Steroids for Severe Influenza?

There’s a little bit of evidence supporting the use of corticosteroids in both severe sepsis and in severe pneumonia. Severe influenza is both of these things, yet neither. Should we try corticosteroids?

Many have – but, unfortunately, few have rigorously evaluated it. This systematic review found 30 eligible studies, all of which were observational excepting one randomized trial. From this poor-quality data, associations between steroid use and increased mortality and increased hospital-acquired infection were observed. While this hardly excludes a potential benefit to steroids in selected cases of severe influenza, it certainly ought to encourage you to defer use of steroids until high-quality data supports the practice, if ever.

“Corticosteroids as Adjunctive Therapy in the Treatment of Influenza: An Updated Cochrane Systematic Review and Meta-analysis.”
https://www.ncbi.nlm.nih.gov/pubmed/31743228

Let’s Sell Andexxa

Have you heard the Good News (from Portola) about andexanet?

It’s an ever-changing landscape of anticoagulants and reversal agents in the Emergency Department – though, it’s not so much as a whirlwind as it is a creeping ooze. The latest developments have all been covered ad nauseum over the past few years – dabigatran, idarucizumab, factor Xa inhibitors, and coagulation factor Xa (recombinant) inactivated-zhzo (andexanet alfa). This final product, trade name Andexxa, has generally been held in a dim view over the past year by many, including yours truly, Rebel EM, the Skeptic’s Guide to Emergency Medicine, EmCrit, first10EM, the American Society of Hematology, and both the European Medicines Agency and the Food and Drug Administration’s own clinical reviewers.

There is, however, a competing viewpoint in which Andexxa is Tier 1 therapy for treatment of major bleeding in the context of of direct Xa inhibitor use – such as this recent “Recommendations of a Multidisciplinary Expert Panel” piece in Annals of Emergency Medicine. What aspect of their review differs so greatly in their affinity for Andexxa?

The expert panel meeting was convened with funds from unrestricted educational grants from Portola Pharmaceuticals and Boehringer Ingelheim to the American College of Emergency Physicians.

And, to no great surprise, the convened panel reflects the funding source:

Dr. Baugh has worked as a consultant for Janssen Pharmaceuticals and previously received research funding from Janssen Pharmaceuticals and Boehringer Ingelheim as a coinvestigator. Dr. Cornutt has received speaker’s fees from Boehringer Ingelheim. Dr. Wilson has worked as a consultant for Janssen Pharmaceuticals, Boehringer Ingelheim, BMS/Pfizer Pharmaceuticals, and Portola Pharmaceuticals, and has also received research funding from them. Dr. Mahan has served on the speaker’s bureau and as a consultant for Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer and as a consultant to Daiichi-Sankyo, WebMD/Medscape, and Pharmacy Times/American Journal of Managed Care. Dr. Pollack is a scientific consultant to Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer; he also received research support from Boehringer Ingelheim, Janssen Pharma, Portola Pharma, Daiichi-Sankyo, CSL Behring, and AstraZeneca. Dr. Milling’s salary is supported by a grant from the National Heart, Lung, and Blood Institute. He serves on the executive committee for the ANNEXA-4 and ANNEXA-I trials, the steering committee for the LEX-209 trial, and the publications committee for the Kcentra trials. He has received consulting fees or research funding from CSL Behring, Portola, Boehringer Ingelheim, Genentech, and Octapharma. He received speaker’s fees from Janssen. Dr. Peacock has received research grants from Abbott, Boehringer Ingelheim, Braincheck, CSL Behring, Daiichi-Sankyo, Immunarray, Janssen, Ortho Clinical Diagnostics, Portola, Relypsa, and Roche. He has served as a consultant to Abbott, AstraZeneca, Bayer, Beckman, Boehringer-Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, and Siemens. He has provided expert testimony on behalf of Johnson & Johnson and has stock and ownership interests in AseptiScope Inc, Brainbox Inc, Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC. Dr. Rosovsky has served as an advisor or consultant to Janssen, BMS, and Portola and has received institutional research support from Janssen and BMS. Dr. Sarode has served as a consultant for CSL Behring and Octapharma and advisor to Portola Pharmaceuticals. Dr. Spyropoulos is a scientific consultant to Janssen, Bayer, Boehringer Ingelheim, Portola, and the ATLAS Group; he also has received research support from Janssen and Boehringer Ingelheim. Dr. Woods is a scientific consultant to Boehringer Ingelheim. Dr. Williams serves as a consultant to Janssen Pharmaceuticals, Boehringer Ingelheim, and Portola Pharmaceuticals.

This work is effectively an advertorial, masquerading as serious academic literature, and part of a well-executed marketing and promotional campaign by the manufacturers of these drugs – particularly Portola, which is having difficulty getting Andexxa on formulary due its cost and controversial clinical data. This publication in Annals is just one of many sponsored products:

The further afield these pseudo-guidelines permeate, the more likely the product – the $25k or $50k a dose Andexxa – is incorporated into hospital formularies and local practice. These also have implications for risk-management assessments, in which the costs – passed along to the patient or payor – are far outweighed by the potential liability of a decision to make the drug unavailable for treatment.

It should be clear from all the non-conflicted opinion the role of Andexxa is yet to be clearly established, with true RCT evidence unfortunately years away. To state otherwise – and to make Tier 1 recommendations – is simply misleading.

“Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel”
https://www.annemergmed.com/article/S0196-0644(19)31181-3/fulltext

The Non-Invasive Testing for Chest Pain Half-Truth

The utility or disutility of non-invasive diagnostic testing for chest pain – CT coronary angiograms, treadmill stress testing, myocardial perfusion imaging and the like – in the Emergency Department remains controversial. A couple days ago, the daily ACEP News Bulletin e-mail referenced an article regarding non-invasive testing featuring the following statement:

“Patients who underwent noninvasive diagnostic testing after evaluation for chest pain in the” emergency department (ED) appeared to have “a lower observed rate of CV death or MI,” researchers concluded.

While this statement is not strictly untrue, it is dramatically clarified by including the next sentence from the authors’ own abstract conclusion:

“This lower rate was driven by the high-risk subgroup.”

The study cited is a propensity-matched cohort of 370,863 patients discharged from the ED after a visit for chest pain in Ontario, Canada. They created matched cohorts featuring 96,457 patients who each either underwent non-invasive cardiac testing in the Emergency Department or did not. Interestingly enough, at 90 days, those who underwent testing had a higher risk of their combined endpoint of cardiovascular death or myocardial infarction. However, by 1 year, the rate of the combined endpoint in those who underwent testing had dropped below the rate for those who did not. The hazard difference was small, however, and driven by small absolute differences in outcomes for those in the high-risk and intermediate-risk cohorts.

Rather than try and read into this study some general advantage to non-invasive testing in the Emergency Department, it would only imply testing of value would be for those who are at intermediate- or high-risk for adverse cardiovascular outcomes. Next, it also does not specifically mandate or imply the testing should be done in the ED or, based on the 90 day outcomes data, even urgently upon discharge. Finally, the newsworthy snippet also does not mention dramatic increases in downstream invasive angiography, PCI, and cardiology visits associated with those in those who underwent non-invasive testing.

The ultimate conclusion is not practice changing in the least: appropriately selected patients may be candidates for the appropriately selected test. Individualized decisions need to be made for those at intermediate- and high-risk for cardiovascular outcomes. Likewise, the relative urgency of testing ought to be determined on an individual basis – and not routinely in the ED. This is, in fact, the authors’ own conclusion – just not well-reflected by the ACEP News Bulletin.

“Clinical Effectiveness of Cardiac Noninvasive Diagnostic Testing in
Patients Discharged From the Emergency Department for Chest Pain”
https://www.ahajournals.org/doi/10.1161/JAHA.119.013824

2019 Early Management of Acute Ischemic Stroke

Well, it’s 2019 – for another couple months – so there’s still time to update your Early Management of Acute Ischemic Stroke.

For what would otherwise sound to be a potentially underwhelming interval update, there is, in fact, a ton to unpack in here. Institutional stroke committees and regional EMS systems thrive on constant change, after all. Most of the changes are “clarity”, but there are many new recommendations, some of which are bland – promoting the use of EMS for stroke symptoms, for example – whereas others are even potentially controversial.

Some of the meat:

  • Expert opinion-based recommmendations to bypass local hospitals in preference of thrombectomy-capable facilities for patients ineligible for IV thrombolysis, but with symptoms of large vessel occlusions.
  • Several new recommendations promoting telestroke as a reasonable means of patient evaluation, even if it’s just telephone consultation.
  • A handful of new recommendations incorporating the use of MRI for stroke assessment, based on WAKE-UP, including the use of IV thrombolysis beyond 4.5 hours.
  • Two new recommendations regarding multimodal imaging in acute ischemic stroke. The first, non-controversial recommendation includes the use of CT perfusion or MRI-DWI for assessment of patients between 6 and 24 hours from symptom onset. However, when symptom onset is less than 6 hours, the new recommendation is to perform endovascular intervention based just on vessel status and ASPECTS. Throw out the high-value care guided by REVASCAT, SWIFT PRIME, EXTEND-IA, and ESCAPE and just treat based on the smaller effect sizes seen in THRACE and MR-CLEAN!
  • Surprisingly, explicit recommendation to withhold thrombolysis of mild non-disabling stroke based on PRISMS.
  • Thrombolysis with tenecteplase makes its first appearance as a reasonable alternative to alteplase.
  • A new recommendation to cover initiation of short-term dual antiplatelet therapy for minor stroke not treated with alteplase.
  • An entire massive new section with recommendations regarding in-hospital imaging modalities to help regarding secondary prevention of ischemic stroke.

There’s something in here for just about everyone!

“Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke.”
https://www.ncbi.nlm.nih.gov/pubmed/31662117

CRASH-3!

Tranexamic acid, an anti-fibrinolytic, helps reduce bleeding. When bleeding can be attenuated, patient-oriented outcomes related to bleeding can be improved. Its effect on outcomes, however, mirrors its clinical effect: quite small. In CRASH-2, general adult trauma with significant extracranial bleeding, the 28-day all-cause mortality reduction was 1.5%. In WOMAN, death due to bleeding from post-partum hemorrhage was reduced 0.4%.

Now, we address the use of TXA for intracranial bleeding. This has been evaluated before, however, in the TICH-2 trial. The primary outcome for TICH-2 was functional status at day 90, which was not reliably different between groups, nor was mortality at 90 days. There were, however, only 2,325 participants in this trial. CRASH-3, on the other hand, has enrolled 12,737.

With nearly six times as many patients, there are likewise about six times as many events – leading to detection of a small difference in head injury-related death, 18.5% in those receiving TXA versus 19.8% receiving placebo. Broken down further, the authors refine source of this difference primarily to those receiving TXA within three hours, and in those with mild and moderate head injury. Beyond three hours and in those with severe head injury, TXA administration was not associated with any reliable benefit (or harm).

However, any enthusiasm for TXA must evaporate when the results are no longer parsed based solely on head injury-related death. All-cause mortality is ultimately no different, with a reported RR of 0·96 (0·89–1·04). It would certainly be preferable if TXA were clearly beneficial, as opposed to observing an excess of non-head injury-related deaths to counterbalance its seeming benefit. Furthermore, looking at their various measures of disability, no clear advantage is seen favoring TXA. The ultimate flavor of their observations are somewhat embittered by these loamy morsels.

What should we do with these results? Well, probably, what we’ll likely do is expand the use of TXA. The good news is this is unlikely to be harmful and TXA is inexpensive. The bad news is, the minimal effect TXA does have on attenuating bleeding simply doesn’t result in a easily measured excess of functional adults post-injury. Practice variation is certainly acceptable surrounding the use of TXA, but we certainly ought not be dogmatic about the necessity of its application in isolated head injury.

“Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial”

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32233-0/fulltext

The Vitamins in Sepsis Parade Begins

A couple years back, we saw one of the first reports describing the potential efficacy of treating sepsis with a cocktail of vitamin C, thiamine, and steroids. These observational findings have been viewed with a healthy dose of skepticism while awaiting prospective, randomized evidence with regard to their validity.

Well, here’s one of the first: a short communication from CITRIS-ALI, a randomized clinical trial that almost, sort of, not quite, addresses the question of interest. This study was designed and initiated well before the aforementioned observational report, and it examines vitamin C monotherapy in patients with sepsis and acute respiratory distress syndrome. Their primary outcome and goal was to see if vitamin C could reduce sequential organ failure assessment scores, along with biological markers of inflammation and vascular injury.

With 1,262 patients screened leading to 167 patients receiving their randomized interventions, the answer is: no. Neither modified SOFA scores, c-reactive protein, nor thrombomodulin were different between groups.

But, wait! There’s more! In fact, 46 additional pre-specified secondary outcomes – 43 of which showed no difference. These included both the esoteric – angiopoietin-2 levels, tissue factor pathway inhibitor – and patient-oriented. It is these patient-oriented outcomes that pique the most interest: at 28 days, mortality in the vitamin C group was 29.8%, as compared with 46.3% with placebo. Ventilator-free days and ICU-free days similarly favored the vitamin C cohort.

So, interesting data incapable of informing practice. Another small sample, designed (appropriately) around a different target and primary outcome, with a secondary outcome still falling into the realm of hypothesis-generating. This will likely influence no one. Anyone already giving vitamins in sepsis – cheap, likely harmless – will continue to do so, and those awaiting a more informative trial will, also, continue to do so.

“Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure”

https://jamanetwork.com/journals/jama/fullarticle/2752063

ATS + IDSA CAP 2019

As the authors of this document lead off, it has been more than 10 years since the last American Thoracic Society/Infectious Diseases Society of America community-acquired pneumonia guideline – and much has changed. And, reflecting this, Much Has Changed.

A few interesting tidbits:

  • Do not obtain blood cultures in the outpatient setting, and blood cultures are recommended as inpatients only for severe CAP and when MRSA and P. aeruginosa are being covered. This, of course, is likely moot given our current triage of potential sepsis.
  • Basic outpatient CAP should be amoxicillin, doxycycline, or macrolide (based on local resistance) monotherapy. Add in comorbidities, and combination therapy or monotherapy with a respiratory fluoroquinolone is indicated.
  • Procalcitonin is not reliable to augment clinical judgment when CAP is suspected.
  • The Pneumonia Severity Index is the preferred decision instrument to augment clinical judgement regarding hospitalization.
  • Inpatient antibiotics are universally ß-lactam plus macrolide, or monotherapy with a respiratory fluoroquinolone. Empiric MRSA and P. aeruginosa coverage is suggested only if prior infection, not in those with risk factors alone.
  • No routine empiric anerobic coverage for suspected aspiration pneumonia.
  • No routine steroids for CAP, even severe.
  • Various recommendations regarding nfluenza and suspicion of CAP – treat with both antiviral and antibiotic therapy.
  • No follow-up chest x-ray documenting resolution of infiltrates is necessary in the outpatient setting if the patient is clinically improved.

Details, doses, and rationale within – many caveats, conditional recommendations, and need for additional research.

“Diagnosis and Treatment of Adults with Community-acquired Pneumonia: An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America”
https://www.atsjournals.org/doi/10.1164/rccm.201908-1581ST

It’s Lefamulin Time

New antimicrobials – particularly those with novel mechanism of action – are rare. Lefamulin, a pleuromutilin class antibiotic, is not new, but it’s new to humans – or, even more specifically, new to oral and intravenous availability in humans.

This article in JAMA details LEAP-2, the sequel (of course) to LEAP-1. This clinical trial demonstrates the non-inferiority of oral lefamulin to oral moxifloxacin for the treatment of generally mild community-acquired pneumonia. LEAP-1, as I’m certain you recall, demonstrated its non-inferiority as an intravenous-to-oral regimen for slightly-less-mild CAP in whom hospitalization was reasonable. Without belaboring the results too greatly, “early clinical response in the intention to treat population” and “test of cure in modified intention to treat populations” were generally similar, with response rates of about 90% for each arm. However, lefamulin is certainly less well-tolerated – diarrhea, nausea, and vomiting far exceeded the frequency observed in the moxifloxacin cohort.

These are likely valid results with respect to efficacy and a 10% non-inferiority margin, considering pleuromutilin antibiotics have been used effectively in animals for decades. This was, however, a tightly-controlled trial, narrowly targeted at meeting the threshold for approval in Europe and the United States (i.e., 50% of patients required to be PORT Class II, so 50.4% of them were). All authors, study procedures, and analyses were overseen by the sponsor, and trial sites were scattered across the (somewhat) developing world. Irregularities regarding efficacy differences and assessments were seen at several sites and addressed in the supplementary appendix, noting mostly the exclusion of results from these sites would not have affected the overall trial outcome. All these signals, however, do raise concerns regarding underreporting of adverse events and systematic minimization of any efficacy differences.

It’s splendid to have a new option for cases of multidrug resistance. For $200 to $300 a day, however, no need to indulge unnecessarily – or be the first on your block to drive the new hotness.

“Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia”
https://jamanetwork.com/journals/jama/fullarticle/2752331

Saving Lives with Lifesaving Devices

Automated electronic defibrillators are quite useful in many cases of out-of-hospital cardiac arrest – specifically, those so-called “shockable rhythms” in which defibrillation is indicated. Ventricular fibrillation, if treated with only bystander conventional cardiopulmonary resuscitation, has dismal survival. However, when no AED is available, the issue is mooted.

This is an interesting simulation exercise looking to improve access to AEDs such that availability might be improved in cases of cardiac arrest. These authors pulled every AED location in Denmark, along with the locations of all OHCAs between 2007 and 2016. Then, they used all OHCA from 1994 until 2007 as their “training set” to help derive an optimal location for AED placement with which to simulate. Optimal AED placements were dichotomized into “intervention #1” and “intervention #2” based on whether their building location provided business-hours access, or 24/7 access.

In the “real world” of 2007 to 2016, AED coverage of OHCA was 22.0%, leading to 14.6% bystander defibrillation. Based on their simulations and optimization, these authors propose potential 33.4% and 43.1% coverage, depending on business hours, leading to increases in bystander defibrillation of 22.5% and 26.9%. This improved coverage and bystander defibrillation would give an absolute increase in survival, based on the observed rate, of 3.4% and 4.1% over the study period.

This is obviously a simulation, meaning all these projected numbers are ficticious and subject to the imprecision of the inputs, along with extrapolated outcomes. However, the underlying principle of trying to intelligently match AED access to OHCA volume is certainly reasonable. It is hard to argue against distributing a limited resource in some data-driven fashion.

“In Silico Trial of Optimized Versus Actual Public Defibrillator Locations”
https://www.sciencedirect.com/science/article/pii/S0735109719361649

Counterpoint: Topical Anesthetics for Corneal Abrasions

We’ve seen a few articles recently discussing the potential utility of topical anesthetics for analgesia for corneal abrasions. The general point: there’s no consistent, modern evidence of harm, so why should we cling to older ways?

Counterpoint from the corneal specialist community: cling to old ways.

In this long correspondence, the authors detail the physiologic basis for their opposition to topical anesthetics as it relates to stimulation of endothelial growth. They follow this up with a three question survey regarding the practice, distributed to “an international community of cornea trained specialists”.

The clear winner in each of their three questions: “strongly disagree” with provision of topical anesthetics for acute corneal abrasions.

Interestingly, they also conflate these results with lack of justification for a clinical trial to further explore the safety and efficacy of such use:

“Often when there is a difference in clinical practice or clinical equipoise, there is an opportunity for a clinical trial. However, it is our hypothesis that within the ophthalmology community, there is not equipoise with respect to our practice of not prescribing topical anesthetics after traumatic corneal abrasions.”

I think it’s clear these specialists are making valid points regarding the potential for topical anesthetic abuse, but their citations hardly support their practice stance. I do agree, at least, regarding the lack of utility of clinical trials – but not because their use is so dangerous it cannot be tested. Rather, any clinical trial simply would be of low value as adverse events would be so rare it would be unlikely to reliably detect a difference between management strategies. It is clear topical anesthetic use will not be safe in all clinical situations, but it is rather more appropriate to provide guidance on the proper use of topic anesthetics than to simply ban them completely while continuing to cite the same anachronistic, limited evidence.

“Cornea Specialists Do Not Recommend Routine Usage of Topical Anesthetics for Corneal Abrasions”
https://www.ncbi.nlm.nih.gov/pubmed/31445551