Primecuts – This Week in the Journals

March 20, 2017

Cherry_Blossom_in_Branch_Brook_Park,_NJ_-_2012By Katharine Lawrence, MD

Peer Reviewed

Last week, the Accreditation Council for Graduate Medical Education (ACGME) announced that the cap on residents’ duty hours would be adjusted to include 28 hour shifts for first-year residents[1]. This is a shift from the 2011 ‘duty hours’ requirements, which limited maximum shift duration for interns to 16 hours.

In a statement on the Common Program Requirements, the ACGME announced “that the hypothesized benefits associated with the [2011 policy] have not been realized, and the disruption of team-based care and supervisory systems has had a significant negative impact on the professional education of the first-year resident, and effectiveness of care delivery of the team as a whole.” This was based largely on data from the FIRST Trial, published in 2016, which showed that “flexible”, less restrictive duty-hour policies were associated with non-inferior patient outcomes, and no significant difference in satisfaction with duty-hour policies[2]. The results from more recent studies on duty hours, including the iCOMPARE trial, are still underway.

In lighter news, last Friday medical students from around the country celebrated the annual Match Day, basking in their acceptances to residency and the next steps of their careers. Time will tell what the future of residency will look like for this next generation of physicians-in-training. Moving from future physicians to the future of medical practice, here are this week’s prime cuts: 

Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States: A Population-Based Cohort Study

This week in The Annals of Internal Medicine, researchers undertook evaluation of survival data from two major national registries – the Canadian Cystic Fibrosis Registry (CCFR) and U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) – to calculate cystic fibrosis survival estimates in Canada and the United States[3].

The researchers attempted to confirm previously observed differences in survival of CF patients in Canada and the US by using a standardized approach to data processing and survival calculations of population-based cohort data from the above mentioned registries. Survival data were adjusted for multiple variables, including sex, race, age at diagnosis, F508 homo/heterozygous status, pancreatic status, and transplant status, as well as clinical characteristics like FEV1, BMI, CFRD, and microbiology. The results of the study confirm a significant survival gap of 10 years between Canada and the United States in persons living with cystic fibrosis (median survival 50.9 years [95% CI, 50.5 to 52.2 years] vs. 40.6 years [CI, 39.1 to 41.8 years]). Patients in the US tended to die at a younger age then patients in Canada (26.9 years vs 31.9 years; SD, 29.5). Interestingly, when U.S. patients were categorized according to their insurance status, Canadians had a 44% lower risk for death than U.S. patients receiving continuous Medicaid or Medicare (HR, 0.56 [CI, 0.45 to 0.71]; P < 0.001), a 77% lower risk than those with unknown or no health insurance (HR, 0.23 [CI, 0.14 to 0.37]; P < 0.001), and no difference in risk than those with private coverage(HR, 0.85 [CI, 0.67 to 1.07]; P = 0.15).

The major limitation of the study is derived from its design, and the lack of definitive casual inferences in population-based registry data. Ascertainment bias due to missing data or nonrandom loss to follow-up might affect the results as well. Overall, fewer Canadian patients were lost to follow-up in the registry (2.5% vs. 5.5%), and a higher proportion of U.S. than Canadian patients lost to follow-up had received transplants. Despite this, the authors made considerable efforts to establish a systematic, standardized approach to data comparison between the registries, and to describe their handling of disparate and missing data.

Prevalence and Localization of Pulmonary Embolism in Unexplained Acute Exacerbations of COPD : A Systematic Review and Meta-analysis

Acute exacerbations are a common sequelae of COPD (AE-COPD); in 30% of AE-COPD cases, no clear cause of the inflammation is identified. Previous studies suggest that patients who are at increased risk of inflammation may also be at risk for thrombosis, due to overlap in the pathophysiology of these processes. As such, AE-COPD in some patients may be caused by underlying DVT and PE.

In a study published in the March 2017 issue of Chest, Aleva, et al. performed a systematic review and meta-analysis to determine the prevalence, location, clinical relevance, and clinical markers of PE in patients with an unexplained AE-COPD[4]. The primary outcome of this study was the prevalence of PE in unexplained AE-COPD. Secondary outcomes included prevalence of DVT, localization of PE, clinical outcome, and clinical markers of PE. A search of MEDLINE and EMBASE platforms from 1974 to October 2015, yielded 3,000 publications on COPD and PE. 22 of these studies, representing 880 patients, were selected for inclusion in the meta-analysis. The pooled prevalence of PE in unexplained AE-COPD was 16.1% (95% CI, 8.3%-25.8%). Mortality and length of hospital admission seemed to be increased in patients with unexplained AE-COPD and PE. Ultimately, researchers concluded that PE is frequently seen in unexplained AE-COPD; two-thirds of these emboli are found at locations that have a clear indication for anticoagulant treatment, and more research is merited on the diagnosis and treatment of PE in COPD patients.

Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia

In 2001, imatinib, a selective BCR-ABL tyrosine kinase inhibitor, was approved for the treatment of CML, partially based on early results from the International Randomized Study of Interferon and ST1571 (IRIS) trial. These results showed that imatinib was more active, achieved better rates of cytogenetic response and freedom from progression to accelerated phase, and was associated with fewer side effects than interferon alfa plus cytarabine in patients with newly diagnosed CML. This week in The NEJM the final analysis of IRIS, reviewing the long-term outcomes of patients with CML treated with imatinib, was published[5].

The trial enrolled 1106 patients who were age 18-70 with previously untreated chronic phase Philadelphia chromosome positive CML and randomized them to treatment with imatinib or interferon alf plus cytarabine. All patients were for followed for 7 years after which follow up for imatinib treated patients, both randomized and cross over, was extended. The long-term primary end point was overall survival in the imatinib group. The median duration of follow-up was 10.9 years, including follow-up after discontinuation of study treatment. The estimated overall survival rate at 10 years among patients receiving first-line imatinib treatment was 83.3% (95% CI, 80.1 to 86.6). The estimated rate of event-free survival at 10 years was 79.6% (95% CI, 75.9 to 83.2) among the patients randomly assigned to imatinib, as compared with 56.6% (95% CI, 51.5 to 61.6) among those assigned to interferon alfa plus cytarabine. These findings reflect similar values reported in the early part of the IRIS trial, and confirms the earlier findings.

Of note, among the patients who had been randomly assigned to interferon alfa plus cytarabine, 363 (65.6%) crossed over to imatinib. The median duration of first-line therapy with interferon alfa plus cytarabine before crossover was 0.8 years, compared to 8.9 years in the imatinib group. Because of the high rate of crossover and the subsequent closing of the group of patients receiving interferon alfa plus cytarabine, most long-term analyses (including safety, response rates, and landmark analyses) included only patients who had been randomly assigned to imatinib. In addition, the authors note a large portion of patients (20.1%) had an unknown survival status at time of data analysis; varying analyses estimated the range of survival at 10 years as between 64 and 84%.

The long-term results of the IRIS trial demonstrate a durable efficacy and safety of imatinib in the treatment of CML. While these results are reassuring, concerns remain about the cost of treatment with imatinib, which carries an $80,000 annual price tag.

Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Valvular Heart Disease

Previous studies comparing non–vitamin K antagonist oral anticoagulants (NOACs) with warfarin for the treatment of atrial fibrillation (AF) largely excluded patients with moderate/severe mitral stenosis or mechanical heart valves, and variably included patients with other valvular heart disease (VHD) and valve surgeries. As a result, vitamin K antagonists are currently the only recommended oral anticoagulants for these patients. This week in the Journal of the American College of Cardiology, researchers from the TIMI Study Group published an article on the relative safety and efficacy of the NOACs in patients with AF and VHD[6]. 

In this study, researchers performed a meta-analysis of phase III AF trials of available NOACs versus warfarin in patients with coexisting VHD, to assess estimates of relative risk for stroke/systemic embolic events (SSEE), major bleeding, intracranial hemorrhage (ICH), and all-cause death. Inclusion criteria were English-language phase III randomized clinical trials conducted between 2007 and 2016. Four trials were identified, the RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI trials, representing 13,585 patients with VHD. Compared with warfarin, the rate of SSEE in patients treated with higher-dose NOACs was lower among the 13,585 patients with VHD (RR: 0.70; 95% CI: 0.58 to 0.86) and the 58,098 patients without VHD (RR: 0.84; 95% CI: 0.75 to 0.95; interaction p = 0.13 for VHD/no-VHD difference). Major bleeding in patients on higher-dose NOACs versus warfarin was similar and consistent among patients with VHD (RR: 0.93; 95% CI: 0.68 to 1.27) or without VHD (RR: 0.85; 95% CI: 0.70 to 1.02; interaction p = 0.63 for VHD/no-VHD difference). Intracranial hemorrhage was lower with higher-dose NOACs than with warfarin irrespective of VHD (RR: 0.47; 95% CI: 0.24 to 0.93, and RR: 0.49; 95% CI: 0.41 to 059, respectively; interaction p = 0.91). Ultimately, the authors concluded higher-dose NOACs provide overall efficacy and safety similar in AF patients with or without VHD, confirming what many physicians are seeing in practice and beginning to use as best-practice.

Limitations of the study included lack of ability to perform in-depth subgroup analyses on aggregated data, as well as the variability in study design and methodology between the reviewed trials, in particular as regards to inclusion/exclusion criteria, the definition of VHD, and the classification of lesion severity.

Minicuts

The American College of Physicians (ACP) has published updated guidelines for the non-invasive treatment of low back pain[7]. The recommendations offer an update from the 2007 guidelines, and are at least partially in response to the growing concern in the medical and lay community about the treatment of chronic pain with opioid analgesics. 

The American Diabetes Association (ADA) also released new guidelines last week, The Standards of Medical Care in Diabetes[8].  A major change in treatment guidelines is extension of metformin therapy to include patients with eGFRs of 30ml/min/1.73m^2 or greater

The CDC published a report further characterizing the highly virulent, multi-drug resistant yeast pathogen Candida auris. The yeast, which was first identified from an ear infection in Japan in 2009, has drawn attention because of its reduced susceptibility to antifungals, and its high rates of candidemia in infected patients. The CDC study demonstrated the bio-film forming capacity of the yeast, which contributes to its virulence and resistance, as well as its susceptibility to chlorhexidine as a disinfectant.

Dr.  Katharine Lawrence is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Ian Henderson, MD, 3rd year internal medicine resident, NYU Langone Medical Center and Contributing Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References: 

  1. Gever, John. ACGME Raises Ceiling on Resident Duty Hours” Medscape. March 10, 2017. https://www.medpagetoday.com/hospitalbasedmedicine/graduatemedicaleducation/63752
  2. Bilimoria, et al. National Cluster-Randomized Trial of Duty-Hour Flexibility in Surgical Training. N Engl J Med 2016; 374:713-727 http://www.nejm.org/doi/full/10.1056/NEJMoa1515724#t=article
  3. Stephenson AL, Sykes J, Stanojevic S, Quon BS, Marshall BC, Petren K, et al. Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States: A Population-Based Cohort Study. Ann Intern Med. [Epub ahead of print 14 March 2017] http://annals.org.ezproxy.med.nyu.edu/aim/article/2609289/survival-comparison-patients-cystic-fibrosis-canada-united-states-population-based
  4. Aleva, et al. Prevalence and Localization of Pulmonary Embolism in Unexplained Acute Exacerbations of COPD: A Systematic Reciew and Meta-analysis. CHEST 2017; 151(3):544-554. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science/article/pii/S0012369216537520 
  5. Hochhaus, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med 2017; 376:917-927. http://www.nejm.org.ezproxy.med.nyu.edu/doi/10.1056/NEJMoa1609324
  6. Renda et al. Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Valvular Heart Disease. JACC VOL. 69, NO. 11, 2017 MARCH 21, 2017:1363 – 71. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science/article/pii/S0735109717303443
  7. Qaseem A, Wilt TJ, McLean RM, Forciea MA, for the Clinical Guidelines Committee of the American College of Physicians. Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. [Epub ahead of print 14 February 2017]http://annals.org.ezproxy.med.nyu.edu/aim/article/2603228/noninvasive-treatments-acute-subacute-chronic-low-back-pain-clinical-practice
  8. Chamberlain JJ, Herman WH, Leal S, Rhinehart AS, Shubrook JH, Skolnik N, et al. Pharmacologic Therapy for Type 2 Diabetes: Synopsis of the 2017 American Diabetes Association Standards of Medical Care in Diabetes. Ann Intern Med. [Epub ahead of print 14 March 2017]http://annals.org.ezproxy.med.nyu.edu/aim/article/2609290/pharmacologic-therapy-type-2-diabetes-synopsis-2017-american-diabetes-association
  9. Sherry L, Ramage G, Kean R, et al. Biofilm-Forming Capability of Highly Virulent, Multidrug-Resistant Candida auris. Emerging Infectious Diseases. 2017;23(2):328-331. https://wwwnc.cdc.gov/eid/article/23/2/16-1320_article

 

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