences in the risk of death when comparing patients exhibiting less susceptibility to the antibiotic vancomycin to patients with more vancomycin susceptible strains of S. aureus, according to a study published in JAMA. The study is being released early online to coincide with the IDWeek 2014 meeting.

Staphylococcus aureus is among the most common causes of health care-associated infection throughout the world. It causes a wide range of infections, with blood­stream infections (S aureus bacteremia [SAB]) among the most common and lethal. For more than 50 years, the primary therapy for S aureus infections has been either semisynthetic penicillins or vancomycin. More recent reports have documented an increase in the minimum inhibitory concentration (MIC; the lowest concentration of an antimicrobial agent that inhibits the growth of a microorganism) for vancomycin, referred to as vancomycin “MIC creep” (the development of reduced susceptibility to vancomycin). There have been reports suggesting that elevations in vancomycin MIC values may be associated with increased treatment failure and death, according to background information in the article.

Andre C. Kalil, M.D., M.P.H., of the University of Nebraska Medical Center, Omaha, and colleagues conducted a review and meta-analysis of the evidence regarding the association of vancomycin MIC elevation with mortality in patients with SAB. The researchers identified 38 studies that met criteria for inclusion.

Among 8,291 episodes of SAB included in the studies, overall mortality was 26.1 percent. The adjusted absolute risk of mortality among patients with SAB with high-vancomycin MIC (≥ 1.5 mg/L [less susceptible]; n = 2,740 patients; mortality, 26.8 percent) was not statistically different from patients with SAB with low-vancomycin MIC (< 1.5mg/L; [more susceptible] n = 5,551 patients; mortality, 25.8 percent). In studies that included only methicillin-resistant S aureus (MRSA) infections (n = 7,232), the mortality among SAB episodes in patients with high-vancomycin MIC was 27.6 percent, compared with a mortality of 27.4 percent among patients with low-vancomycin MIC. The authors note that the findings cannot definitely exclude an increased risk of death. No significant differences in risk of death were observed in subgroups with high-vancomycin MIC vs low-vancomycin MIC values across different study designs, types of microbiological susceptibility assays, MIC cutoffs, clinical outcomes, duration of bacteremia, previous vancomycin exposure, and treatment with vancomycin. The researchers write that the findings of this study may have implications for clinical practice and public health, including that standards for vancomycin MIC most likely do not need to be lowered; routine differentiation of MIC values between 1mg/L and 2 mg/L appears unnecessary; and the use of alternative antistaphylococcal agents may not be required for S aureus isolates with elevated but susceptible vancomycin MIC values. “These conclusions are consistent with current Infectious Disease Society of America treatment guidelines that recommend use of vancomycin for treatment of MRSA bacteremia with consideration for alternative agents based on the patient's clinical response and not the MIC.” (doi:10.1001/jama.2014.6364; Available pre-embargo to the media at https://media.jamanetwork.com) Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. [ama_toc_item id="27976"] # # #