Weekly EBM Update: 12.7.2018 (Feat. Guest Star)

Welcome to the EBM Weekly Update!

This week we have an evidence update from the annual American Society of Hematology (ASH) meeting regarding the use of DOAC's for the treatment of cancer associated VTE. While in practice this had been done for sometime, this is one of the first trials (maybe the first?) showing superior efficacy with the use of a DOAC over LMWH. 

The second article review was selected and written by someone near and dear to many an IM residents’ heart- Dr. Daniel Green. Yes, we convinced this recent OHSU grad to make a cameo appearance from his Kaiser abode in sunny southern California and grace us with his EBM wisdom regarding the overzealous and potentially lethal use of oxygen therapy in nearly all hospitalized patients. We are forever grateful for his contribution! Thanks Dan ;) If any of you other current residents, alums, or faculty out there want to contribute to this effort, we’d love to have you!!


Apixaban, Dalteparin, in Active Cancer Associated Venous Thromboembolism, the ADAM VTE Trial (ASH 2018)

Historically, low molecular weight heparin (LMWH) was used for both prophylaxis and treatment of cancer associated DVT. Its superiority was demonstrated to coumadin in the CLOT trial (NEJM 2003), which demonstrated fewer episodes of venous thromboembolic disease (VTE) amongst patients receiving LMWH vs. oral anticoagulation with a coumadin derivative. However, with the advent of newer oral agents such as direct oral anticoagulants (DOAC’s), if LMWH remains superior remains to be seen. A non-inferiority trial published early this year in NEJM (2/2018) demonstrated that edoxaban was non-inferior to LMWH in patients with cancer associated DVT, however this was at the expense of increased bleeding, particularly amongst patients with GI malignancies. The authors of the above study evaluated the efficacy of 6 months of treatment with Apixaban (a DOAC) compared to dalteparin (LMWH) in the treatment of cancer associated VTE amongst 300 patients (287 included in primary analysis with colorectal, lung, pancreas, and breast the most prevalent cancer types). The authors found significantly fewer VTE’s in patients receiving apixaban compared to dalteparin (3.4% vs 14.1%, p-value: 0.0182). There was no difference in major bleeding between groups (0 and 2 patients, respectively), nor clinically relevant non-major bleeding.

Take Home: Among patients with cancer associated VTE, oral anticoagulation with apixaban appears to be a safe and effective treatment compared to LMWH. Further subgroup analysis is warranted to evaluate the safety of these agents amongst patients with GI malignancies.

Link to Conference Abstract Here


Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. (Lancet 4/2018) (By Contributor Dr. Daniel J. Green)

Background:  Most patients that are in the hospital will have a nasal cannula on whether they need it or not.  How do we know who needs supplemental oxygen therapy?

METHODS:  Systematic review and meta-analysis of randomized control trials in a variety of different databases comparing liberal versus conservative oxygen therapy in acutely ill adult inpatients (pts with chronic respiratory disease and a few other things like ECMO were excluded).  The outcome of interest was mortality (in hospital, 30-day, longest follow-up reported) and morbidity (hospital-acquired pneumonia, any infection, length of hospital stay, others).

Findings:  Twenty-five RCTs including ~16,000 patients with diseases such as sepsis, critical illness, stroke, trauma, myocardial infarction, cardiac arrest, and emergency surgery.  They compared conservative oxygen strategy (‘less is more’) verses liberal oxygen strategy (O2 sat median greater than 96%). More oxygen had a relative risk for in-hospital death of RR 1.2, 30-day mortality relative risk RR 1.14, all were statistically significant, and the I-square test for heterogeneity was low (favorable, meaning the studies were similar and easy to compare).

Critical Appraisal:  Broadly speaking, internally valid with high quality of evidence, low risk bias with low heterogeneity among numerous large randomized control trials.  Reasonably well generalized as the patient's included had a variety of different medical conditions.  Our veteran population has a high prevalence of chronic respiratory disease, I could not easily find what this term includes. If they excluded stable COPD, asthma patients etc., it would limit the generalization to our VA population.

 Take Home:  There is small but persistent risk of death, both short and long-term, from supplemental oxygen therapy titration to a saturation greater than ~96%.  Consider removing the nasal cannula to prevent death, prevent your patient from sitting in bed all day unnecessarily, and prevent dry nasal passages and discomfort.  But mostly death.

Link to Paper Here

Weekly EBM Update 11.9.018

Changes in Prevalence of Health Care–Associated Infections in U.S. Hospitals (NEJM 11/2018)

Healthcare associated infections are a common cause of morbidity and mortality. Additionally, a concern exists regarding increasing antimicrobial resistance in the form of multidrug resistant (MDR) organisms. As such, a large push to minimize hospital acquired infections such as catheter associated UTI’s (CAUTI’s), central line associated bloodstream infections (CLABSI), and ventilator associated pneumonia (VAP) has been seen across the country and are often reported as hospital performance measures or quality measures. The authors of the above study conducted an observational point prevalence study to investigate changes in healthcare associated infections from 2011 to 2015. The most common pathogens found (at frequencies of 10% or greater) included Clostridioides difficile, Staphylococcus Aureus (of which 45% of isolates were MRSA), and Escherichia Coli. There was no significant change in the rate of ventilator associated or healthcare associated pneumonia (the most common healthcare associated infection), C. Difficile associated diarrhea, or CLABSI between time periods. There was a significant decrease in CAUTI’s and surgical site infections. Patients admitted in 2015 had significantly less healthcare associated infections (3.2% vs. 4.0%), and after adjustment for age, time from admission to survey, presence of devices, and status of being in a large hospital, patients in 2015 were approximately 16% less likely to have a healthcare associated infection (RR 0.84, 95% CU 0.74-0.95).

Take home: Healthcare associated infections decreased in prevalence from 2011 to 2015. There was a reduction in UTI’s and surgical site infections, likely due to improved recognition and quality improvement measures aimed at prevention of these infections. Healthcare associated pneumonia and C. difficile infections did not decrease significantly over this time period. C. difficile, E. coli, and Staph Aureus (both MSSA and MRSA) remain the most common hospital acquired pathogens.

Read the article here

Acute Clinical Care for Transgender Patients A Review (JAMA IM 11/2018)

Transgender patients often have negative experiences with healthcare providers. The review included here cites the 2015 US transgender survey, which noted that 33% of transgender responders reported at least 1 negative experience with the healthcare system, and 23% reported avoiding medical care out of fear of mistreatment. From the standpoint of the provider, clinical care directed towards the needs of transgender patients is growing, but remains a small field. This integral review touches on topics from how to address transgender patients using appropriate terminology to the benefits and risks associated with hormone gender-affirming hormone therapy. It is an easy, and essential read for all healthcare providers in order to continue providing high quality care for all of our patients.

Take home: Read this review! Or at the very least, save it somewhere it can be accessed for future reference.

Read the article here

Weekly Evidence Updates 7.2.18

Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function (JAMA 7/2018)

Metformin has long been associated with a risk of lactic acidosis, leading to cautious prescribing practices. This has led to curtailed use in individuals with decreased renal function (ie. CKD or patients with CHF). Most of this concern arose from a cousin of metformin, phenphormin- which was removed from the US market in 1978. More recent data has shown significant benefit to metformin use amongst these patient populations, ultimately leading to changes in FDA guidelines surrounding metformin prescribing (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. doi: 10.7326/M16-1901). Due to these changes, the Authors of the above article aimed to evaluate metformin use in 75,000 patients with varying stages of CKD. Patients with ESRD or an eGFR < 15 mL/min were excluded. The primary outcome was hospitalization for acidosis other than DKA. Metformin use was associated with a risk of acidosis (HR 2.01) at an eGFR < 30 mL/min. Acidosis was also more common amongst patients with CKD either on or off metformin- an important point the authors mention as a potential confounder in prior studies. Interestingly, sulfonylurea had a similar association with acidosis overall compared to metformin.

Take Home: Metformin use appears safe down to an eGFR of 30 mL/min. It should not be initiated at an eGFR below 45 mL/min. This trial confirmed current FDA labeling which recommends against metformin use with an eGFR < 30 mL/min. New prescribing guidelines focus on the eGFR, and no longer consider a creatinine > 1.5 in men or 1.4 in women as contraindications to metformin use.

Click here for the full article


Aldosterone Antagonist Therapy and Mortality in Patients With ST-Segment Elevation Myocardial Infarction Without Heart Failure (JAMA 7/2018)

The mineralocorticoid receptor antagonists (MRA), specifically the aldosterone antagonists eplerenone and spironolactone have been cornerstones of therapy for congestive heart failure since the publishing of the RALES trial (NEJM, 1999) that demonstrated a decreased mortality in patients with NYHA class III-IV HF and an EF < 35%. Since then, further studies have looked at the role of MRA therapy in the ACS setting. Specifically, the EPHESUS trial (NEJM,2003) showed a reduction in morbidity and mortality in patients post-ACS for patients with an EF < 40% and clinical heart failure, or diabetes. The authors of this meta-analysis of 10 studies (4,147 patients) evaluated the role of MRA therapy in STEMI patients with an LVEF > 40% and without clinical heart failure. Most patients included received MRA therapy within 24 hours post-STEMI, and had a follow up period of 6-12 months. The authors found MRA therapy reduced mortality (OR 0.62 (0.42-0.91)) compared to controls. MRA therapy was also associated with a small but significant increase in LVEF (mean difference 1.58%, p=0.03, I2=99). There was no reported difference in the rate of recurrent MI, CHF, or ventricular arrhythmias. Adverse effects included elevated potassium levels.

Take home: Aldosterone Antagonists may improve mortality in patients following STEMI who do not have an LVEF < 40% or clinical heart failure. Ongoing RCT’s are currently being conducted further assess the role of Aldosterone antagonists in post-STEMI care.

Click here for the full article

Weekly Evidence Updates 6.25.18

Combined analysis of Asthma Safety Trials of Long-Acting 2- Agonists (NEJM 6/2018)

Controversy has surrounded whether or not long acting beta agonist (LABA) medications are safe in patients with asthma, with some trials showing increased mortality with their use, and others demonstrating that they are safe to use when combined with an inhaled corticosteroid (ICS). The study presented above is the result of a pooled, prospective analysis of a randomized controlled trial assessing the non-inferiority of LABA+ICS vs ICS alone. The authors looked at asthma related intubation and death as a primary outcome. Secondary outcomes included serious asthma related events (which added in hospitalizations), and asthma exacerbations. The authors found no difference in the rate of serious asthma related events, but fewer asthma exacerbations with the LABA+ICS combination. This data arrives on the heels of 2 other recently published studies looking at the use of budesonide/formoterol as both maintenance and reliever therapy (SMART therapy: Single Maintenance And Reliever Therapy) for patients with mild asthma (O’byrne, Paul M., et al. "Inhaled combined budesonide–formoterol as needed in mild asthma." New England Journal of Medicine 378.20 (2018): 1865-1876.). It is worth noting that industry was heavily involved in the above study as this safety trial was mandated by the FDA.

Article Link

Take home: LABA+ICS appears safe for use in patients with asthma (current guidelines already use for moderate persistent asthma and more severe asthmatics). Their use may be worthwhile in patients with mild persistent asthma as single agent reliever therapy. Their use as a first line maintenance therapy with overall less corticosteroid exposure compared to ICS maintenance has yet to be studied.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock (APROCCHSS Trial) (NEJM 3/2018)

Steroids have been used in septic shock for some time. Some trials demonstrated a mortality benefit (ie. Annane D, Sébille V, Charpentier C, et al. Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock. JAMA. 2002), while others have not demonstrated this such as the ADRENAL (nejm 2018), HYPRESS (JAMA 2016), and CORTICUS (nejm 2008). The effects of steroids in shock are not entirely clear, but are thought to augment vascular tone in response to vasopressors. The APROCCHSS trial randomized patients to hydrocortisone+fludrocortisone (50 mg Q 6 hours and 50 mcq QD, respectively) vs. drotrecogin alfa (aPC- now off the market), a combination of all three drugs, or placebo. These were given for 7 days in patients with evidence of indisputable or probable septic shock (documented infection+SOFA score 3-4 in at least 2 organ systems for at least 6 hours, and vasopressors for ≥ 6 hours). The Authors found that the combination of hydrocortisone plus fludrocortisone reduced all cause mortality at day 90, at discharge from the ICU or hospital, and at day 180. Mortality overall was high (43% in treatment arm, and 49% in control arm at day 90), speaking to the high mortality seen in septic shock. Significant adverse events were not seen, other than more hyperglycemia in the steroid group.

Article Link

Take Home: For patients with septic shock who have been on vasopressor therapy for at least 6 hours, addition of hydrocortisone and fludrocortisone improves overall mortality at 90 days and hospital discharge.