Primecuts-This Week in the Journals

July 6, 2017

800px-Lab_coatsBy David Rhee, MD
Peer Reviewed
A warm welcome to all the new interns! As the future of healthcare is debated in congress, there has been a great deal of attention on Medicaid and the Affordable Care Act (ACA). This week, our first two articles explore some of the effects Medicaid, Medicare, and the ACA had on patient outcomes either through the Hospital Value-Based Purchasing initiatives or through the growing use of observation units. Our third article reviews a study on non-vitamin K anticoagulation agents in low-risk patients with atrial fibrillation. Our last article analyzes the efficacy of yoga in treating chronic low back pain.

Changes in Hospital Quality Associated with Hospital Value-Based Purchasing

Let’s start with a Special Article recently published in the NEJM that looked into the outcomes of the ACA’s initiative of Hospital Value-Based Purchasing program. In the HVBP program, Medicare will withhold a certain amount of money (1-2% of the diagnosis-related group reimbursement) from the hospital that can be earned back if the hospital meets certain goals in healthcare metrics. These metrics include quality measure, patient experience, and cost of care. This was a major shift of payment models from the fee-for-service model to a value-based model.

Investigators from the University of Michigan explored the effects of this value-based payment model on healthcare outcomes in 2011-2015 in a study published this month in the NEJM[4]. The outcomes included improvement in clinical care/process, patient satisfaction, and 30-day mortality. They compared about 2000 acute-care hospitals exposed to HVBP against control hospitals (small rural hospitals that were not exposed).

They found that the outcomes in clinical care/process metrics and patient experience had similar improvement in both groups of hospitals (the difference-in-differences were 0.08 SD [95% CI, -0.14 to 0.30] and -0.09 SD [95% CI, -0.31 to 0.12] respectively). There were also no significant differences between the 30-day mortality rates for acute myocardial infarction and heart failure (difference-in-differences were -0.28 percentage points [95% CI, -1.72 to 1.15] and 0.21 percentage points [95% CI, -0.53 to 0.11] respectively). Of note, the mortality rate for pneumonia was higher in the control group (-0.43 percentage points [95% CI, -0.71 to -0.15]). In sum, the study suggests that HVBP did not result in meaningful improvements in clinical process, patient satisfaction, or a significant reduction in 30-day mortality. To better under why HVBP did not improve outcomes, the research group contrasted these findings against the effects of the ACA’s Hospital Readmission Reduction Program success on readmission rates. They suggest the HVBP may have a larger effect if there were more financial incentives and simplified performance criteria.

Outcomes after observation stays among older adult Medicare beneficiaries

Observation units, technically an outpatient service, were created to provide short-term treatment with frequent reassessments instead of a short-term inpatient hospitalization. They are generally reimbursed less than inpatient stays, but payers (such as Medicare and Medicaid) have implemented financial incentives to encourage observation stays rather than inpatient stays. As a result, they have become more prevalent and utilized over the past decade. In 2013, 1.5 million Medicare beneficiaries received care in an observation unit. However, the outcomes after discharges from these units are not well known.

In a study published in this week’s BMJ, a group of authors from Yale compiled 360,000 observation stays, 2,500,00 emergency room visits, and 2,600,000 inpatient admissions of Medicare patients over 65 in the years 2006-2011[5]. They compared the 30-day rates of emergency department treatment-and-stays, observation stays, inpatient stay, any hospital revisit, and mortality after a discharge from the observation unit with those after a discharge from the emergency department or an inpatient admission.

They found that the 30-day outcomes were similar between patients discharged from the observation unit and from the emergency department. The revisit rates were 20.1% and 19.9%, respectively, with a difference of 0.2% (95% CI, 0.1 to 0.3%). The mortality rates were 1.8% for discharges from both emergency rooms or observation units.). The outcomes after a discharge from an inpatient stay were worst (22% revisit and 5% mortality, with differences of 1.8% [95% CI, 1.6 to 1.9%] and 3.3% [95% CI, 3.3 to 3.4%] compared to discharges from an observation unit respectively).
In my interpretation of the study, it was encouraging that patients in observation units whose illness severity presumable lies somewhere between those discharged from the ED and those admitted as an inpatient had similar outcomes to ED patients rather than outcomes approaching those of patients being discharged from the inpatient admission. This suggests patients received adequate care while treated in an observation unit, but they would benefit more from improved transitional care during and after an ED discharge.

Effectiveness and Safety of Standard-Dose Non-vitamin K Antagonist Oral Anticoagulants and Warfarin Among Patients with Atrial Fibrillation With a Single Stroke Risk Factor

Prior studies comparing NOACs to warfarin have included high-risk patients with atrial fibrillation and 2 or more risk factors. Despite this, NOACs have been approved for use in low-risk patients. In a nationwide cohort study from Denmark, Lip GYH, et al. looked at the effectiveness and safety of such use in low-risk patients [6]. The study included14,000 Danish patients with atrial fibrillation and 1 CHA2DS2-VASc risk factor who were taking an oral anticoagulant. The primary outcome was rate of stroke/systemic embolization at 1 and 2.5 years of follow up, and they compared dabigatran, rivaroxaban, apixaban against warfarin. They found that there was no difference between the groups in overall occurrence of ischemic stroke or systemic embolism. (HR 0.81 [95% CI, 0.49-1.34], 1.46 [95% CI, 0.79-2.70], and 1.01 [0.51-2.01] respectively).

They also found significantly decreased mortality associated with the NOACs compared to warfarin (HR 0.47 [95% CI, 0.29-0.76] for apixaban, 0.59 [95% CI, 0.43-0.81] for dabigatran, and 0.52 [95% CI, 0.34-0.79] for rivaroxaban). However, based on their sensitivity analysis on this appeared mainly driven by intrinsic selective prescription patterns by physicians and warrants cautious interpretation. They also found significantly less bleeding with apixaban and dabigatran compared to warfarin (HR 0.35 [95% CI, 0.17-0.72] and 0.48 [95% CI, 0.30-0.77], respectively). This study was broadly consistent with many prior studies and suggested similar effectiveness of NOACs to warfarin with possibly a better safety profile. However, the study’s falsification end points generally did not falsify, suggesting that there was residual confounding across these analyses, presumably related to selective prescribing and unobserved comorbidities. This is a large limitation of this study.

Yoga, Physical Therapy, or Education for Chronic Low Back Pain

Chronic low back pain is the leading cause of disability worldwide. Increasingly, yoga is being offered as an alternative treatment method to traditional physical therapy, however no studies have assessed its effectiveness. A group in Boston performed a randomized non-inferiority trial of 320 predominantly low-income patients with nonspecific, chronic low back pain to assess the effectiveness of yoga [7]. Patients were randomized into one of three groups: one received weekly yoga classes, another received PT visits, and the last received educational printouts (self-care book and newsletters).
The primary outcomes (back-related function measured by the Roland Morris Disability Questionnaire [RMDQ] and pain) were obtained after a 12-week treatment phase, and periodically during a subsequent 40-week maintenance phase. Improvements in the RMDQ or pain index for yoga were non-inferior to those for PT (mean differences -0.26 [1-sided CI, -∞ to 0.83] and 0.51 [1-sided CI, -∞ to 0.97]) at 12 weeks. Both yoga and PT were more likely to have clinically meaningful responses in RMDQ than the education group (odds ratios 3.1 [95% CI, 1.6 to 6.2] and 2.0 [95% CI, 1.0 to 4.0] respectively) and less likely to use pain medications (odds ratios 0.36 [95% CI, 0.17 to 0.78] and 0.31 [95% CI, 0.14 to 0.67]. The follow-up data during the maintenance phase, while reported in the supplemental materials as overall similar to the 12-week results, appears limited by dropouts and nonadherence.
Fewer than half of participants met adherence criteria of at least 70% attendance (44% in yoga, 36% in PT, and 44% in education) despite the classes being free and surveys being financially incentivized. While yoga classes (based on a specific 12-week program initially developed by Boston Medical Center) appear to be a viable therapy option for chronic low back pain, I remain concerned that the patients I see will have significant barriers to access any yoga classes.

Bioresorbable Scaffolds
Now, they are making stents that are bioresorbable. Are these effective? Are they safe? This group from the Netherlands compared the outcomes from 1,800 patients who received either a drug-eluting bioresorbable stent or a drug-eluting metallic stent[8].

Morning Report
Call me sentimental, but it’s the end of a year. For some, the first year as a doctor — for others, the last as a resident. Dr. Singh tells a story of a morning when she was a medicine intern at Stanford [9].

Moral Dilemma
Another vivid tale, this time by a surgical resident in Iraq who is trapped between a young female decompensating from a tension pneumothorax and a conservative surrogate who refuses to let him touch the patient [10].

David Rhee, MD is a second year internal medicine resident at NYU Langone Medical Center
Peer Reviewed by Ian Henderson, MD Associate Editor, Clinical Correlations
Image courtesy of Wikimedia Commons

[1] Park H, Sanger-Katz M. How Senate Republicans Plan to Dismantle Obamacare. The New York Times. 2017 Jun 22. Accessed June 25,2017.
[1] April 2017 Medicaid and CHIP Enrollment Data Highlights. Centers for Medicare & Medicaid Services. Accessed June 25, 2017.
[2] Sanger-Katz M. G.O.P. Health Plan is Really a Rollback of Medicaid. The New York Times. 2017 Jun 20. Accessed June 25, 2017.
[3] Martin J, Burns A. Republican Senator Vital to Health Bill’s Passage Won’t Support It. The New York Times. 2017 Jun 23. Accessed June 25, 2017.
[4] Ryan AM, Krinsky S, Maurer KA, Dimick JB. Changes in Hospital Quality Associated with Hospital Value-Based Purchasing. NEJM. 2017 Jun 15; 376:2358-2366.
[5] Dharmarajan K, et al. Outcomes after observation stay among older adult Medicare beneficiaries in the USA: retrospective cohort study. BMJ. 2017 Jun 20; 357:j2616.
[6] Lip GYH, et al. Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin Among Patients With Atrial Fibrillation With a Single Stroke Risk Factor: A Nationwide Cohort Study. JAMA Cardiology. 2017 Jun 14 [Epub ahead of print]. Accessed June 25, 2017.
[7] Saper RB, et al. Yoga, Physical Therapy, or Education for Chronic Low Back Pain: A Randomized Noninferiority Trial. Annals of Internal Medicine. 2017 Jun 20 [Epub ahead of print]. Accessed June 25, 2017.
[8] Wykrzykowska JJ, et al. Bioresorbable Scaffolds versus Metallic Stents in Routine PCI. NEJM. 2017 Jun 15; 376:2319-2328.
[9] Singh S. Morning Report. NEJM. 2017 Jun 15; 376:2316-1317.
[10] Al-Shamsi M. Moral Dilemma in the ER. Annals of Internal Medicine. 2017 Jun 20; 166(12):909-910.

Primecuts – This Week in the Journals

June 22, 2017

Vegas_Golden_Knights_logoBy David Pineles, MD
Peer Reviewed

In a major blow to the Democratic party, Republican Karen Handel won the special congressional election in Georgia, fending off Democrat Jon Ossoff [1]. While some see this as a victory for President Trump, others are viewing this as a win despite Mr. Trump’s actions [2]. In world news, Britain’s Prince Phillip, the 96-year old husband of Queen Elizabeth, spent his second night in King Edward VII Hospital for an unspecified infection [3]. In sporting news, the the National Hockey League held an expansion draft for the newly formed Las Vegas Golden Knights [4]. This will be the first major professional sporting team to reside in Las Vegas.

In this week’s Primecuts we will discuss utilizing the DAPT Score in post-PCI patients, treating recurrent C. diff infection with freeze-dried fecal transplant capsules, treating bronchiectasis with atorvastatin, and treating Barrett’s esophagus with low-grade dysplasia.

Use of the Dual-Antiplatelet Therapy (DAPT) Score to Guide Treatment Duration After PCI [5]

Use of dual-antiplatelet therapy with aspirin and an oral P2Y12 adenosine diphosphate receptor inhibitor following percutaneous coronary intervention (PCI) is an evidence based guideline. However, the duration of DAPT therapy remains somewhat controversial one year out from PCI, with guidelines recommending individualization of the treatment plan based on bleeding risk. The PRODIGY trial in 2012 was the first major trial to address this matter. The PRODIGY trial was a multicenter, randomized control trial reported in Circulation in 2012 [6]. This study randomized patients 30 days post-PCI (with stratification for bare-metal and drug eluting stents) to either 6 or 24 months of DAPT. They found that there was no significant difference in their primary end point (composite death of any cause) between the two groups. However, there were significantly more bleeding events in the 24-month of DAPT arm.

The DAPT score is a new clinical tool which aids in predicting benefit and harm (ie: cardiovascular events and bleeding) of DAPT beyond the one year mark. The DAPT score ranges from -2 to 10 and is calculated based on a set of criteria including: age, diabetes diagnosis, smoking status, prior PCI or MI, and history of CHF or left ventricular EF <30%. A score of

In the PRODIGY cohort, 45% of patients studied (884 participants) had a high DAPT score (≥2) and 55% (1086 participants) had a low score (<2). There was a significantly greater reduction in the primary efficacy outcome with 24 versus 6 months of DAPT in the patients with high scores than those with low scores [RD of -2.05 (95% CI, -5.04 to 0.95, p=0.30)]. There was also a significant increase in the primary safety outcome (major bleeding) with 24 versus 6 months in patients with low scores than those with high scores (RD 2.58, 95% CI, 0.71 to 4.46, p=0.046).

Although limited by the applicability of the DAPT score (can the scoring system be applied to the PRODIGY trial population?), the findings suggest that we should better stratify post-PCI patients in order to better assess their personalized benefit or harm from DAPT.

Successful Resolution of Recurrent C. Diff Infection Using Freeze-Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study [7]

With the widespread use and over prescribing of antibiotics by healthcare providers, there has
been a rise in incidence of Clostridium difficile infection (CDI). Standard treatment for this infection(ie: metronidazole and vancomycin) has good efficacy, however, these antibiotic treatments also suppress normal gut microbiota leaving patients vulnerable to recurrence. Fecal
microbiota transplant (FMT) has emerged as a potential tool to treat recurrent infections; however the logistics of FMT delivery remain problematic. This week in The American Journal of Gastroenterology the efficacy and safety of a freeze-dried, encapsulated fecal microbiota pill for patients with recurrent CDI were reported.

This was a single center, prospective study which enrolled 49 patients with recurrent C. difficile infection. Patients were included with at least 2 spontaneous recurrences of CDI following initial treatment and failure of at least one extended antibiotic regimen. Donor fecal material was obtained from two healthy male donors and the capsules were freeze-dried and categorized based on the number of bacteria in each capsule. The study protocol evolved over the course of the study. Initially, the protocol used ~2.5×1012 bacteria contained in 24–27 capsules in addition to a colon purgative before administration. However, due to limited number of FMT capsules, the authors had to decrease the dose in later stages of the trial and instead used ~2.1–2.5×1011 bacteria contained in a single dose of 2–3 capsules without a preceding colon emptying. At 2 months, there was an 87.8% (43/49) success rate in preventing CDI recurrence. No serious adverse events occurred during this time period.

Although this study does demonstrate strikingly positive results, there are numerous limitations that should be mentioned. First, the small sample size of 49 participants significantly limits the power of this study. Second, the trial was not randomized or controlled which allows for many possible confounding factors and biases to influence the results. Third, the fact that the investigators changed the protocol and altered the intervention mid-study raises questions in regards to standardization and confounding. Fourth, the study was only 2 months in duration which may not be long enough to capture all recurrences. Despite these limitations, this study highlights progress made in the delivery of FMT and its potential efficacy for recurrent CDI.

A randomised control trial of atorvastatin in bronchiectasis patients infected with Pseudomonas aeruginosa- a proof of concept study [8]

Bronchiectasis is characterized by permanently damaged airways with excessive neutrophilic inflammation with ongoing bacterial colonization. Statins have been shown to have anti-inflammatory properties by modulating both the innate and adaptive immune systems. It was recently demonstrated in a randomized control trial that patients with moderately severe bronchiectasis treated with 6 months of atorvastatin 80 mg daily experienced reduced cough, enhanced sputum neutrophil apoptosis, and reduced serum IL-8 [9]. In a newly published article in Chest, investigators sought to investigate whether atorvastatin treatment in patients with more severe bronchiectasis and chronically infected with P. aeruginosa would result in similar effects.

Bedi et al. performed a single center, double blinded, randomized controlled trial of 32 adult patients with severe bronchiectasis and chronic infection with P. aeruginosa to receive 80 mg of atorvastatin daily or placebo for three months. The primary measured outcome was the perceived reduction in cough using the mean Leicester Cough Questionnaire (LCQ) score. The investigators found no significant difference in cough between the two groups, but did find a significant improvement in quality of life assessed by the St. George’s respiratory questionnaire (mean difference = -5.62, 95% CI [-10.13 to -1.13], p=0.016) in the high dose statin group. There was a significant difference in inflammatory markers between groups including serum IL-8 (p=0.04), TNF (p=0.01), and ICAM1 (p=0.04). No significant improvement in PFT’s or in the number of exacerbations was found in the atorvastatin group.

The study failed to meet its primary endpoint of improvement in cough and while the investigators did demonstrate an improvement in quality of life of these patients, this could not be explained by the addition of a high dose statin to the patient’s medical therapy. Given this study’s relatively small study cohort and short follow up period, its findings are limited. Overall, statin medications are not benign drugs and can have significant side effects to the patients taking them. As such, it does not appear that there is enough evidence here to change practice in this patient population and further trials need to be performed to better examine this topic.

Disease Progression in Barrett’s Low-Grade Dysplasia with Radiofrequency Ablation Compared with Surveillance: Systematic Review and Meta-Analysis [10]

The incidence of esophageal adenocarcinoma (EAC) has greatly increased over the past several years. Barrett’s esophagus (BE) is the only identifiable pre-malignant condition for EAC. Treatment options for BE depend on the degree of dysplasia. While the management for high-grade dysplastic BE and non-dysplastic BE remain clear, the management of BE with low-grade dysplasia remains controversial. In a recent study published in the American Journal of Gastroenterology, Qumseya et al. performed a meta-analysis to investigate the relative risk of disease progression among patients with BE with low-grade dysplasia treated with radiofrequency ablation compared with surveillance alone.

The investigators identified 19 eligible studies meeting their inclusion criteria which incorporated a total of 2,746 patients. The primary outcome was the relative risk of disease progression among patients with BE with low-grade dysplasia treated with RFA compared with those who underwent surveillance alone. They found a RR of disease progression in patients with BE-LGD treated with RFA compared with surveillance alone of 0.14% (95% CI, 0.04-0.45, p=0.001). This suggests an 86% reduction in the risk of disease progression in RFA compared with surveillance. Further, the authors found an absolute risk reduction from RFA compared with surveillance of 10.9% with a number needed to treat of 9.2.

Interestingly, as opposed to current guidelines which recommend surveillance endoscopy for BE-LGD, this meta-analysis demonstrates that RFA is associated with significant reduction in disease progression among patients with BE-LGD and is superior to surveillance alone. The limitations of this study include potential publication bias as alluded to by the authors in the not provided funnel plot. Additionally, as mentioned by the authors, significant inter- and intraobserver variability exists among pathologists with regard to ND-BE, indefinite for dysplasia, and LGD. As such this variability may affect data utilized in the meta-analysis. Despite these limitations, this article appears to put forward strong evidence to support a change in practice for a disease process with significant burden to the United States population.

1. CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis [11]
In a recently published article in Chest, investigators prospectively measured serum CA-125 levels in 241 LAM patients. Of note, multivariate analysis discovered that higher serum CA-125 levels correlated with lower FEV1 and pleural effusions (p<0.001) and decreased after sirolimus treatment (p=0.002). Although further larger trials need to be performed, these findings suggest CA-125 may be a biomarker for disease activity in this patient population.

2. A Trial of Itraconazole or ” Amphotericin B for HIV-Associated Talaromycosis [12]
In this newly published article in NEJM, authors performed a non-inferiority trial comparing amphotericin B and itraconazole for the treatment of T. marneffei infections, a rare but extremely fatal disease. The authors found that the mortality at 6 months was 11.3% in the amphotericin B group and 21.0% in the itraconazole group with an absolute risk difference of 9.7% (95% CI, 2.8 to 16.6, p=0.006). Overall, amphotericin was superior to itraconzole as initial treatment for this infection when comparing 6-month mortality and clinical response.

3. Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among Cognitively Normal Persons [13]
This study published in JAMA prospectively analyzed cognitively normal individuals with elevated brain amyloid and found an increased risk of developing Alzheimer-related cognitive decline. Although the clinical significance of these findings remains unclear, these findings suggest a relationship between amyloid levels and cognitive decline that warrants further study.


1. Martin, J., Fausset, R. “Karen Handel Wins Georgia Special Election, Fending Off Upstart Democrat.” The New York Times. 20 June 2017.

2. Dionne Jr. E.J. “Karen Handel’s win was a victory for Republicans – but not for Trump.” The Waashington Post. 20 June 2017.–but-not-for-trump/2017/06/21/e157fc00-56bc-11e7-b38e-35fd8e0c288f_story.html?utm_term=.77e40264508a

3. Costas, P. “Britain’s Prince Phillip to spend second night in hospital.” Reuters. 21 June 2017.

4. Elliott, H. “Vegas holds all the cards in NHL expansion draft.” The Los Angeles Times. 20 June 2017.
5. Piccolo R, Gargiulo G, Franzone A, et al. Use of the Dual-Antiplatelet Therapy Score to Guide Treatment Duration After Percutaneous Coronary Intervention. Ann Intern Med. 2017.

6. Kubbajeh M, Cavazza C, et al. Randomized comparison of 6- versus 24-month clopidogrel therapy after balancing anti-intimal hyperplasia stent potency in all-comer patients undergoing percutaneous coronary intervention: design and rationale for the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia study (PRODIGY). Am Heart J. 2010;160:804–811

7. Staley C, Hamilton MJ, Vaughn BP, et al. Successful Resolution of Recurrent Clostridium difficile Infection using Freeze-Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study. Am J Gastroenterol. 2017;

8. Bedi P, Chalmers JD, Graham C, et al. A randomised control trial of atorvastatin in bronchiectasis patients infected with Pseudomonas aeruginosa- a proof of concept study. Chest. 2017

9. Mandal P, Chalmers JD, Graham C, Harley et al. Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial. Lancet Respir Med. 2014 Jun;2(6):455-63.

10. Qumseya BJ, Wani S, Gendy S, Harnke B, Bergman JJ, Wolfsen H. Disease Progression in Barrett’s Low-Grade Dysplasia with Radiofrequency Ablation Compared With Surveillance: Systematic Review and Meta-Analysis. Am J Gastroenterol. 2017;112(6):849-865.

11. Glasgow CG, Pacheco-rodriguez G, Steagall WK, et al. CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis. Chest. 2017

12. Le T, Kinh NV, Cuc NTK, et al. A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis. N Engl J Med. 2017;376(24):2329-2340.

13. Donohue MC, Sperling RA, Petersen R, et al. Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among Cognitively Normal Persons. JAMA. 2017;317(22):2305-2316.

Primecuts – This Week in the Journals

May 22, 2017

ladybugBy Michelle Lo, MD

Peer Reviewed

This past week marks the first leg of president Trump’s foreign trip starting at Saudi Arabia, where he was lavished with extravagant gifts. While former president Obama slowed military cooperation with the kingdom from the concerns of the country’s indiscriminate bombing of civilians in Yemen, Trump may seek to expand them.

The number of suspected cases of Ebola has now risen to 29 in less than a week the Democratic Republic of Congo. The risk of spread is high given the level of surveillance and access to healthcare. Aid groups are struggling to reach the area given road conditions.

In other news, Dr. Saito from the University of Tokyo have engineered an artificial wing in the ladybug in order to study rapid, repetitive storage and deployment of parachute like objects, learning a valuable lesson for engineering deployable structures such as umbrellas and satellites. 


Novel Noninvasive Measurement of Inflammation in Crohn’s Patients [1]

Multispectral optoacoustic tomography (MSOT) is an imaging technique that emits short pulsed laser light with near infrared wavelength (700 – 900 nm) towards target erythrocytes in the small and large bowel. Through thermoelastic expansion of the erythrocytes, detectable soundwaves return as measurements of total, oxygenated, and deoxygenated hemoglobin. The quantification of tissue oxygenation and perfusion allows for surrogate measurement of the extent of inflammation in the bowel.

In this single-center, cross-sectional study published in NEJM, 107 patients with various degree of Crohn’s disease activity were evaluated using MSOT. Patients with active and non-active diseases were determined clinically (Harvey-Bradshaw index), endoscopically (simplified endoscopic score for Crohn’s disease, or SES-CD), and histologically (modified Riley score). MSOT were also referenced against conventional ultrasound techniques, which measures intestinal wall thickness and perfusion (Limberg score). Six different wavelengths were tested, yielding levels total, oxygenated, deoxygenated hemoglobin as well as oxygen saturation as measurements of Crohn’s activity.

Using endoscopy (n = 44) and histology (n=42) as reference values, there were significant (P<0.001) differences in MSOT values comparing patients with active versus non-active disease, especially at wavelengths of 760nm. Significant differences were also found between patients in remission and those with low grade active disease (P=0.02, P0.03 respectively). However, with only clinical scoring (n=86) as the only reference point, MSOT was unable to yield clinically significant measurements, suggesting that at present MSOT along may not replace invasive diagnostics entirely.

The study was limited by small sample size and lack of external validation. MSOT technology may also be operator dependent given that 17 patients were excluded because they could not be evaluated. Given the risks and preprocedural prep required of invasive imaging in Crohn’s patient to detect disease activity with treatment, MSOT provides a new alternative towards noninvasive options for distinguishing active disease from remission in patients with Crohn’s disease.

Teprotumumab Targeting Thyroid- Associated Opthalmopathy [2]

Current treatments of Graves showed marginal effects on proptosis. High dose glucocorticoids and radiotherapy have mostly shown benefit in reducing symptoms of inflammation. The rational for treatment ineffectiveness may stem from incompletely understanding the pathophysiology of Graves opthalmopathy, the mechanism which is mediated by autoantibody stimulation of the thyrotropin receptor. Thyrotropin receptors, however, are not always detected in orbital tissues, suggesting that additional autoantibodies may be involved in the disease process.

IGF-1 and its receptor IGF-1R have been shown to be overexpressed by orbital fibroblasts, T cell, and B cells in Graves disease. Activation of IGF, IGF-1R may synergistically enhance the action of thyrotropin. Inhibitory antibodies targeting IGF-1R can therefore attenuate the actions of IGF-1, thyrotropin, and thyroid stimulating immunoglobulins. Teprotumumab is such a monoclonal antibody inhibiting IGF-1R.

In this article, Smith et al conducted a multi-center, double blinded, randomized, controlled trial comparing teprotumumab versus placebo in patients with active moderate to severe opthalmopathy. Patients were diagnosed 9 months after onset of symptoms, have not received surgical or medical treatment other than oral glucocorticoids. Patients were assessed every 3 weeks until total of 48 weeks.

Response was measured using a 7 point score for clinical activity, exopthalmometer for proptosis, and questionnaire for quality of life.

Eighty-eight patients were randomized. Scores were identical at onset, and at week 24 Teprotumumab was shown to be statistically more effective than placebo in reducing both proptosis and clinical activity score (Intention to treat AOR 8.86, P<0.001, per protocol AOR 12.73, P<0.001). The treatment group also showed statistically more rapid onset, faster time to first response, further reduction in activity score, sustained improvement throughout the treatment course, as well as improved quality of life scores.

Teprotumumab was associated with hyperglycemia, worse in patient with preexisting diabetes, requiring some titration of diabetic medication to achieve optimum control. The safety profile of the medication was encouraging. The trial is limited by enrolling patients only with active disease of recent onset and those with severe clinical activity score. Thus the benefit of treatment on milder cases are still unclear, and longer term follow up beyond 24weeks may be necessary.

Bystander Efforts and 1-Year Outcomes in Out-of Hospital Cardiac Arrest [3]

The rates of hospital survival after out of hospital cardiac arrest due to improvement in public awareness and in post-CPR care in the hospital. However, little is known about subsequent long term outcomes, specifically post cardiac arrest such as anoxic brain injury, limited activities of daily living, and nursing home admissions. Using the Denmark EMS Cardiac Arrest Registry, Kragholm et al included all people 18 years and older who were 30 day survivors of out-of-hospital cardiac arrest from 2001 to 2012. Follow up data was obtained from national registries and national nursing home admission data.

Between 2001 to 2012, 2855 (8.3%) patients who had an out-of-hospital cardiac arrest, whom resuscitation was attempted, and who survived for 30 days were included in the study. In comparison to prior data, the percentage of 30-day survival over 10 years has increased from 3.9% to 12.4%. From initial demographics of the 30-day survivor group showed that the bystander CPR, defibrillation group had greater proportions of men, witnessed arrest, public location of arrest and lower Charleston comorbidity index scores.

Upon 1 year follow up, 276 (9.7%) out of the 2855 patients died, of which 197 (71.4) had a presumed cardiovascular cause. Three hundred (10.5%) had anoxic brain damage or were admitted to the nursing home of which 59 died within 1 year. The median time between event or nursing home admission to death was 85 days. Between 2001 to 2012 the rates of bystander intervention increased while the proportion of negative outcomes decreased. Compared to no intervention, initial intervention with bystander CPR or defibrillation was associated with lowered risk of all cause mortality, anoxic brain damage, or nursing home admission.

The lowest absolute risk was seen in EMS-witness cardiac arrest (3.7% 95% CI 2.5 – 4.9), lowest risk of death seen in bystander-defibrillation group (2%, 95% CI 0 – 4.2). The highest risk of anoxic brain injury and nursing home admission was seen in the no bystander resuscitation group (18.6%, 95% CI 16 -22.2). All cause mortality was also higher in the no bystander resuscitation group (15.5% 95% CI 12.5-18.6). The results suggest that bystander out of hospital resuscitation of cardiac arrest was associated with lower 1 year risk of morbidity and mortality. Over the course of the study over 10 years, with increasing rates of bystander out of hospital resuscitation was associated with lower rates of morbidity and mortality.

KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma [4]

Targeted therapy towards treatment of airway hyperresponsiveness may lead to more effective symptom control in asthma. Difficult to control asthma has been shown to have high levels of tryptase, surrogate for mast cell burden and degranulation, in bronchoalveolar washings. Despite glucocorticoid treatments, mast cells may continue to survive due to presence of long living hematopoietic effector cells. Imatinib inhibits tyrosine kinase activity of receptor KIT protooncogene, which is a stem cell factor essential for mast cell survival. Currently imatinib is used for treatment of patients with chronic myeloid leukemia and pulmonary hypertension but this mechanism may extend to treating patients with refractory asthma.

This was a randomized, double blind, placebo, proof of principal trial involving 7 academic centers from 2010 to 2015. The study enrolled patients ages 18-65, with severe refractory asthma not controlled despite inhaled beclamethasone, with Asthma Control Questionnaire (ACQ-6) score 1.5 or higher, FEV1 decrease of over 20% upon methacholine challenge, and a FEV1 at 40% of predicted value. Patients were randomized to imatinib 200mg per day for 2 weeks then 400mg per day versus placebo. Both medications were dosed once daily.

Bronchoscopy and airway biopsy were performed before randomization and repeated at week 24. The primary outcome measured were change in airway hyperresponsiveness as PC20 score (concentration of methacholine needed to produce a 20% fall in FEV1 from baseline). Secondary outcomes measured were FEV1, peak expiration flow, mast cell count, tryptase level, and smooth muscle biopsy samples. In addition, blood eosinophil, histamine, leukotriene, and prostaglandins were measured. Also assessed were allergy skin testing, asthma symptom index, and patient reported quality of life questionnaire.

One hundred seventy-six patients were screened and 62 were equally randomized, no significant differences were noted in baseline characteristics. For primary outcome, imatinib was noted to increase methacholine PC20 by mean of 1.2 + 0.52 doubling doses from baseline by month 3 (P = 0.03), 1.73 + 0.6 by month 6 (P = 0.008) compared to 0.03 +0.42 (P = 0.94) and 1.07 + 0.6 (P= 0.08) respectively of the placebo group. Difference between treatment and placebo over course of trial was P = 0.048.

Regarding secondary outcomes, total and BAL tryptase level decreased in imatinib and increased with placebo. Mast cell count both decreased without statistically significance towards greater reduction in the treatment group. Treatment group had fewer asthma exacerbations, greater reduction airway wall thickness, higher peak expiratory flows, and greater improved patient reported outcomes however were not statistically significant. No significant differences were found for counts of eosinophil, histamine, leukotriene, prostaglandins. Side effects did not differ significantly between groups and included muscle cramps and metabolic abnormalities which abated since discontinuing treatment.

In conclusion, imatinib was associated with clinically significant increase in FEV1 and improvement in PC20 scores that correlated with reductions in endobronchial mast cell counts which may help support the role of mast cells in persistent refractory asthma. The improvements may be secondary to imatinib’s inhibition of lymphoid cell producing cytokines causing eosinophilic and neutrophilic inflammation, as well as platelet derived growth factors. Mast cells also were not completely eliminated at 6 months of treatment. This study should be expanded upon with larger and longer trials. 


New Development on Zika Virus Vaccines [5]

The Zika virus epidemic which started in 2015 brings about intersection of global public health and the debate on elective termination of pregnancy. Currently there are no licensed vaccine or antiviral drug to prevent or treat Zika. Recent reports described successful testing of experimental Zika vaccine in animal models involving engineered mRNAs encoding the viral precursor membrane glycoprotein and envelope glycoprotein critical to viral attachment and replication.  Vaccinated mice showed development of binding IgG antibodies and neutralizing antibodies as well as antigen specific CD4+ T cells after vaccination. The same mice were protected from viremia when later challenged with a strain of the Zika. 

Compound Accumulation Rules in Designing The Next Broad-Spectrum Antibiotic. [6]

Since the quinolones, no new class of antibiotics have been introduced that targets gram negative bacteria. The ideal small molecule must traverse porins through the membrane bilayer faster than they are pumped out through efflux pumps. This article assembles a complex, structurally diverse set of 100 compounds and tested them on E coli, then using computer analysis to yield predictive guidelines for small molecule accumulation in Gram negative bacteria. Testing compounds showed benefit of an ionizable nitrogen embedded in a compound with strict geometric constraints, with diminished accumulation with increasing substitution on the amine group.

T Cells Get a Ride [7]

New articles published in Science Translational Medicine described combining immune checkpoint blockade with angiogenesis inhibition to improve targeted elimination of cancer cells. Angiogenesis inhibitors promotes vascular normalization and limit the development of dysfunctional tumor vessels. Antibody target angiopoetin (ANG2) and vascular endothelial growth factor (VEGFA) in mouse models of breast, pancreatic, colon cancer and melanoma were shown to promote lymphocyte infiltration and activity.

Dr. Michelle Lo is a resident at NYU Langone Medical Center

Peer reviewed by David Kudlowitz, MD, department of medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


[1] Knieling, F et al. Multispectral Optoacoustic Tomography for Assessment of Crohn’s Disease Activity. N Engl J Med. 2017 Mar 30.  Accessed May 20.

[2] Smith, T. J. et al. Teprotumumab for Thyroid-Associated Opthalmopathy. N Engl J Med. 2017 May 4. Accessed May 20.

[3] Kragholm, K et al. Bystander Efforts and 1-Year Outcomes in Out-of Hospital Cardiac Arrest. N Engl J Med. 2017 May 4. Accessed May 21.

[4] Cahill, K N. et al. KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med. 2017 May 18. Accessed May 21.

[5]  Thomas, S J. Zika Virus Vaccines – A Full Field and Looking for the Closers. N Engl J Med. 2017 May 11.  Accessed May 20.

[6] Richter, M. F. et al. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature. 2017 May 18. Accessed May 20.

[7] Villanueva M. T. et al. T cells get a ride. Nature Reviews Drug Discovery. Nature. 2017 May 19. Accessed May 20.




Primecuts – This Week in the Journals

May 17, 2017

Electronic_medical_recordBy Maxine W Stachel, MD

Peer Reviewed

The past week saw a massive worldwide cyber-hacking attack that affected many well-known brands and, disturbingly, at least a dozen hospitals in Britain’s National Health Service. Using a program allegedly stolen from the US National Security Administration, hackers were able to freeze NHS electronic medical records, which left doctors unable to access patient files and patients unable to access care. Outpatient appointments and elective surgeries were cancelled. Some emergency departments were even forced to divert patients needing urgent care to other institutions until the ransomed computers were unlocked.

As anyone who routinely uses Quadramed or CPRS can avow, our hospital electronic medical records are woefully out-of-date. And given the enormous amount of sensitive information contained on hospital servers, EMRs make especially attractive targets for ransomware. While some of the systems-wide problems will take significant investments of time and money to address, you can do your part by updating your computer regularly and not clicking on dodgy email links at work. And if that doesn’t alleviate your anxiety, you can always take solace in the steady progress of evidence-based medicine, as outlined in this week’s Primecuts: 


Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatits: A Meta-analysis[1]

Nonalcoholic steatohepatitis is a leading cause of liver disease in the US, and is expected to become the primary indication for liver transplantation by 2020. While there are no drugs currently approved for the treatment of NASH, there is a growing body of literature to support the use of thiazolidinediones (TZDs) in patients with the condition.

In a new meta-analysis on the subject, investigators examined eight RCTs using TZDs (five using pioglitazone and three using rosiglitazone) in a combined 516 patients with biopsy-proven NASH. Patients were followed for 6-24 months, The researchers found that TZDs were associated with improvement in advanced fibrosis (OR 3.15; 95% CI, 1.25-7.93; p=0.01), improvement in fibrosis of any stage (OR 1.66; 95% CI, 1.12-2.47; p=0.01) and resolution of NASH (OR 3.22; 95% CI, 2.17-4.79, p<0.001). Impressively the results remained significant even when diabetic patients were excluded from the analysis. All of these effects were attributed to pioglitazone use; rosiglitazone produced no statistically significant effects. Side effects of TZDs included weight gain and lower extremity edema.

This study suggests that TZDs (specifically pioglitazone) might be used to reverse advanced fibrosis in NASH and thereby improve the prognosis of patients at highest risk for poor outcomes. The fact that the effect extended to non-diabetics suggests that it might be reasonable to expand the approved indications for pioglitazone use. Although the study failed to show improvement in NASH with rosiglitazone use, it seems possible that the effect seen with pioglitazone is indeed a class-wide effect of TZDs and that an insufficient number of rosiglitazone RCTs were included to make it apparent. Likewise, while the meta-analysis demonstrated only mild adverse effects of weight gain and pedal edema, it was not powered to uncover more serious effects such as the development of congestive heart failure. The short duration of the trials may also have limited the number of adverse outcomes seen in the study population.

The results of the trial are encouraging overall, but further and more longitudinal studies will be necessary to demonstrate that improvements in a surrogate endpoint will translate into clinical recovery of patients with NASH. 

Cancer-Associated Mutations in Endometriosis without Cancer[2]

Endometriosis affects approximately 10% of women of child-bearing age, and commonly presents with dysmenorrhea, pelvic pain and infertility. While ectopic endometrial tissue is usually considered benign, it can bear some of the hallmarks of cancer, including local invasiveness and resistance to apoptosis. In particular, the deep infiltrating subtype of endometriosis manifests with nodules that locally invade pelvic structures, causing patients to suffer deep dyspareunia and dyschezia. Medical therapy with progestins or gonadotropin-releasing hormone analogues often produces unacceptable side effects or insufficient efficacy. The genetic basis and pathogenesis of deep infiltrating endometriosis remain unclear, encumbering efforts to produce novel therapies to address the condition.

In a study published this week in NEJM, researchers analyzed deeply infiltrating endometriotic lesions from 39 women with a mean age of 37 years. Three types of independent molecular genetic analyses were conducted simultaneously: exome-wide sequencing with confirmation of cancer-driver mutations by Safe-SeqS and immunohistochemical stains in one sample set; panel-based sequencing validated by droplet digital PCR in another set of samples; and droplet PCR alone in a third set. Through the combination of these “next-generation” sequencing and validation tools, the researchers discovered that most of the lesions contained somatic mutations.

Ten of 39 lesions (26%) carried mutations in well-documented cancer driver genes ARID1A, PIK3CA, KRAS and PPP2R1A.

These findings have several important implications for research into both cancer and endometriosis. First, given the benign nature of most endometriotic lesions, these findings call into question the reliability of testing for genetic mutations to predict or monitor cancer risk. Epigenetics play an increasingly recognized role in the development of cancer, and this study highlights the caution with which doctors and patients should interpret the results of genetic cancer screens. In addition, the findings of this study begin to answer some of the long-standing questions about the phenotypic heterogeneity of endometriosis and variability in its pathogenesis. Such detailed genetic analysis may ultimately enlighten diagnosis of the disease and speed development of targeted treatments.

The Dietary Approaches to Stop Hypertension (DASH) diet, Western diet, and risk of gout in men: prospective cohort study[3] 

Gout is the most common inflammatory arthritis, and its prevalence in the US has steadily increased to 3.9% (over 8 million adults).[4] More than half of patients suffer comorbid hypertension and metabolic syndrome. The traditional dietary recommendation for patients at risk of gout has been a diet low in purines, which often results in increased consumption of refined carbohydrates and unhealthy fats, leading to increased insulin resistance and a worsened cardiovascular risk profile. Affected patients would benefit from a more comprehensive dietary strategy.

In a prospective cohort study published in BMJ, researchers enrolled 44,444 men with no history of gout and used validated food frequency surveys to assign each participant a DASH dietary pattern score (high intake of fruits, vegetables, legumes, low fat dairy, whole grains, and low intake of sodium, sweet drinks, and red and processed meats) and a Western dietary pattern score (high intake of red and processed meats, fried foods, refined grains, desserts). Dietary pattern scores were re-calculated every four years, and non-dietary factors (BMI, medications, medical conditions, gout incidence) were assessed biennially.

Over 26 years of follow-up, the researchers documented 1731 confirmed cases of gout meeting American College of Rheumatology criteria. The DASH dietary pattern was associated with significantly reduced risk of gout (adjusted relative risk for extreme fifths 0.68, 95% CI 0.57-0.80, p<0.001) while a higher Western dietary pattern score was associated with elevated risk (1.42, CI 1.16-1.74, p=0.005). The relationship remained after adjusting for age, BMI, diuretics use, history of HTN and renal failure, and coffee and alcohol intake.

The most important limitation of this study is its observational design, which is not powered to prove causation. RCTs that assign patients to various diets will be necessary to definitively determine whether a specific diet might prevent gout. It should also be noted that the demographics of the current study skew very heavily toward white men, which could limit generalizability to more diverse populations. However, given higher prevalence and incidence of gout in the African American community, the present study likely underestimates the effect in this group. With further study and reinforced patient compliance, the DASH diet might well offer a new tool for preventing gout and its comorbidities in motivated, high-risk patients.

Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update from the American College of Physicians[5]

More than half of Americans over 50 years old are at risk for osteoporotic fracture, and over 50 million already carry a diagnosis of osteoporosis or osteopenia. Last revised in 2008, this updated guideline compares risks and benefits of treatment options for low bone density in men and women. In the development of the new guidelines, the ACP performed a systematic analysis of RCTs, review articles, large observational studies and case reports published between 2005-2011. As in other ACP guidelines, the evidence was graded according to Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

The first and strongest recommendation, based on highest-quality evidence, is that clinicians offer treatment with alendronate, risedronate, zoledronic acid or denosumab to reduce the risk for hip and vertebral fractures in women with known osteoporosis. Weaker recommendations suggest that clinicians avoid estrogen and raloxifene therapies in menopausal women with osteoporosis, as these therapies do not reduce most fractures in this population. (This is a significant change from the 2008 guideline, which reported that estrogens could reduce fractures in the broader categories of postmenopausal women or women with low bone density). Estrogens and raloxifene were also noted to increase risk for CVAs and VTEs. The overall effect of calcium, vitamin D or physical activity alone was unclear.

Other relatively weak recommendations (supported by low quality evidence) are to [1] treat osteoporosis in women for 5 years (very few studies evaluated longer treatment, and one RCT of bisphosphonates found no difference in outcomes at 10 years vs. 5 years), [2] avoid bone density monitoring during the 5-year treatment period (it has not been shown to change management), [3] offer bisphosphonate therapy to men with osteoporosis to reduce risk of vertebral fracture (seems reasonable, but very few RCTs studied men specifically), [4] treat osteopenia in women over 65 on a case-by case basis (depending on individual patient preference and risk profile). The guidelines also recommend prescription of generic drugs wherever possible, to reduce costs and help improve compliance.

Overall these recommendations emphasize the growing importance of osteoporosis diagnosis and treatment to our aging population. They also highlight areas still lacking for high quality research data, and encourage clinicians to make informed treatment decisions on a patient-specific basis.


Bioengineering of an Intraabdominal Endocrine Pancreas[6]

As part of an ongoing study ( number NCT02213003), deceased donor islet cells were successfully transplanted onto the omentum of a 43 year old woman with a 25-year history of Type I diabetes. The patient was maintained on immunosuppressive agents and a low carbohydrate diet and exercised regularly. She was successfully weaned from 33 U daily exogenous insulin regimen, and at 1 year remained euglycemic with an HbA1c level of 6.0%. Studies of long-term safety and feasibility are ongoing.

Leukotriene B4 antagonism ameliorates experimental lymphedema[7]

Lymphedema is a common, debilitating, and often iatrogenic condition with no pharmacologic treatment options. Stanford scientists have shown that the development of lymphedema is an inflammatory phenomenon marked by LTB4 elevation in animal models and humans. Clinical tests of an LTB4 inhibtor (bestatin) already used as a cancer drug in Japan are raising hopes for patients with secondary lymphedema (caused by radiation, surgery or trauma).

Use of the National Heart, Lung, and Blood Institute Data Repository[8]

NHLBI instituted a formal data repository (BioLINCC) in 2000, requiring that all investigators receiving NHLBI funding for observational studies or clinical trials make their de-identified data available to the scientific community within two years of study completion. In this review of the repository use, it was found that from 2000-2016, 370 investigators requested clinical trial data, resulting in over 200 additional publications. Most the data (72%) were used for post-hoc secondary analysis of new questions, and 7-9% were used for new statistical analyses and meta-analyses; only twice were primary studies repeated by subsequent investigators. 

Subjective Crepitus as a Risk Factor for Incident Symptomatic Knee Osteoarthritis: Data from the Osteoarthritis Initiative[9]

In one of the first long-term studies on the relationship between crepitus and joint disease, researchers at Baylor University followed thousands of patients at high risk for osteoarthritis for at least 4 years, and assessed them annually using surveys and X-rays. Researchers found that crepitus without pain was associated with the presence of joint deformity and the development of arthritis within one year.

Dr. Maxine W Stachel is an intern, internal medicine at  NYU Langone Medical Center

Peer reviewed by Neha Jindal, MD, department of medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


[1] Musso G, et al. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: A meta-analysis. JAMA Int Med. 2017 May 15.

[2] Anglesio MS, et al. Cancer-associated mutations in endometriosis without cancer. N Engl J Med. 2017 May 11; 376:1835-1848. DOI: 10.1056/NEJMoa1614814. Accessed May 14, 2017.

[3] Rai SK, et al. The Dietary Approaches to Stop Hypertension (DASH) diet, Western diet, and risk of gout in men: prospective cohort study. BMJ. 2017 May 9;357:j1794. DOI: 10.1136/bmj.j1794. Accessed May 14, 2017.

[4] Zhu Y, et al. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011 Oct;63(10):3136-41. doi: 10.1002/art.30520.. Accessed May 15, 2017.

[5] Qaseem A, et al. Treatment of low bone density or osteoporosis to prevent fractures in men and women: A clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017 May 9. DOI: 10.7326/M15-1361. Accessed May 14, 2017.

[6] Baidal DA, et al. Correspondence: Bioengineering of an Intraabdominal Endocrine Pancreas. N Engl J Med. 2017 May 11; 376:1887-1889. DOI: 10.1056/NEJMc1613959. Accessed May 14, 2017.

[7] Tian W, et al. Leukotriene B4 antagonism ameliorates experimental lymphedema. Science Transl. Med. 2017 May 10;6(389). DOI:10.1126/scitranslmed.aal3920. Accessed May 14, 2017.

[8] Coady SA, et al. Use of the National Heart, Lung, and Blood Institute Data Repository.

N Engl J Med. 2017 May 11;376:1849-1858. DOI: 10.1056/NEJMsa1603542. Accessed May 14, 2017.

[9] Lo GH, et al. Subjective crepitus as a risk factor for incident symptomatic knee osteoarthritis: data from the osteoarthritis initiative. Arthritis Care & Research. 2017 May 4. DOI: 10.1002/acr.23246. Accessed May 14, 2017.


Primecuts – This Week in the Journals

May 8, 2017
HALLANDALE BEACH, FL - APRIL 01:  #4 Always Dreaming (FL) wth jockey John Velazquez on board, wins the Xpressbet Florida Derby (Grade I) at Gulfstream Park on April 01, 2017 in Hallandale Beach, Florida. (Photo by Liz Lamont/Eclipse Sportswire/Getty Images)

HALLANDALE BEACH, FL – APRIL 01: #4 Always Dreaming (FL) wth jockey John Velazquez on board, wins the Xpressbet Florida Derby (Grade I) at Gulfstream Park on April 01, 2017 in Hallandale Beach, Florida. (Photo by Liz Lamont/Eclipse Sportswire/Getty Images)

By Alicia Cowley, MD, MBA

Peer Reviewed

This past Thursday, the American Health Care Act narrowly survived a full vote in the House. The American College of Physicians, the American Medical Association, the American Academy of Family Physicians, and at least a dozen other health care organizations have released statements imploring the Senate to dismiss this bill that reduces coverage and protection for our country’s most vulnerable patients. This event represents one of the rare instances in which major associations representing doctors, hospitals, insurers, and seniors have all been in agreement.

Meanwhile, on the other side of the Atlantic, the centrist candidate (and new president-elect) Emmanuel Macron was hit by a hacking attack that resulted in 9GB of internal emails and documents a mere 24 hours before facing Marine Le Pen, the far-right candidate of the National Front, at the ballot box. Since neither candidate represents the two parties that have traditionally dominated French politics, this election cycle speaks to the divisions within France as well as Europe as a whole regarding immigration as well as participation in the European Union.

As we wait with bated breath regarding the aforementioned votes, the news also buzzes with lighter stories such as Always Dreaming’s victory at the Kentucky Derby and the Federal Communications Commision’s investigation of Stephen Colbert’s controversial Trump joke. As healthcare has its moment at center stage, here are some of the latest updates in clinical care.

Clinical Outcomes of Metformin Use in Populations with Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease

Phenformin, a binguanide previously used for glycemic control, was withdrawn in the late 1970s due to its association with often fatal lactic acidosis in patients with renal impairment. As a related biguanide, metformin came with a boxed warning regarding the risk of lactic acidosis when it was first approved by the US Food and Drug Administration (FDA) in 1994, especially in the setting of chronic kidney disease (CKD). Furthermore, it came with a recommended caution in patients whose comorbid conditions may promote lactate accumulation (e.g. congestive heart failure (CHF) and chronic liver disease (CLD)). The literature suggests that there actually is no clear link between metformin use and lactic acidosis [1].

More recently, the FDA has dialed back its strict boxed warning. In the last decade, the FDA removed chronic, stable CHF as a contraindication to metformin use. In April 2016, the FDA modified its exclusion criteria for CKD patients by switching its definition of renal impairment from a creatinine-based one to a more inclusive one based on estimated glomerular filtration rate. With metformin’s expanding use in patients with historical contraindications or precautions, it is important to promote informed prescribing practices among providers.

In a systematic review and meta-analysis, Crowley and colleagues explored the outcomes of metformin use in patients with type 2 diabetes and moderate to severe CKD (with eGFR as low as 30 mL/min/1.73 m2), CHF, or CLD with hepatic impairment [2]. In these patients, metformin was associated with reduced all-cause mortality, fewer heart failure readmissions in patients with CKD or CHF, and a lower hypoglycemia rate among those with moderate CKD. Although quite favorable, these results are flawed in that available results were observational studies with high risk for bias given the possibility of unaccounted-for between-group differences in disease severity, the inability to capture potential differences in hazard over time, and post-baseline medication changes when looking at patients with metformin use at baseline versus comparator patients. Despite these limitations, metformin is a safe, effective, and inexpensive first-line option for patients with type 2 diabetes. In adults with type 2 diabetes and moderate to severe CKD, CHF, or CLD with hepatic impairments, metformin is associated with improvements in key clinical outcomes, including all-cause mortality and hospital readmission.

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

Although Pfizer has discontinued its global clinical development program for bococizumab, its cholesterol-lowering proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, the clinical information put forth by Ridker and colleagues’ Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) program still highlight the evolving treatment and market landscape for lipid-lowering agents [3]. Ridker et al conducted two parallel, multinational lipid-lowering trials enrolling a total of 27,438 high-risk patients (mean age 62.9 years, 29.6% women, LDL-C 94 mg/dL in SPIRE-1 and 135 mg/dL in SPIRE-2) who were treated with maximally tolerated statin doses (92.9% on any statin dose, 84.5% on high-intensity statin) as well as 150 mg of bococizumab or placebo subcutaneously every two weeks and were followed for up to one year.

The primary outcome included incidence of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina requiring revascularization. In SPIRE-2, bococizumab reduced cardiovascular events in patients with higher baseline LDL levels (>100 mg/dL) who were followed for a longer duration (median 12 months) (hazard ratio [HR] of 0.79, 95% confidence interval [CI] 0.65 to 0.97, P=0.02). However, the PCSK9 inhibitor did not demonstrate any effect on cardiovascular events in SPIRE-1 (HR 0.99, 95% CI 0.80 to 1.22; P=0.94), which included patients with lower baseline LDL levels (>70 mg/dL) who were followed for a shorter duration (median 7 months). Antidrug antibodies developed in almost half (48%) of the patients who received bococizumab and neutralizing antibodies developed in 29%. These antibodies are thought to have substantially attenuated LDL-cholesterol lowering over time.

These antidrug antibodies appear to be limited to bococizumab, a partial murine-based agent, and is not an issue with the fully human monoclonal antibodies evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/Regeneron). Last month, new data on alirocumab published in the New England Journal of Medicine, shows that antidrug antibodies develop in just 5.1% of patients (vs 1.0% of controls) and neutralizing antibodies in 1.3% [4]. Amgen recently completed a  large cardiovascular-outcomes study, FOURIER, to study the effects of evolocumab on the same primary endpoints explored by the SPIRE program. In just shy of a year, evolocumab was able to reduce LDL cholesterol levels by 59% compared to placebo (from a median baseline value of 92 mg/dL to 30 mg/dL, P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary point already defined by SPIRE (1344 patients [9.8%] vs 1563 patients [11.3%]; hazard ratio 0.85; 95% CI 0.79 to 0.92; P<0.01). These results were consistent across subgroups, including those patients with the lowest quartile for baseline LDL cholesterol (medial 74 mg/dL), suggesting that patients with atherosclerotic cardiovascular disease (ASCVD) may benefit from lowering LDL below current targets.

Despite the promise that PCSK9 inhibitors may have for atherosclerotic cardiovascular disease prevention, their annual cost does not meet cost-effective thresholds [6]. According to Kazi et al’s insightful simulation model of US adults aged 35 to 94 years, adding PCSK9 inhibitor therapy to current statin regimens for patients with heterozygous familial hypercholesterolemia or ASCVD is estimated to cost $423,000 per quality-adjusted life-year (QALY) gained and could increase US health care costs by $565 billion over 5 years. In contrast, adding ezetimibe is almost three times less expensive at $152,000 per QALY and starting statins in all high-risk patients who are not currently on statins and are statin-tolerant is estimated to save $12 billion on a national scale.

Stroke in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic, systemic inflammatory disease that has been associated with increased risk of cardiovascular disease [7]. Although stroke has previously been studied as a composite endpoint in conjunction with cardiovascular disease, a group at the Karolinska Institute recognized that stroke is an important cause of morbidity and mortality in SLE that warranted its own investigation [8]. The group studied 3,390 SLE adult patients from the Swedish National Patient Register from 2003 to 2013, matched by age, sex, and residential county to 16,730 non-SLE controls obtained from the Total Population Register.

Compared to the general population, individuals with SLE had a twofold-increased rate of ischemic stroke (HR 2.2, 95% CI 1.7 to 2.8). The HR for intracerebral hemorrhage was 1.4 (95% CI 0.7 to 2.8). When further stratifying the data, the highest HRs were for females and individuals less than 50 years old. The rate of ischemic stroke was highest in the first year of follow-up (HR 3.7, 95% CI 2.1 to 6.5). Although this study has an impressive body of long-term data for a large population that spans both inpatient and outpatient settings, it does recognize its limitations, especially in regards to possible misclassification of SLE and stroke. The date of the second SLE-coded visit was used as the date of incident disease, which can result in misclassification of time to diagnosis of SLE as well as the exclusion of individuals who experienced a stroke soon after their first SLE diagnosis but before a second SLE diagnosis in a non-primary care setting was given. In other words, requiring specialist visits to confirm SLE minimized SLE misclassification but could have resulted in missed early strokes. These missed cases could lead to an underestimation of the stroke risk in the first year after SLE diagnosis.

Regardless of these limitations, the data speaks for itself and first encounters with SLE patients present an opportunity for primary care physicians and rheumatologists to intervene. Furthermore, studies such as this may promote the development of an SLE-specific risk score and evidence-based guidelines for stroke prevention.

Clinical Quality and the Patient-Centered Medical Home

The Patient-Centered Medical Home (PCMH) is a health care delivery model whereby patient treatment is coordinated through his or her primary care physician. According to the Agency for Healthcare Research and Quality (AHRQ), the medical home is a centralized setting that supports the following five functions: comprehensive care, patient-centered, coordinated care, accessible services, as well as quality and safety [9]. PCMH accreditation is a signal to payers, policymakers, and patients that a practice is committed to aligning patient preferences with payer and provider capabilities. In the near future, Medicare will likely use PCMH accreditation to award bonuses through its future value-based payment programs.

There are legitimate concerns regarding accredited practices’ sustainable commitment to PCMH efforts. There is a fear that accreditation consists of just checking off boxes. For example, in a capitation payment model, payers need reliable, external validation to justify their bonuses. More importantly, patients and their families want to know whether PCMH practices actually focus on delivering high quality, patient-centered, coordinated care for every patient.

Regardless of whether one works in a PCMH model or not, there is no denying that the aforementioned functions should improve patient care and it would be helpful to find out which are the biggest drivers of improved clinical quality. A study published in JAMA conducted a patient-level observational study through the Veterans Health Administration (VHA) to gauge clinic-level PCMH implementation through the VHA’s own PCMH initiative, the Patient Aligned Care Team (PACT) program [10]. PACT encompasses eight core domains: access, continuity, care coordination, comprehensiveness, self-management support, patient-centered care and communication, shared decision-making, and team-based care.

The group assessed clinic-level PCMH implementation in 909 clinics using the PACT Implementation Progress Index (Pi2). When modeling the association between quartile of Pi2 component and 48 clinical quality indicators, it was no surprise that higher scores on each of Pi2’s eight components was associated with better performance in clinical quality indicators. Out of those eight domains, the strongest drivers of quality are care coordination, access, continuity, and communication. High levels of care coordination resulted in clinics having significantly better quality scores on 33 of 48 (69%) quality measures compared with lower-performing clinics. Comparable results were seen when it comes to improved access (32 [67%]), continuity (29 [60%]), and communication (25 [52%]).

By extrapolating these results to the entire VHA primary care population (5.4 million patients), it is estimated that 310,468 additional high-quality services could have been delivered if all clinics performed equally well as the high-quartile clinics in regards to care coordination. Similar improvements in quality metrics are estimated to occur with better access (n= 258,999), continuity (n=253,816), and communication (n=285,193). As with any associational study, these results can not be used to generate a conclusion that invokes causation. That being said, this insight can help residency programs who are implementing PCMH models in their teaching clinics, which are often resource-constrained entities in underserved communities, focus their efforts on the highest yield domains first.


There is mounting evidence surrounding the role of gut microbial dysbacteriosis in the pathogenesis and perpetuation of inflammatory bowel disease (IBD). Oral iron treatment has long been the standard intervention for iron deficiency anemia in patients with IBD given its safety profile, low cost, and convenient route of administration, A new study in Gut suggests that high concentrations of luminal iron affect gut microbiota and fecal metabolites, especially in patients with Crohn’s disease who are more prone to iron replacement therapy-induced shifts [11]. Future practices may turn to intravenous iron therapy as first-line therapy for anemic Crohn’s disease patients with unstable microbiota.

As Bhattacharjee and colleagues at the University of Chicago review the evolving definition of sepsis, we gain a better understanding of how sepsis was traditionally monitored on the medicine wards (SIRS) and the advancements that we are striving for to achieve improved specificity [12]. Interestingly, we catch a glimpse of the data behind automatic electronic medical record (EMR)-based sepsis alerts – in one interventional study, a triggered alert resulted in a significant decrease in median time to any sepsis-related intervention by a median difference of 3.5 hours (P=0.02) [13]. Future directions point to procalcitonin as a promising biomarker as well as better application of machine learning to our EMR data.

How many times have we been frustrated by medication non-compliance, especially when patients say they just forgot to take their pills? The REMIND trial looked at the effect of three low-cost reminder devices on medication adherence [14]. Participants included individuals ages of 18 and 64 taking one to three oral medications with suboptimal adherence to all their prescribed medications (medication possession ratio 30% to 80% at baseline) and stratification based on medication categories (cardiovascular or other non-depression chronic conditions versus antidepressants) as well as dosing schedule. Unfortunately, there was no statistical difference in adherence between those in the control group and those who received a reminder device (standard pillbox, digital timer cap, or pill bottle strip with toggles). Looks like it’s back to the drawing board to come up with more effective interventions.

Dr. Alicia Cowley is a resident at NYU Langone Medical Center

Peer reviewed by Kevin Hauck, MD, internal medicine, NYU Langone Medical Center

Image courtesy of Horse Racing Nation:


  1. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2010, Issue 4. Art. No.: CD002967.
  2. Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB, Stanifer JW, Mock CK, et al. Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review. Ann Intern Med. 2017;166:191-200.
  3. Ridker PM, et al. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. N Engl J Med 2017;376:1527-1539.
  4. Roth EM, et al. Antidrug Antibodies in Patients Treated with Alirocumab. N Engl J Med 2017;376:1589-1590.
  5. Sabatine MS, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Eng J Med 2017;376:1713-1722.
  6. Kazi DS, Moran AE, Coxson PG, Penko J, Ollendorf DA, Pearson SD, Tice JA, Guzman D, Bibbins-Domingo K. Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease. JAMA. 2016;316(7):743-753.
  7. Schoenfeld SR, Kasturi S, Costenbader KH. The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review. Semin Arthritis Rheum 2013;43(1):77–95.
  8. Arkema, Elizabeth V, et al. Stroke in systemic lupus erythematosus: a Swedish population-based cohort study. Ann Rheum Dis. Published online Apr 11, 2017.
  9. Defining the PCMH:
  10. Nelson K, Sylling PW, Taylor L, Rose D, Mori A, Fihn SD. Clinical Quality and the Patient-Centered Medical Home. JAMA Intern Med. Published online May 01, 2017.
  11. Lee T, Clavel T, Smirnov K, et al. Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD. Gut 2017;66:863-871.
  12. Bhattacharjee, Poushali, et al. Identifying Patients With Sepsis on the Hospital Wards. Chest. 2017 Apr;151(4):898-907.
  13. Kurczewski L, Sweet M, McKnight R, Halbritter K. Reduction in time to first action as a result of electronic alerts for early sepsis recognition. Crit Care Nurs Q. 2015;38(2):182–187.
  14. Choudhry NK, Krumme AA, Ercole PM, Girdish C, Tong AY, Khan NF, Brennan TA, Matlin OS, Shrank WH, Franklin JM. Effect of Reminder Devices on Medication Adherence: The REMIND Randomized Clinical Trial. JAMA Intern Med. 2017;177(5):624-631.


Primecuts – This Week in the Journals

May 1, 2017

march for scienceBy Janine Knudsen, MD

Peer Reviewed

In the first major demonstration of scientists and science-lovers in the US, last Saturday thousands of people descended on the Mall in Washington, DC, and rallied in the March for Science. Clever signs abounded as the marchers protested against the threats to governmental science funding, the use of “alternative facts”, and many issues in between. Down the street at the White House, Trump was busy turning out new policies before April 29th, his 100th day in office. This past week saw the release of his proposed tax cuts, a plan to renegotiate NAFTA, and a new healthcare bill. Lawmakers are struggling to keep up, with partisanship dominating major legislative efforts.

With the threat of an ACA repeal looming yet again, policy research aimed at understanding the skyrocketing costs of our healthcare system is more important than ever. Read on for the latest literature in health policy, public health, and clinical care from this week.

Variation in Physician Spending and Association With Patient Outcomes

In 2012, the landmark Dartmouth Healthcare Atlas[1] revealed that health care spending and quality varied widely across geographic regions of the US and even across hospitals in the same city. In a new JAMA Internal Medicine research study, researchers have performed an even more microscopic review of quality and cost variation, focusing on the differences among physicians at the same hospital.[2] Their retrospective review quantifies this variation and also assesses whether higher-spending physicians achieve better outcomes.

Using a retrospective data analysis of 20% of Medicare beneficiaries hospitalized between 2011 and 2014, the researchers analyzed Part B Medicare costs by physician for 1.3 million admissions. They excluded cost outliers (top and bottom 5% hospitalizations by cost) and used observed vs. expected cost as their main variable, with logistic regression adjusting for hospital, patient, and physician characteristics and patient severity of illness.  

The study showed that spending varied more across individual physicians than across hospitals (for hospitalists, 8.4% across physicians vs 7.0% across hospitals; for general internists, 10.5% across physicians vs 6.2% across hospitals). Spending was 40% higher for physicians in the top quartile compared to the lowest quartile. Furthermore, higher spending was not associated with lower mortality or readmission rates (adjusted odds ratio [aOR] for additional $100 in physician spending, 1.00, p = .47). These results suggest that just as financial and structural incentives have led hospitals to focus on reducing unnecessary cost and improving quality, interventions at the level of individual physicians may be as important and effective. 

Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation.

Ever since the arrival of new oral anticoagulants, comparative effectiveness trials have proliferated to assess their safety compared to traditional anticoagulants in various clinical situations. The latest of these, the RE-CIRCUIT trial published this past week in the New England Journal of Medicine, is a multicenter randomized controlled trial that compares dabigatran to warfarin in patients undergoing ablation for atrial fibrillation.[3]

In this multicenter RCT, 704 patients undergoing ablation for non-valvular atrial fibrillation were randomized to receive either dabigatran (150mg twice daily) or warfarin (target INR 2 to 3). Anticoagulation was continued uninterrupted from 4 weeks prior to ablation through the day of ablation and the following 8 weeks. The primary end point of major bleeding events was significantly lower in the dabigatran group (1.6% [5 patients] vs. 6.9% [22 patients]; P<0.001), driven primarily by reduced rates of pericardial tamponade and groin hematomas. Interestingly, while medication adherence to dabigatran topped 97%, the warfarin group was only within its INR goal 66% of the time. Thromboembolic events, a secondary outcome, occurred only once, and this single event occurred in the warfarin group. However the study was underpowered to assess this outcome since its participants had low stroke risk; both groups had an average CHADSVASC score of 2 and underwent pre-op TTEs to rule out atrial thrombus.

This important study demonstrates the safety of continuing dabigatran during atrial ablation with regards to bleeding risk and supports changing the current practice of switching patients to warfarin in the peri-procedure period or interrupting treatment. However, further research is needed to confirm whether dabigatran is as effective as warfarin in preventing stroke, a major complication of these procedures.

Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis

As a consequence of America’s obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has risen to become the country’s leading cause of liver disease. The morbidity and mortality of this condition is increasing, however the risk factors associated with more severe disease and progression to cirrhosis are not well understood.

A study published this week in the Journal of Gastroenterology attempts to shed light on the metabolic profiles associated with progression from NAFLD to nonalcoholic steatohepatitis (NASH), a precursor to cirrhosis.[4] Using an animal model, the investigators compared the “metabolomes,” or serum and liver molecules, of mice bred to spontaneously develop steatohepatitis to those of control mice. These metabolomes were compared to the serum metabolomes of 535 patients with biopsy-proven NAFLD (both simple steatosis and NASH).

The study found that serum and liver metabolomes correlated in mice with NAFLD, with higher levels of triglycerides, diglycerides, fatty acids, ceramides, and oxidized fatty acids present in both blood and tissue compared to controls. The researchers identified serum metabolomic signatures for 2 NAFLD subtypes in both humans and mice, and for each subtype they identified specific panels of markers that could distinguish patients with NASH from patients with simple steatosis. This study may lead to the develop of serum biomarkers that could be used to identify patients with NAFLD at risk for NASH and cirrhosis, monitor disease progression in patients with NAFLD and identify therapeutic targets for patients with these diseases.

Medical Marijuana Laws May Be Associated With A Decline In The Number Of Prescriptions For Medicaid Enrollees

In a fascinating and unexpected consequence of new medical marijuana legislation, states with legalized marijuana are seeing a decline in prescription drug use with potentially enormous cost savings, according to researchers at the University of Georgia. Their latest study on Medicaid prescription drug use follows an earlier study of the Medicare population published in 2016, which first identified this trend.[5]

In their Health Affairs study published this week[6], they analyzed data from CMS’s State Drug Utilization Database, which collects information on FDA-approved drugs prescribed to patients with Medicare and Medicaid in the years before and after marijuana was legalized in 28 states. Focusing on the Medicaid population, they restricted their analysis to drugs used to treat clinical conditions for which marijuana might be a potential treatment alternative, specifically anxiety, depression, glaucoma, nausea, pain, psychosis, seizure disorders, sleep disorders, and spasticity. Controls included both states that did not pass marijuana legalization laws and conditions not treated by marijuana.

The study found that marijuana laws were associated with significant reductions in prescription drugs for depression, nausea, psychosis, seizure disorders, and pain, with prescriptions decreasing by at least 10%. They found no significant reduction in drugs for anxiety, glaucoma, sleep disorders, or spasticity. Total estimated Medicaid savings totaled $475.8 million in 2014, equaling about 2% of the respective Medicaid budget.

This population level study adds to the growing literature on the utility of marijuana as an alternative to traditional prescription medications, although individual conclusions about efficacy and safety cannot be drawn. The authors conclude that their data empowers both physicians and policy makers to push for more legalized use of marijuana, currently a DEA Schedule I drug, and encourages more research on this important subject.


Emergency Medicine physicians and Chest Pain Units everywhere can breathe a huge sigh of relief thanks to two new articles published in Circulation this past week proposing new strategies for early rule-out of acute coronary syndrome in patients with chest pain.[7] These strategies, which rely on high sensitivity troponin testing to more quickly identify patients at very low risk, have yet to be validated in a prospective cohort, but could significantly improve the negative predictive value of current protocols and prevent thousands of chest pain unit admissions nationwide.

In a special Lancet series dedicated to Equity and Equality in Health, researchers and physician advocates seek to tease apart the myriad factors contributing to the disparities in our healthcare system.[8] With 5 articles covering issues from income inequality and the financial burden of healthcare, to mass incarceration and racism, they proposes potential solutions through healthcare reform, research, and advocacy.

For those who can’t get enough of ICU rounds, the latest issue of Chest includes a thorough, evidence-based review of central venous pressure (CVP) interpretation, with a deep-dive into the literature behind fluid resuscitation and volume measurements in critically ill patients.[9] Shedding light on a complex topic, the paper warns of the finicky nature of CVP measurement, provides tips to improve accuracy, and covers the pathophysiology of volume status in various disease states.

Dr. Janine Knudsen is a resident at NYU Langone Medical Center

Peer reviewed by Dana Zalkin, MD, internal medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


[1] Dartmouth atlas:

[2] Tsugawa Y, Jha AK, Newhouse JP, Zaslavsky AM, Jena AB. Variation in Physician Spending and Association With Patient Outcomes. JAMA Intern Med. 2017 Mar 13.

[3] Calkins H, Willems S, Gerstenfeld EP, Verma A, Schilling R, Hohnloser SH, Okumura K, Serota H, Nordaby M, Guiver K, Biss B, Brouwer MA, Grimaldi M; RE-CIRCUIT Investigators. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med. 2017 Apr 27;376(17):1627-1636.

[4] Alonso C, Fernández-Ramos D, Varela-Rey M, Martínez-Arranz I, Navasa N, Van Liempd SM, Lavín Trueba JL, Mayo R, Ilisso CP, de Juan VG, Iruarrizaga-Lejarreta M, delaCruz-Villar L, Mincholé I, Robinson A, Crespo J, Martín-Duce A, Romero-Gómez M, Sann H, Platon J, Van Eyk J, Aspichueta P, Noureddin M, Falcón-Pérez JM, Anguita J, Aransay AM, Martínez-Chantar ML, Lu SC, Mato JM. Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis. Gastroenterology. 2017 May;152(6):1449-1461.e7

[5] Bradford AC, Bradford WD. Medical marijuana laws reduce prescription medication use in Medicare Part D. Health Aff (Millwood). 2016; 35(7):1230–6.

[6] Bradford AC, Bradford WD. Medical Marijuana Laws May Be Associated With A Decline In The Number Of Prescriptions For Medicaid Enrollees. Health Aff (Millwood). 2017 Apr 19.

[7] Morrow DA. Clinician’s Guide to Early Rule-Out Strategies With High-Sensitivity Cardiac Troponin. Circulation. 2017 Apr 25;135(17):1612-1616.

[8] Dickman SL, Himmelstein DU, Woolhandler S. Inequality and the health-care system in the USA. Lancet. 2017 Apr 8;389(10077):1431-1441.

[9] Magder S. Right Atrial Pressure in the Critically Ill: How to Measure, What Is the Value, What Are the Limitations? Chest. 2017 Apr;151(4):908-916.


Primecuts – This Week in the Journals

April 20, 2017

MOABBy Sakinah Sabadia, MD

Peer Reviewed

Since we’re late to press this week, let’s turn straight to news on the medical front.

Revascularization Targets in Chronic Total Occlusions:

This review article summarizes the data regarding percutaneous coronary intervention (PCI) in chronic total occlusions (CTO). CTOs exist in up to 20% of patients with CAD (1), however the outcomes of PCI on these lesions have not been extensively studied, and thus limited data is available regarding the utility of such interventions.

The majority of patients who present for PCI for a CTO are scheduled for an elective catheterization for symptomatic relief of angina. The CTO-PCI population comprises approximately 4% of the patients who undergo PCI, and they are shown to have significantly lower success rates with associated higher adverse event rates compared to patients who undergo non-CTO PCI. Additionally, one study shows no mortality benefit with successful versus failed PCI with CTO.

One explanation for this disparity in treatment outcomes between CTO and non-CTO PCI is that candidates for CTO-PCI have more extensive CAD at baseline, and may otherwise quality for CABG though are poor surgical candidates. Additionally, within the CTO-PCI group, success rates are higher in individuals who are younger, current smokers, and have left anterior descending artery CTO (2). However, current European and American guidelines indicate CTO-PCI as class IIa (level of evidence B) without clear definitions for patient selection.

Given the high prevalence of CTO within CAD, and the reported symptomatic relief, improvement in functional status and decrease in consequent coronary artery bypass grafting after a successful CTO-PCI, further studies are imperative to elucidate the risks, benefits, and target population for CTO-PCI with more clear guidelines for intervention.

NSAID Use in Arthritis with coexistent CAD on Aspirin and Prior Gastrointestinal Bleeding

Patients with arthritis treated with non-steroidal anti-inflammatory drugs (NSAIDs) with coexistent cardiovascular disease and history of gastrointestinal bleeding present a complex treatment dilemma for physicians. Daily aspirin for coronary artery disease (CAD) lowers the risk of myocardial infarction and death, however aspirin and NSAIDs both increase the risk of gastrointestinal bleeding.

To address patients with prior gastrointestinal bleeds who require treatment with concomitant aspirin and NSAID for CAD and arthritis, this study compares selective to nonselective NSAIDs in safety in regards to recurrence of gastrointestinal bleeding. Specifically, it tested the hypothesis that cyclooxygenase-2-selective (COX-2) NSAIDs with a proton pump inhibitor (PPI) is a superior treatment compared to nonselective NSAIDs with a PPI in preventing recurrent bleeds in subjects with history of ulcer bleeds on aspirin (3). The researchers conducted a double-blinded, double-dummy randomized trial in a hospital in Hong Kong. Subjects were patients with prior diagnoses of arthritis and cardiothrombotic disease who presented with upper gastrointestinal bleeding while on NSAIDs and aspirin, and were negative for Helicobacter pylori. After treatment and healing of ulcers, patients were randomly assigned to one of two treatment arms: celecoxib 100mg twice a day or naproxen 500mg twice a day. Both treatment arms were given esomeprazole 20mg daily and aspirin 80mg daily. The primary endpoint was recurrence in gastrointestinal bleeding in 18 months with intention-to-treat. Secondary endpoints were serious cardiovascular events and efficacy in regard to global disease activity.

By 18 months, 21 patients (8%) in the celecoxib arm and 17 (7%) in the naproxen arm stopped treatment due to adverse events that were not the primary endpoint. The incidence of recurrent gastrointestinal bleeding in the remaining subjects was 5.6% (95% CI 3.3-9.2) in the celecoxib group and 12.3% (95% CI 8.8-17.1) in the naproxen group (p=0.008, hazard ratio 0.44). There was no significant difference in cardiovascular events between the two groups, and both arms showed significant reduction in global disease activity. The conclusion of this study is that celecoxib is the preferred treatment compared to nonselective NSAIDs in treatment of arthritis in patients with prior upper gastrointestinal bleeds and concomitant aspirin requirement for treatment of cardiothrombotic disease, with no significant effect on cardiovascular events or global disease activity.

Midlife Vascular Risk Factors and Brain Amyloid Deposition

Vascular risk factors in midlife, namely smoking, diabetes, hypertension and hypercholesterolemia, have been associated with dementia in later stages of life. Additionally, brain amyloid deposition is seen in Alzheimer’s disease (AD), the most common cause of dementia. This study was conducted to determine if there is an association between midlife vascular risk factors with subsequent development of brain amyloid deposition.

The Atherosclerosis Risk in Communities (ARIC)-PET Amyloid Imaging Study (4) is a prospective cohort study that followed 322 subjects (out of an initial 15,792 recruited) between the ages of 45-64 from 1987-1989 without dementia, stratified them by number of vascular risk factors and markers, and assessed them annually/semiannually over the course of 25 years, most recently between 2011-2013. The vascular risk factors assessed included hypertension, diabetes, 10-year stroke risk, smoking history, BMI, cholesterol level, and presence of APOE e4 alleles. Subjects were stratified by 0, 1, and 2 or more risk factors. Subjects included had a baseline MRI and underwent brain MRI and PET scans at the final visit, and underwent interval neuropsychological testing for cognitive function at each visit.

In the sample analyzed, elevated BMI during midlife was the only vascular risk factor that was associated with statistically significantly increased late-life brain amyloid (odds ratio 2.06, 95% CI 1.16-3.65). Additionally, higher number of vascular risk factors (specifically 2 or more) in midlife was associated with increased brain amyloid compared to midlife subjects with no vascular risk factors (61% vs. 30.4%, 95% CI 16.4-44.3%). However the same was not true for vascular risk factors in late life.

This study concludes that increased vascular risk factors in midlife are associated with increased brain amyloid deposition. These results highlight the importance of early intervention of vascular risk factors to prevent or slow the progression of amyloid deposition.

Rivaroxaban versus Warfarin in Patients with Unprovoked VTE

Since the advent of dabigatran and its approval by the FDA in 2010, physicians have been prescribing direct oral anticoagulants (DOACs) for stroke prevention in non-valvular atrial fibrillation, venous thromboembolism (VTE) and thromboprophylaxis in hip/knee replacement surgeries (5). One cohort study compared the effectiveness and safety of rivaroxaban, a DOAC, to warfarin in the treatment of unprovoked VTE (6). The subjects included were hospital patients in Denmark with new unprovoked VTE who were not previously exposed to rivaroxaban or warfarin. Exclusion criteria included patients with outpatient diagnosis of VTE, other indications for anticoagulation (such as atrial fibrillation), prior oral anticoagulation exposure, patients who were not prescribed either anticoagulation within 1 week of diagnosis, and patients who were prescribed both or alternate anticoagulants. The patients were followed for 6 months, and a total of 1,734 subjects were included in the analysis. The primary endpoint for effectiveness was recurrent VTE, and for safety was major bleeding.

The rate of recurrent VTE at 6 months was 9.9 incidents per 100 person-years with rivaroxaban and 13.1 incidents with warfarin (hazard ratio [HR] 0.74, 95% CI 0.56-0.96). Major bleeding occurred at an incidence of 2.4 per 100 person-years with rivaroxaban and 2.0 with warfarin (HR 1.19, 95% CI 0.66-2.13). This study concludes that rivaroxaban treatment is associated with a reduced rate of recurrence of VTE after first unprovoked VTE, with no significant difference in major bleeding.


This week, the British Medical Journal published an article analyzing the rates of adverse events associated with short-term oral corticosteroid use, prescribed most commonly for upper respiratory tract infections, spinal conditions and allergies. Within one month of the beginning of the course of treatment, there was a significantly increased risk of sepsis, fracture, and venous thromboembolism, even at doses under 20mg daily (7).

With an eye on lupus patients, the Annals of the Rheumatic Diseases published a report on the occurrence of cerebrovascular accidents (CVAs) in patients with systemic lupus erythematosus (SLE). Compared to the general population, patients with SLE had a significant increased risk of stroke, with a hazard ratio of 2.2 for ischemic stroke. The highest relative risk for ischemic stroke was seen within the first year of diagnosis (8).

A new drug on the horizon, inclisiran, is a synthetic small interfering RNA that targets PCSK0 messenger RNA with the purpose of lowering low-density lipoprotein (LDL) cholesterol levels. A phase 2 multicenter double-blinded trial showed dose-dependent reduction in LDL cholesterol levels in subjects with high cardiovascular risk who were treated with inclisiran, with statistically significant decreases compared to placebo with all doses studied (9).

Dr. Sakinah Sabadia is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Ben Milgrom, MD, a contributing editor, Clinical Correlations

Image courtesy of Wikimedia Commons


  1. Bass TA. Percutaneous Coronary Interventions for Chronic Total Occlusions. As the Technology Expands, Our Responsibilities Increase. 2017;135:1385-1387.
  2. Brilakis ES, Banerjee S, Karmpaliotis D, Lombardi WL, Tsai TT, Shunk KA, Kennedy KF, Spertus JA, Holmes DR, Jr., Grantham JA. Procedural outcomes of chronic total occlusion percutaneous coronary intervention: a report from the NCDR (National Cardiovascular Data Registry). JACC Cardiovascular interventions. 2015;8:245-253.
  3. Chan FKL, Ching JYL, Tse YK, Lam K, Wong GLH, Ng SC, Lee V, Au KWL, Cheong PK, Suen BY, Chan H, Kee KM, Lo A, Wong VWS, Wu JCY, Kyaw MH. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. The Lancet.
  4. Gottesman RF, Schneider AC, Zhou Y, et al. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA. 2017;317:1443-1450.
  5. Adcock DM, Gosselin R. Direct Oral Anticoagulants (DOACs) in the Laboratory: 2015 Review. Thrombosis Research. 2015;136:7-12.
  6. Larsen TB, Skjøth F, Kjældgaard JN, Lip GYH, Nielsen PB, Søgaard M. Effectiveness and safety of rivaroxaban and warfarin in patients with unprovoked venous thromboembolism: a propensity-matched nationwide cohort study. The Lancet Haematology.
  7. Waljee AK, Rogers MAM, Lin P, Singal AG, Stein JD, Marks RM, Ayanian JZ, Nallamothu BK. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017;357.
  8. Arkema EV, Svenungsson E, Von Euler M, Sjöwall C, Simard JF. Stroke in systemic lupus erythematosus: a Swedish population-based cohort study. Annals of the Rheumatic Diseases. 2017.
  9. Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RPT, Turner T, Visseren FLJ, Wijngaard P, Wright RS, Kastelein JJP. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. New England Journal of Medicine. 2017;376:1430-1440.


Primecuts – This Week in the Journals

April 11, 2017

neil gorsuchSusan Creighton, MD

Peer Reviewed

Judge Neil M. Gorsuch was confirmed to the Supreme Court after Senate Republicans voted to lower the threshold required for Supreme Court nominations. Last week Senate Democrats used a filibuster to block the nomination, which would have required 60 votes before the rule change. At 49 years old, Justice Gorsuch could have a long tenure on the Supreme Court and shape the legal landscape for decades. Reproductive rights groups oppose Justice Gorsuch’s nomination because as part of the 10th Circuit he held that the government could not require corporations to cover contraception through the Affordable Care Act (ACA) in the well-known Hobby Lobby case.

None of the cases that are awaiting trial in the Supreme Court will affect the issue of reproductive rights, so for now read on for research published in the medical journals this week.

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism 

Subclinical hypothyroidism, defined as an elevation in serum thyrotropin (TSH) with a normal serum free thyroxine level, can be clinically difficult to interpret, as patients are often asymptomatic. A recent double-blind, placebo-controlled, parallel-group trial in the NEJM investigated whether elderly patients with subclinical hypothyroidism benefitted from treatment with levothyroxine [1]. The study included 737 adults over 65 years of age who were identified from databases if they fit the laboratory definition of subclinical hypothyroidism with a TSH between 4.6 to 19.99 mIU per liter. Patients with current prescriptions for levothyroxine or other thyroid medications, a history of thyroid surgery or radioactive iodine in the previous 12 months, dementia, acute coronary syndrome, or hospitalization in the previous 4 weeks were excluded from randomization. Patients randomized to the treatment arm were started on levothyroxine at 50mcg, which was then titrated according to protocol. The control group received a placebo with mock adjustments.

The primary outcomes of the trial were the Hypothyroid Symptoms score and the Tiredness score from the Thyroid-Related Quality-of-Life Patient-Reported Outcome measure (ThyPRO) at both baseline and 12 months of treatment. The results showed that treatment with levothyroxine consistently lowered serum TSH levels compared to placebo but had no significant effect on the primary outcomes. There was no difference in adverse events between the intervention and control groups. Of note, very few of the patients in the study had TSH >10, so the results may be harder to extrapolate to patients with more elevated levels of TSH.

Treating asymptomatic older patients with subclinical hypothyroidism and TSH <20 does not increase quality of life or decrease fatigue and it may contribute to pill burden. Based on this study primary care providers should not treat asymptomatic older adults for subclinical hypothyroidism but may consider further monitoring or treatment for patients who develop symptoms or have a TSH > 10.

Cardiometabolic Abnormalities Among Normal-Weight Persons From Five Racial/Ethnic Groups in the United States: A Cross-sectional Analysis of Two Cohort Studies

Obesity is a well-known risk factor for cardiovascular disease. However, individuals with a normal weight can also have an abnormal metabolic profile, increasing their risk of cardiovascular events. The relationship between weight and the extent of cardiometabolic risk seems to differ among different ethnicities. This week, the Annals of Internal Medicine used cross-sectional data from the Multi-Ethnic Study of Atherosclerosis (MESA) and Mediators of Atherosclerosis in South Asians Living in America (MASALA) study to determine the prevalence of metabolic abnormality but normal weight (MAN) in different ethnic groups [2].

A total of 7617 Caucasian, ChineseAmerican, African American, Hispanic and South Asian participants were included in the study. The cardiometabolic abnormalities that factored into the analysis were decreased HDL, elevated triglycerides, elevated fasting glucose and hypertension. The definition of normal weight was a BMI 18.5-24.9 kg/m2 for white, African American and Hispanic participants and a BMI 18.5-22.9 kg/m2 for Asian participants.

The prevalence of MAN was about one third of overall participants, with the highest prevalence in South Asians (43.6%) and the lowest in whites (21%). The authors extrapolated these results to determine ethnic-specific BMI risk-based thresholds. To have the equivalent cardiometabolic abnormalities of white participants with a BMI of 25 the corresponding BMIs were 22.3 in African Americans, 21.5 in Hispanics, 20.5 in Chinese Americans and 18.9 in South Asians.  This study shows that BMI alone is a not a good predictor of cardiometabolic risk, especially in non-white minorities.

Prognosis of Undiagnosed Chest Pain: Linked Electronic Health Record Cohort Study

Chest pain is a common symptom among primary care patients; however, a substantial portion of patients does not receive a diagnosis for this symptom. This week BMJ published the results of a cohort study examining the long-term outcomes of patients with undiagnosed chest pain [3]. The study was set in the Cardiovascular disease research using Linked Bespoke studies and Electronic health Records (CALIBER) program, which links primary care data with the national registry of acute coronary syndromes in the UK.  The subjects of the study were any patients in the database with a first coded record of chest pain between 2002 and 2009. Patients with a history of angina from known cardiovascular disease were excluded.

Over 170,000 subjects were placed in one of three cohorts: unattributed chest pain, non-coronary chest pain and angina. The primary outcomes were incidence of myocardial infarction (MI) and any recorded cardiovascular disease. Baseline prevalence of cardiovascular risk factors was also examined. The results showed that rates of cardiovascular events were higher in the unattributed group than in the non-coronary group but less than in the angina group. In the first year the hazard ratio was 1.95 (confidence interval 95%) for those in the unattributed group compared to the non-coronary group.

The results of this study suggest that patients with unattributed chest pain still have a significant risk for cardiac disease. However, this study looked at a large number of patients based on electronic medical record codes, which could contribute to error from flaws or variability in assigning codes. Additionally the study did not try to ascertain if any of the patients in the unattributed group had any other risk factors for coronary disease to see if that could explain some of the findings. It is possible that patients whose chest pain is left unattributed rather than labeled non-coronary have some other risk factors that make their providers reluctant to label the pain non-coronary.

Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice

Primary Aldosteronism (PA) is characterized by hypertension and aldosterone overproduction that is independent from the renin-angiotensin axis. PA is a cause of secondary hypertension that is frequently diagnosed in patients with hypokalemia or resistant hypertension, but the true prevalence of PA among all hypertensives is not known. This week in JACC, a cohort study of hypertensive patients recruited from primary care practices was published estimating the prevalence and phenotypes of PA.

The study included a cohort of over 1500 patients who underwent screening for PA by measuring the serum aldosterone concentration to plasma renin activity ratio (ARR). The screening was considered positive in patients with an ARR greater than 30 and an aldosterone level greater than 10 ng/dl who then went on to confirmatory testing with either an intravenous saline loading test or a captopril challenge. Additional subtype classification with adrenal vein sampling to aldosterone-producing adenoma or bilateral adrenal hyperplasia was performed on those with confirmed PA. A total of 232 patients had positive results in the initial testing for ARR and 99 of them were diagnosed with PA (5.9% of the total sample). The prevalence was highest in patients with stage 3 hypertension.

In conclusion, this study suggests that PA occurs with a prevalence of about 6% in a general hypertensive population in Italy. The authors of the study suggest that most patients with hypertension should be screened for PA with the ARR test, however, the confirmatory testing for PA is more complicated, expensive and invasive than the screening test. Additional research is necessary to determine which hypertensive patients will benefit most from a workup for PA.


Research published last week in Circulation found that there are genetic variants linked to QTc prolongation. Using 61 common genetic variants they created a genetic QT score that correlates with risk of drug-induced QT prolongation.

An editorial in JAMA explains the recent US Preventive Services Task Force (USPSTF) decision not to recommend screening for Celiac disease in asymptomatic patients. Although rates of Celiac disease seem to be increasing in the US and screening tests are now widely available the USPSTF decided there was not enough evidence on the harms and benefits of screening and that more research is needed.

Finally, this editorial in the Journal of General Internal Medicine examines the problems with how primary care is taught in medical schools and residency programs. It argues that to inspire students and residents to go into primary care they need training environments that model effective interdisciplinary primary care delivery, which academic medical centers usually cannot provide.

Dr.  Susan Creighton, is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Kerrilynn Carney, MD, Chief Resident, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


  1. Stott DJ, Rodondi N, Kearney PM, et al. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. NEJM. 2017 Apr 3. [Epub ahead of print]
  2. Gujal UP, Vittinghof E, Mongraw-Chaffin M, et al. Cardiometabolic Abnormalities Among Normal-Weight Persons From Five Racial/Ethnic Groups in the United States. Ann of Intern Med. 2017 Apr 4. [Epub ahead of print]
  3. Jordan KP, Timmis A, Croft P, et al. Prognosis of Undiagnosed Chest Pain: Linked Electronic Health Record Cohort Study. BMJ. 2017 Apr 3:357:j1194
  4. Monticone S, Burerello J, Tizzani D, et al. Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. JACC. 2017 Apr:69(14)
  5. Strauss DG, Vincente J, Johannesen L, et al. Common Genetic Variant Risk Score is Associated with Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study. Circulation. 2017 Apr 4; 135(14): 1300-1310
  6. Choung RS, Murray JA. The US Preventive Services Task Force Recommendation on Screening for Asymptomatic Celiac Disease: A Dearth of Evidence. JAMA. 2017 Mar 28; 317(12): 1221-1223.
  7. Cassel C, Wilkes M. Location, Location, Location: Where We Teach Primary Care Makes All the Difference. J Gen Intern Med. 2017 Apr:32(4): 411-415

Primecuts – This Week in the Journals

April 4, 2017

1024px-USGS_Rikers_IslandBy Jillian Diuguid, MD

Peer Reviewed

On Friday, March 31, New York City Mayor Bill de Blasio announced his support for a plan to shutter Rikers Island, the controversial East River island jail known for its history of violence by both inmates and corrections officers.  Per the Mayor, the closure plan will be complicated and difficult, taking 10 years, with significant reductions necessary in the number of jailed city inmates in order to make it possible.  The Mayor hopes this will be the end of an era of mass incarceration in NYC.  As clinicians caring for these inmates at Bellevue Hospital, we hope any reforms support inmate safety and well-being.

As the world is buzzing with politics, March Madness upsets, and the retirement of the Crayola color Dandelion, we present recent primecuts articles from the medical community.

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism

For many people with venous thromboembolism (VTE), it is unclear if it is beneficial to extend anticoagulation treatment beyond the standard treatment course.  A randomized controlled trial (RCT) published in the New England Journal of Medicine examines patients in equipoise regarding whether or not to continue anticoagulation, meaning it would be equally reasonable to continue them on anticoagulation or not.  The study randomized 3395 patients who had completed 6-12 months of anticoagulation therapy for VTE to receive daily treatment-dose rivaroxaban (20 mg), prophylaxis-dose rivaroxaban (10 mg), or aspirin (100 mg), with intended extended treatment duration of 12 months.  The primary outcome was recurrent symptomatic VTE and key safety outcomes of major bleeding and clinically relevant non-major bleeding.

The study showed significantly less recurrent VTEs for rivaroxaban 20 mg (17/1107, 1.5%) and 10 mg (13/1127, 1.2%) compared with aspirin (50/1131, 4.4%), p-values <0.001. In addition, the rivaroxaban groups did not have significantly more major bleeding or clinically relevant non-major bleeding than the aspirin group (rates of major bleeding were 0.5% for rivaroxaban 20 mg, 0.4% for rivaroxaban 10 mg, 0.3% for aspirin, and rates of relevant non-major bleeding 2.7%, 2.0%, 1,8% respectively).  The NNT to prevent one VTE event on rivaroxaban versus aspirin was 30-33.

This study was a well-done RCT using intention-to-treat analysis, with compelling evidence for continuing rivaroxaban treatment over aspirin in VTE, and which supports current ACCP guidelines regarding extended VTE therapy.  It does not address how to further stratify patients as to who should get extended treatment. Of note, the study was not powered to establish non-inferiority between 10 mg and 20 mg of rivaroxaban, so conclusions regarding which dose is more appropriate cannot be made.

African Ancestry–Specific Alleles and Kidney Disease Risk in Hispanics/Latinos

The Journal of the American Society of Nephrology published a genome-wide association study

of  genes associated with chronic kidney disease risk in Hispanic/Latino populations.  Hispanics are genetically heterogenous, with African, indigenous American, and European roots.  The two genes of interest in the study were African-ancestry associated alleles of the gene APOL1 and the sickle cell trait allele, HBB rs334,.  Both genes confer increased CKD risk; for more information on APOL1, read this piece written in Clinical Correlations.

This study compared the presence of these alleles with albuminuria and eGFR < 60 in 12,226 Hispanics. APOL1 alleles were directly measured and HBB rs334 was imputed, meaning statistically inferred.  Correlations were done with the overall study population and stratifying it by “Caribbean” versus “Mainland” Hispanics.

The Caribbean group had greater prevalence of 2 copies of high-risk APOL1 alleles than the Mainland group (1.0% v 0.1%), and of HBB rs334 (2.0% v. 0.7%).

In the overall study population, those with 2 copies of high-risk APOL1 had significant 3.5 times higher odds of albuminuria (p < 0.001, CI 1.7-6.4) and nearly significant 2.8 times higher odds of decreased eGFR (p = 0.06, CI 1.0 – 7.9).  Similarly, those with HBB rs334 had 2.4 times higher odds of albuminuria (p <0.001, CI 1.8 to 3.3) and 2.6 times higher odds of decreased eGFR (p < 0.001, CI 1.8 – 3.8).

African ancestry-associated genetic risk factors for CKD thus were associated with presence of CKD in Hispanics, with higher presence of these risk factors in Caribbean Hispanics. Consider these risk factors in evaluating Hispanic patients with CKD, particularly those with Caribbean ancestry.  This study highlights Hispanic diversity and African ancestry.

Association Between Radiation Therapy, Surgery, or Observation for Localized Prostate Cancer and Patient-Reported Outcomes After 3 Years


Association Between Choice of Radical Prostatectomy, External Beam Radiotherapy, Brachytherapy, or Active Surveillance and Patient-Reported Quality of Life Among Men With Localized Prostate Cancer

For men with localized prostate cancer, there are many treatment options; JAMA this week published 2 prospective population based cohort studies comparing quality of life after different prostate cancer treatments.

Barocas et al studied 2550 men with localized prostate cancer, comparing patient-reported outcomes for those undergoing radical prostatectomy, external beam radiotherapy, and active surveillance. Chen et al studied 1141 men with localized prostate cancer, and compared these same treatment modalities plus brachytherapy.

In both studies, the most frequent treatment modality was radical prostatectomy; (60% in Barocas, 41% in Chen).  External beam radiation therapy was pursued by 22%-23% of patients in both studies and brachytherapy by 10% in Chen.  Radical prostatectomy was associated with worsened sexual function and urinary incontinence than other treatments, but with better urinary irritative outcomes than active surveillance.    People receiving the two radiation therapies had worse bowel problems (in particular, urgency) than other treatments initially, but this improved over time.

Active surveillance was pursued by 17% in Barocas and 28% in Chen; however, both studies noted that there was progression towards other treatments for those who initially chose active surveillance.  Disease-specific survival was the same across all groups in Barocas, but was not reported in Chen.

With good survival in localized prostate cancer, quality of life matters. These studies show that current treatments have different short-term benefit and side effect profiles.  Active surveillance minimizes side effects but is not always symptom-free, and many progress to other treatment eventually.  Treatment including surveillance should be tailored to patient values, but the decision of how and when to treat, like the decision of how and when to screen, remains uncertain.

Association between clinically recorded alcohol consumption and initial presentation of 12 cardiovascular diseases: population based cohort study using linked health records

This BMJ cohort study used linked health records to associate recorded alcohol consumption with first presentation of 12 cardiovascular diseases.  Nearly 2 million British adults with no history of cardiovascular disease were studied; median follow-up time was 6 years.  Study participants were divided into 5 alcohol consumption categories: non-drinkers, former drinkers, occasional drinkers, moderate drinkers, and heavy drinkers.  Moderate drinkers comprised 60% of study participants and hazard ratios were calculated with moderate drinkers as baseline.  During the study period, 114,859 people developed cardiovascular disease.

All-cause mortality, fatal cardiovascular disease, and fatal-and-non-fatal combined cardiovascular disease were significantly worse for all groups when compared with moderate drinking. Results were heterogeneous for alcohol consumption and the 12 stratified cardiovascular outcomes.

Overall, there appeared to be a protective effect for moderate alcohol consumption for many cardiovascular diseases, and worse outcomes for heavy drinkers in all but coronary disease.  Strengths of this study are its large size and separation of non-drinkers from former drinkers.  Weaknesses include bias in self-reported alcohol consumption and confounders.  For example, non-drinkers were more likely to be in the bottom socio-economic quintile than moderate drinkers, and this impact is difficult to measure.  This study helps tailor counseling particularly in regard to heavy drinking, but still does not answer if clinicians should recommend alcohol consumption to their patients.


JAMA Internal Medicine published an article on correlations between Joint Commission visits and 30-day mortality for Medicare patients in nearly 2000 hospitals across the US. The authors found an ever-so-slight but statistically significant difference in mortality, with lower 30-day mortality for admissions occurring during Joint Commission visit weeks than those in the surrounding weeks.

In JGIM, a national study of veterans examined the association between the socioeconomic status of neighborhoods that veterans lived in and the veterans’ mortality; after controlling for individual socioeconomic status, demographics, and health status of the veterans, those living in lower SES neighborhoods had higher rates of mortality than those living in higher SES neighborhoods.

Finally, remember your ABCS – an updated ASCVD risk assessment tool is coming, whose goal is to better tailor CV risk reduction to individual patients.  The ABCs are Aspirin therapy, BP control, Cholesterol management, and Smoking Cessation.

Dr. Jillian Diuguid is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Neil Shapiro, Editor-In-Chief, Clinical Correlations

Image courtesy of Wikimedia Commons


  1. Goodman, JD. Mayor Backs Plan to Close Rikers and Open Jails Elsewhere.  New York Times, March 31, 2017.
  2. Weitz JI, Lensing AW, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017;
  3. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-52.
  4. Kramer HJ, Stilp AM, Laurie CC, et al. African Ancestry-Specific Alleles and Kidney Disease Risk in Hispanics/Latinos. J Am Soc Nephrol. 2017;28(3):915-922.
  5. Saadiq, A. Decoding the APO1L Kidney, Clinical Correlations. Sept 25, 2013. 
  6. Barocas DA, Alvarez J, Resnick MJ, et al. Association Between Radiation Therapy, Surgery, or Observation for Localized Prostate Cancer and Patient-Reported Outcomes After 3 Years. JAMA. 2017;317(11):1126-1140.
  7. Chen RC, Basak R, Meyer AM, et al. Association Between Choice of Radical Prostatectomy, External Beam Radiotherapy, Brachytherapy, or Active Surveillance and Patient-Reported Quality of Life Among Men With Localized Prostate Cancer. JAMA. 2017;317(11):1141-1150.
  8. Bell S, Daskalopoulou M, Rapsomaniki E, et al. Association between clinically recorded alcohol consumption and initial presentation of 12 cardiovascular diseases: population based cohort study using linked health records. BMJ. 2017;356:j909.
  9. Barnett ML, Olenski AR, Jena AB. Patient Mortality During Unannounced Accreditation Surveys at US Hospitals. JAMA Intern Med. 2017;
  10. Nelson K, Schwartz G, Hernandez S, Simonetti J, Curtis I, Fihn SD. The Association Between Neighborhood Environment and Mortality: Results from a National Study of Veterans. J Gen Intern Med. 2017;32(4):416-422.
  11. Lloyd-Jones DM, Huffman MD, Karmali KN, Sanghavi DM, Wright JS, Pelser C, Gulati M, Masoudi FA, Goff DC.  Estimating Longitudinal Risks and Benefits From Cardiovascular Preventive Therapies Among Medicare Patients: The Million Hearts Longitudinal ASCVD Risk Assessment Tool: A Special Report From the American Heart Association and American College of Cardiology, Circulation. 2017;135:e793-e813, originally published November 4, 2016.

Primecuts – This Week in the Journals

March 28, 2017

Primecuts 3.28.17By Stephanie Charles, MD 

Peer Reviewed

This week marked an important point in our national health care debate. The American Health Care Act put forth by the Republican party failed to pass by Congress, allowing for the continuation of the Affordable Care Act, at least for now. Read below to learn of the important work published by the medical community this week. 

Trial of Pregabalin for Acute and Chronic Sciatica

Pregabalin (Lyrica, Pfizer) is an antiepileptic medication that has been shown to reduce symptoms of neuropathic pain in patients with post-herpetic neuralgia and peripheral neuropathy. This double-blind, placebo-controlled, randomized trial sought to investigate the role of pregabalin in the treatment of acute sciatica [1]. 108 patients with sciatica were randomized to receive pregabalin while 101 patients received placebo. Inclusion criteria included sciatic pain for a minimum of one week and a maximum of one-year, moderate-severe intensity leg pain, and 18 years of age. Exclusion criteria included serious spinal pathology, pregnancy, breastfeeding, planned spinal surgery, the concomitant use of antiepileptic, antidepressant, or sedative medications, or a history of severe depression with suicidal ideation. Patients in the treatment group received a starting dose of pregabalin 150 mg with gradual increases to a maximum of 600 mg daily; the study period lasted for a total of 8 weeks. The primary outcome was leg-pain intensity assessed at week 8 and week 52. Secondary outcomes included extent of disability, back pain, and quality of life. The mean difference between the two groups in leg-pain intensity score was not significant at week 8 (3.7 in treatment group, 3.1 in placebo group, P =0.19), nor at week 52 (3.4 in the pregabalin group, 3.0 in the placebo group, P= 0.46). There was no effect of pregabalin, as compared with placebo, observed in the secondary outcomes of disability at week 8, back pain intensity at week 8, and quality of life scale at week 8 and week 52. The number of reported serious adverse events was small and similar in both groups; however, the number of reported overall adverse events was significantly higher in the treatment group (227 in the treatment group versus 68 in the control group, P=0.002), with dizziness being the most common reported symptom. The study concluded that pregabalin did not reduce symptoms of acute sciatic or improve quality of life compared to placebo. This implies that the frequent use of pregabalin in clinical practice for the treatment of sciatica is functionally ineffective, and that alternate modalities of treatment should be explored instead.

Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation

Catheter ablation is a commonly employed treatment for atrial fibrillation. Anticoagulation in patients undergoing ablation is important to reduce the risk of periprocedural stroke or transient ischemic attack, however there is little consensus on the management of anticoagulation pre or post-procedure [2]. In this multicenter trial published in the NEJM, patients undergoing catheter ablation for atrial fibrillation were randomized to receive either dabigatran (150 mg twice daily) or warfarin (target INR 2-3). The trial consisted of four consecutive periods: a screening period of 0-2 weeks, a preablation treatment period of 4 to 8 weeks, a postablation treatment period of 8 weeks, and a follow up period of one week. The primary end point was incidence of a major bleeding event from time of ablation to 8 weeks. Secondary end points included incidence of composite stroke, systemic embolism, or TIA, and minor bleeding events during ablation through 8 weeks. 317 patients were randomized to receive dabigatran while 318 received warfarin. The patients received their respective anticoagulant during the preablation period to allow for patients to achieve a therapeutic INR in the warfarin group. The percentage of patients with major bleeding was significantly lower in the dabigatran group compared with warfarin [5 patients (1.6%) vs. 22 patients (6.9%), P<0.001]. There were no events of stroke, systemic embolism, or TIA in the dabigatran group and only one event in the warfarin group from ablation until 8 weeks later. This study concluded that anticoagulation with uninterrupted dabigatran was associated with fewer bleeding events than uninterrupted warfarin in patients undergoing ablation for atrial fibrillation, and may be the preferred method of anticoagulation.

Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor

Hereditary angioedema is a potentially fatal condition caused by deficiency or dysfunction of the C1 inhibitor protein. The disorder is characterized by episodes of swelling without urticaria or pruritus. Regular intravenous C1 inhibitor replacement is effective at reducing the frequency and severity of attacks. However, regular venous administration can be technically difficult and inconvenient. The objective of this study was to evaluate the efficacy and safety of a self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema. The trial was an international, multicenter, randomized, double-blind, placebo-controlled phase 3 trial [3]. Patients were randomized to one of four treatment groups in a cross-over design for 16-week periods: 40IU or 60IU of CSL830 per kilogram body weight twice weekly followed by placebo, or vice versa. The primary outcome was number of attacks of angioedema, and secondary outcomes included percentage of patients who had a response and number of times that rescue medication was used. 90 patients were enrolled in the study, with 45 patients randomized to each treatment arm. Both 40IU and 60IU of CSL830, as compared to placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40IU, -2.42 attacks per month; mean difference with 60IU, -3.51 attacks per month, P<0.001 for both comparisons). The use of rescue medications was reduced from 5.55 uses per month in the placebo group to 1.13 in the 40IU group, and from 3.89 uses in the placebo group to 0.32 uses in the 60IU group. Adverse events were not significantly different between the treatment and placebo groups. Thus, in patients with hereditary angioedema, the use of a prophylactic self-administered twice-weekly C1 inhibitor reduced the frequency of attacks, and may become standard of care for this rare but potentially fatal condition.

The Definitive Management of Primary Hyperparathyroidism. Who Needs an Operation? 

New guidelines for the definitive management of primary hyperparathyroidism were published in JAMA surgery earlier this year, and the guidelines were reviewed this week in JAMA [4]. A multidisciplinary panel reviewed the relevant medical literature between 1985 and 2015 on PubMed and determined the guidelines based on their findings and expert consensus [5]. The guidelines recommend initial evaluation of a patient with suspected primary hyperparathyroidism with 25-hydroxyvitamin D measurement, 24-hour urine calcium measurement, dual-energy x-ray absorption, and supplementation for vitamin D deficiency. The panel recommends that symptomatic patients, as well as asymptomatic patients with osteoporosis, a 24-hour urine calcium level greater than 400mg/dl, a serum calcium level grater than 1mg/dl above the normal range, age younger than 50 years, or decreased renal function be considered for surgery. The panel expanded the number of surgical candidates by including patients with neurocognitive and neuropsychiatric symptoms attributed to elevated parathyroid hormone and some patients with cardiovascular disease. The panel emphasized that primary hyperparathyroidism is a biochemical diagnosis, and does not require imaging for diagnosis. The guidelines recommend preoperative thyroid ultrasonography to detect thyroid neoplasms and/or nodules as a large proportion of patients with primary hyperparathyroidism have concurrent functional thyroid disease at the time of surgery. The guidelines conclude that both minimally invasive parathyroidectomy and bilateral exploration are appropriate and effective options to achieve high cure rates. Postoperatively, patients should be observed for hematoma, evaluated for hypocalcemia, and monitored to assess for cure and hypocalcemia requiring calcium supplementation. 


In this week’s edition of the New England Journal of Medicine, two powerful articles on physician burnout and the stigma of mental health disorders among physicians were published. Kathryn explores how one medical school was impacted by the suicide of a fourth-year student, and how the school is changing its culture of medicine [6]. Breaking the Stigma is an autobiographical piece about one physician’s struggle with depression, and addresses the stigma physicians often face when battling their own mental health challenges [7].

The Lancet published an article on the optimal duration of trastuzamab for early HER2-posiive breast cancer, concluding that one year of treatment significantly improves long-term disease-free survival compared with observation, while two years of treatment had no additional benefit. [8]

Dr. Stephanie Charles is a 1st year resident at NYU Langone Medical Center. 

Peer reviewed by Dr. Amar Parikh, Contributing Editor, Clinical Correlations and 3rd-year resident at NYU Langone Medical Center. 

Image courtesy of 


  1. Mathieson S. Trial of Pregabalin for Acute and Chronic Sciatica. NEJM. 2017; 376 (12): 1111-1120
  2. Calkins H, Williams S, et al. Uninterrupted Dabigatran versus Warfarin for Ablation in Trial Fibrillation. 2017: 1-10
  3. Longhurst H. Prevention of Hereditary Angioedema Attacks With a Subcutaneous C1 Inhibitor. NEJM. 2017; 376 (12): 1131-1140
  4. Wilhelm SM, Wang TS, Ruan DT, et al. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg. 2016; 151(10): 959-968.
  5. Campbell MJ. The Definitive Management of Primary Hyperparathyroidism. Who Needs an Operation? JAMA. 2017; 317 (11): 1167-1168
  6. Muller, D. Kathryn. NEJM. 2017; 376 (12): 1101-1103
  7. Hill, AB. Breaking the Stigma- A Physician’s Perspectibe on Self-Care and Recovery. NEJM. 2017; 376 (12): 1103-1105
  8. Specht, JM, Davidson NE. Optimal Duration of Trastuzumab for early HER2-positive Breast Cancer. The Lancet. 2017; 389 (10075): 1167-1168




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.


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


  1. Gever, John. ACGME Raises Ceiling on Resident Duty Hours” Medscape. March 10, 2017.
  2. Bilimoria, et al. National Cluster-Randomized Trial of Duty-Hour Flexibility in Surgical Training. N Engl J Med 2016; 374:713-727
  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]
  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. 
  5. Hochhaus, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med 2017; 376:917-927.
  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.
  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]
  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]
  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.


Primecuts – This Week in the Journals

March 15, 2017

pacemakerBy Irina Dimitrova , MD

Peer Reviewed

This week in the news, House Republicans at long last unveiled the American Health Care Act, their replacement plan for the ACA. Meanwhile the Justice Department decided to clean house by asking for the immediate resignation of all Obama-appointed district attorneys, with swift consequences for those who did not comply. President Trump debuted version 2.0 of his executive order regarding immigration and refugee status from 6 Muslim majority nations. South Korea, four years after electing its first female president, saw another important first with her impeachment over an ongoing corruption scandal. All this upheaval is enough to give anyone palpitations, but luckily in this week’s Primecuts we can feel more assured sending our palpitation prone patients into strong magnetic fields (no comment on the safety of watching cable news).  

Assessing the Risks Associated with MRI in Patients with a Pacemaker or Defibrillator1

This study seeks to establish guidelines for the safe use of MRI in patients with implantable cardiac devices. Pacemakers or ICDs are generally a contraindication to MRI imaging due to concerns that strong magnetic fields used in MRI can cause heating of implanted devices, leading to myocardial injury. There are FDA approved MRI-conditional devices that have been shown to pose no known risk to patients under certain specified conditions. However, an estimated 2 million people in the United States have non-MRI-conditional implanted devices, potentially excluding them from a vital and versatile imaging modality.

In this study, adults with a non-MRI-conditional pacemaker or ICD who had a clinical indication for a non-thoracic MRI, underwent MRI after reprograming of their device (including no-pacing mode or inactivation of bradycardia or tachycardia therapies)  , and were under careful observation to assess for any adverse events. The primary endpoints of the study were immediate consequences of MRI, including death, arrhythmia, or device malfunction requiring immediate replacement or repair. Secondary endpoints looked at changes in the device settings over several months.

The results of 1246 patients who underwent 1500 MRIs showed no deaths or device failures in patients who underwent imaging with appropriately reprogrammed devices. There was 1 patient who required immediate ICD replacement, however his device had not been appropriately reprogrammed according to the study protocol. Additionally, there were no episodes of ventricular arrhythmia and 6 episodes of atrial arrhythmias that spontaneously resolved within 49 hours.

One important limitation of this study is that it included only non-thoracic MRIs at 1.5 Tesla  (which is the standard strength of the magnetic field used by most commercial MRIs). It is unclear what, if any, differences would be seen if the imaging field was directly over the implanted device or if the stronger magnetic field of newer 3T  (3 Tesla) MRIs had been used. Additionally, patients with pacing dependent ICDs were excluded due to difficulty in appropriately reprogramming such devices prior to imaging. However, despite these limitations this study shows that in appropriately screened patients, and with close device monitoring, a previously avoided imaging modality can safely be used in patients with implanted cardiac devices.

Breast Cancer Screening in Denmark: A Cohort Study of Tumor Size and Overdiagnosis2 

This retrospective cohort study looks at the change in incidence of advanced breast cancer diagnosed in Danish women as a result of initiation of breast cancer screening. In Denmark, routine breast cancer screening for women aged 50 to 69 with biennial mammograms was initiated in select areas in the early 90s, providing a cohort comprising of 20% of Danish women (284,140 women in 2010) in the screened group, and the remaining 80% in the non-screened control group  (1,136,560 women in 2010). Diagnoses of breast cancer amongst all Danish women aged 35 to 84 were collected from 2 well validated national registries. The authors then compared the incidence rates of breast cancer both before and after screening was initiated, as well as within the screened group and the control group.

The results showed that the initiation of routine screening for women aged 50 to 69 did not lead to a lower incidence of advanced tumors. However, they did find that the incidence of non-advanced tumors (defined as tumors less than 20mm) did increase after screening was initiated. The authors calculated the number of over diagnosed tumors as the difference between the number of tumors in the screening areas and the non-screening areas, and estimated that the rate of over diagnosis of invasive breast cancer was between 14.7% and 38.6% (excluding DCIS), depending on which model was used.

This study is unique in that it not only compares rates of breast cancer before and after screening, but also compares the incidence of breast cancer in women who did not undergo screening before and after screening was initiated. This helps to control for any population wide changes in incidence over the study period.

The results of this study indicate that a significant number of women may be negatively impacted by routine breast cancer screening if they undergo unnecessary testing and treatment of tumors that would never have evolved to cause clinical significance. Further research is needed to help clinicians differentiate between clinically significant and insignificant tumors, and further work is needed on the part of clinicians to educate our patients about the potential for false positive results with routine screening. 

Intensive Speech and Language Therapy in patients with chronic aphasia after stroke: a randomized, open-label, blinded-endpoint, controlled trial in a health-care setting3 

This multicenter, parallel group, randomized controlled trial attempts to demonstrate the efficacy of intensive language therapy in treating post-stoke chronic aphasia. The authors of this study specifically chose the chronic aphasia subgroup, defined as aphasia lasting 6 months or longer post stroke, to challenge previously held assumptions that after initial improvement in speech and language function, patients with chronic aphasia were unable to further benefit from intensive language treatment.

In this study patients aged 18-70, who had chronic aphasia secondary to either ischemic and hemorrhagic stroke and had the ability to follow simple instructions were randomized to two groups. The first group received 3 weeks of intensive (greater than 10 hours/week) speech and language therapy, while the second group had a 3-week deferral period, before also receiving 3 weeks of intensive therapy. Both groups were then followed for 6 months, during which they could continue to receive language therapy as covered by their insurer. The primary end point was change in verbal communication effectiveness in everyday life scenarios as determined by the ANELT-A scale from baseline. The authors showed that verbal communication significantly improved by a mean of 3 points from baseline following 3 weeks of intensive speech and language therapy, and that these gains were sustained at 6 months. A subgroup which received 5 weeks of intensive therapy showed a mean improvement of 4 points from baseline. In comparison, previous studies showing improvement in acute (3 weeks post stroke) and post-acute (3 months post stroke) aphasia, have shown ANELT-A improvements of 10 points and 5 points respectively.

This study is unique in that it demonstrates that patients with chronic aphasia are able to benefit from intensive language therapy to a smaller but still significant degree compared to gains seen by patients with acute aphasia, and shows that these gains can be sustained over time. This study also suggests that longer duration of therapy may lead to an even greater benefit as seen by the improvements seen in the subgroup that continued to receive therapy. As this study was conducted in a real-world environment, which included basing duration of therapy on insurance coverage, it provides direct data that intensive speech and language therapy should be covered by insurance for at least 3 weeks, but potentially for longer, to allow for optimal recovery of communication ability in post-stroke patients.

Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia4 

This is a multi-institutional phase 3 randomized control trial studying the improved survival of patients with refractory B-cell ALL treated with blinatumomab vs standard chemotherapy. Blinatumomab is a bispecific antibody that binds to CD-19, a B cell surface antigen expressed by more than 90% of B-cell precursor ALL blasts and to CD3-positive cytotoxic T cells, allowing for T cell mediated destruction of B cells. Patients included in this study were aged 18 or older with refractory B-cell ALL, defined as either refractory to induction or salvage chemotherapy, or first relapse within 12 months of fist remission, or any subsequent relapse. Patients were randomized to receive either induction and consolidation treatments with Blinatumomab or further chemotherapy with a combination of agents.

The primary endpoint evaluated in this endpoint was overall survival. The results showed that median survival in the blinatumomab treated group was 7.7 months as measured from randomization compared to 4 months in the chemotherapy group, results that led to early termination of the study because of the clear benefit observed with blinatumomab therapy. Additionally, patients in the blinatumomab group had higher rates of remission and longer duration of remission compared to the chemotherapy group.

This study shows very promising results of improved survival in patients with refractory ALL, in which 3-5 year survival is generally under 10%. The authors suggest that the efficacy of blinatumomab may be even more robust if combined with immune activation, given all patients in this study had been exposed to immunosuppressive chemotherapy, potentially dampening its immune-based effects. It is also possible to see enhanced effects of blinatumomab in combination with therapies that target additional B-cell receptors, such as rituximab and inotuzumab.

Despite these promising advances, it is important to note that at $178,000 per treatment5, blinatumomab is one of the most expensive cancer treatment drugs. As access to health care coverage is surely to be hotly debated over the next several months, if not years, it will be interesting to note what regulations, if any, are placed to control the costs of targeted cancer treatments such as this, which provide significant benefit to a small number of people at an astronomical cost. 


Linking Immunizations Status and Eligibility for Welfare and Benefits Payments: The Australian “No Jab, No Pay” Legislations6

With increases in outbreaks of preventable diseases, public health policy makers must grapple with the balance between personal liberty and community health. Legislators in Australia have greatly improved the rates of childhood immunizations by predicating childhood immunization for welfare benefits, and provide a model for similar application in the US.

The Promise of a boy: Indian Women are being mis-sold drugs to change their babies’ sex7

Social, economic, and cultural preferences for a male child are putting significant pressure on women in India to take drugs marketed as sex-selecting, with a prevalence as high as 60% amongst women living in certain rural regions whose first child was female. This illegal market is thought to directly contribute to higher numbers of miscarriages as well as widening gender gaps.

Modeling Contagion Through Social Networks to Explain and Predict Gunshot Violence in Chicago, 2006 to 20148

Comparing all arrests in Chicago with all recorded episodes of gun violence during the same time period, researchers were able to create a social network of gun violence that is better able to predict future victims of gun violence based on prior social associations than current models that are more heavily based on demographic and geographic data. This model suggests that gun violence can be transmitted through social interaction in a manner similar to infectious disease.

Dr. Irina Dimitrova is a 1st year resident at NYU Langone Medical Center

Peer reviewed by David Kudlowitz, chief resident, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


  1. Russo, Robert J., et al. “Assessing the Risks Associated with MRI in Patients with a Pacemaker or Defibrillator.” New England Journal of Medicine, vol. 376, no. 8, 2017, pp. 755–764.
  2. Jørgensen, Karsten Juhl, et al. “Breast Cancer Screening in DenmarkA Cohort Study of Tumor Size and OverdiagnosisBreast Cancer Screening in Denmark.” Annals of Internal Medicine, American College of Physicians, 7 Mar. 2017, Accessed 11 Mar. 2017.
  3. Breitenstein, Caterina, et al. “Intensive Speech and Language Therapy in Patients with Chronic Aphasia after Stroke: a Randomised, Open-Label, Blinded-Endpoint, Controlled Trial in a Health-Care Setting.” The Lancet, 2017, doi:10.1016/s0140-6736(17)30067-3.
  4. Kantarjian, Hagop, et al. “Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia.” New England Journal of Medicine, vol. 376, no. 9, Feb. 2017, pp. 836–847., doi:10.1056/nejmoa1609783.
  5. Pierson, Ransdell. “Exclusive: Amgen’s New Leukemia Drug to Carry $178,000 Price Tag.” Reuters, Thomson Reuters, 17 Dec. 2014, Accessed 11 Mar. 2017.
  6. Yang YT, Studdert DM. Linking Immunization Status and Eligibility for Welfare and Benefits PaymentsThe Australian “No Jab, No Pay” Legislation. JAMA. 2017;317(8):803-804. doi:10.1001/jama.2017.0123
  7. Cousins , Sophie. “The Promise of a Boy: Indian Women Are Being Mis-Sold Drugs to Change Their Babies’ Sex.” BMJ, British Medical Journal Publishing Group, 6 Mar. 2017, Accessed 11 Mar. 2017.
  8. Green B, Horel T, Papachristos AV. Modeling Contagion Through Social Networks to Explain and Predict Gunshot Violence in Chicago, 2006 to 2014. JAMA Intern Med. 2017;177(3):326-333. doi:10.1001/jamainternmed.2016.8245