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If you follow this blog, you’ve probably read various critiques of the use of procalcitonin to guide antibiotic prescribing. Procalcitonin, a non-specific inflammatory marker, provides a small amount of informational value regarding the underlying etiology of infection, but my underlying criticism of its envisioned use is:

  • The baseline rate of antibiotic prescribing is so poor, and the likelihood of poor outcomes so low, a safe reduction in prescribing is guaranteed.
  • It provides about the same area-under-the-curve for predicting bacterial etiologies as C-reactive protein.
  • The pro-procalcitonin studies and contributions are effectively covered in the fingerprints of the manufacturers of the assay.

So, then, replace the above complaints with – well, mostly just the top one, because here we are with CRP doing the same things for which procalcitonin is advertised, and the apparent conflict-of-interest is turned down a few notches.

In this study, 86 primary care clinics in England and Wales randomized patients with a diagnosis of COPD and a clinical diagnosis of an acute exacerbation to use of point-of-care CRP testing versus usual care. Similar to those studies seen with procalcitonin, prescribers were provided guidance with respect to various CRP levels and recommendations for either prescribing, possible prescribing, or do not prescribe. The primary outcome and secondary outcomes were associated with receipt of any antibiotics, quality of life, and adverse health outcomes.

Over the course of two years, 649 patients were randomized to the two arms, with a handful of each failing to properly undergo initial study procedures. The prescribing rate at the index visit in the “usual care” group: 69.7%. The prescribing rate with CRP: 47.7%. A winner is CRP!

Except that 76% of patients had CRP less than the threshold at which antibiotics were recommended. Another 12% were in the “antibiotics maybe” group. Thus, nearly 90% of the entire cohort were suspected of having no or limited benefit to antibiotics – so, of course any safety margin to deprescribing would be satisfied. And, considering the baseline rate of prescribing was 70%, again, there is basically no possible way a stewardship intervention could fail.

The editorial accompanying this article is darkly amusing, stating “the findings from this study are compelling enough to support CRP testing as an adjunctive measure to guide antibiotic use in patients with acute exacerbations of COPD”. However, it also goes on to note these data hardly identify “which patients (if any) truly benefit from antibiotic therapy”(emphasis mine). Some trials testing 100% antibiotic prescribing vs. zero prescribing (e.g., placebo) have found minimal, or no, benefit. As with procalcitonin, our problem is a pervasive culture of over-prescribing, and ultimate answer is the same for CRP: we don’t need to introduce a marginally informative test into this low-stakes patient population, we simply need to snap out of our collective insanity.

“C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations”
https://www.nejm.org/doi/10.1056/NEJMoa1803185

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It’s rimegepant again!

As featured in such posts as … yesterday’s … it’s the same calcitonin gene-related peptide receptor antagonist, but in an entirely separate large, multi-center, double-blind, randomized controlled trial.

And, the results are essentially the same. In this trial, 1,466 participants were randomly assigned to rimegepant or placebo for treatment of a single migraine headache of moderate-to-severe intensity. At two hours post-dose, response rates were 21% with rimegepant and 11% with placebo. Adverse events were similarly rare and generally mild.

Yet again, this tells us rimegepant is better than nothing – and in no way informs us regarding efficacy in their hypothetical patient population: those without response to either over-the-counter therapy or non-responsive/intolerant of the triptans.

Yet again, this study is completely funded by Biohaven Pharmaceuticals, with all the authors employed by and owning stock.

So, the same critiques as yesterday apply – and it’s transparently just another page out of the typical pharmaceutical corporation playbook: do enough to obtain approval, and then let the marketing operation kick into high gear.

“Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31606-X/fulltext

Addendum: The protocol does have a non-redacted tidbit of a comparison between rimegepant and sumitriptan, based off some unpublished data from a Phase 2b trial. To be taken with a grain of salt, to be sure, but obviously this would not have looked good for rimegepant if any sort of active comparator would have been used:

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The new sexy business – by which I mean “profitable” – in the treatment of chronic migraine is therapy targeted at the calcitonin gene–related peptide receptor. The past few years have brought several of these to market as ongoing maintenance therapy. This looks at a different application – acute migraine. Their proposed unmet need – the slice of patients for whom various triptans are ineffective.

This is a multi-center, randomized, double-blinded, placebo-controlled trial of rimegepant, an orally-administered CGRP antagonist, administered as a single-dose for acute migraine headache of moderate-to-severe intensity. These authors randomized 1,186 patients in a 1:1 ratio, with the primary end point being freedom from pain at 2 hours after the initial dose.

The winner: rimegepant.

Yes, rimegepant is superior to doing nothing at all for your migraine headache.

And just barely – 19.6% response to rimegepant, compared with 12.0% response to placebo.

The clinical value here is virtually negligible. And, helpfully, the authors provided the primary limitation of this trial for you in the text:

“First, the trial did not include an active comparator to rimegepant.”

The authors note in their introduction many patients receiving triptans do not have a response – 34%! This, however, implies 60+% of patients do have a response – far superior to rimegepant. Then, patients also have an array of over-the-counter options including acetaminophen, ibuprofen, and various caffeine-containing combination therapies. Treating moderate-to-severe migraine attacks with placebo borders on – if not crosses into – unethical territory. Even if this therapy didn’t have a dismal response rate, we still need to generalize it one step further to those who are non-responders to triptans to even have an indication – which would then be the proper enrollment criterion for a trial to ensure the same physiologic features making a patient a triptan non-responder weren’t also a CGPR antagonist non-responder.

Now, no one opposes further exploration of alternative, effective treatments for migraine – headaches, particularly migraine headaches, are relatively common presenting complaints in the Emergency Department. While we have effective abortive treatments for such, there is tremendous value in having a wider array of options for use at home, considering the direct and indirect resource costs and human suffering associated with headaches requiring Emergency Department evaluation and treatment.

But this is junk science – an advertorial in a journal continually proving itself to have virtually no worthy editorial standard:

“Biohaven Pharmaceuticals sponsored the trial, supplied the trial agents, reviewed the trial design, collected the data, and performed data management and analysis. The manuscript was written with the assistance of a medical writer funded by Biohaven Pharmaceuticals. All the authors have confidentiality agreements with Biohaven Pharmaceuticals, either as a condition of employment or in their role as consultants.”

Yet another utter embarrassment for the New England Journal of Medicine.

“Rimegepant, an Oral Calcitonin Gene–Related Peptide Receptor Antagonist, for Migraine”

https://www.nejm.org/doi/full/10.1056/NEJMoa1811090

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It would seem the Pediatric Emergency Care Applied Research Network (PECARN) is gearing up to develop another decision instrument – this time for cervical spine injuries.

This is a prospective, observational study of 4,091 pediatric blunt trauma patients across four pediatric level-1 trauma centers, surveying treating providers about the presence or absence of factors suspected to be implicated with cervical spine injuries. The factors were selected based on previous studies, as well as those suspected as having potential physiologic plausibility and good interrater reliability. The stated purpose – to ultimately develop a decision instrument akin to their prior work for clinically important minor head injury.

Overall, the prevalence of a cervical spine injury – vertebral fractures, ligamentous injury, intraspinal hemorrhage, or spinal cord injury – was 1.8%. The vast majority of patients in their cohort (78.2%) underwent some sort of imaging, although only 15.8% underwent CT. The most predictive items identified are those already typically considered: diving injuries, axial loading injuries, clotheslining, loss of consciousness (including intubation), neck pain, altered mental status (frequently associated with obvious head injuries), limited range of motion, focal neurologic deficits, and substantial torso and thoracic injuries. Of the 74 patients with CSI in their cohort, effectively only one would have been missed by a decision instrument based on these factors – a fall from 10 feet whose symptoms localized to the thoracic spine, and had a C7 burst with T2-T4 compression fractures. Obviously, this was not missed clinically – again revealing the role of clinical judgment outside of any decision instrument.

The most interesting tidbit, leading into the most substantial implications for generalizability, is their note regarding “high-risk MVC”. They comment previous case-control studies determined both predisposing conditions (e.g., congenital abnormalities of the cervical spine) and high-risk MVC were identified as risk factors, whereas in this study they were not. They discuss the low prevalence in their cohort of those with predisposing conditions, and, conversely, the high prevalence of high-risk mechanisms, to justify their lack of multivariate effect on predicting CSI. Even though they did not fall out as predictive elements in this cohort, a future prediction model intended for general use may yet include such features. As such, these data ought not be fully relied upon to downgrade those potential risk factors.

“Cervical Spine Injury Risk Factors in Children With Blunt Trauma”
https://pediatrics.aappublications.org/content/early/2019/06/18/peds.2018-3221

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After many years of various studies of moderate size looking at the diagnostic performance of high-sensitivity troponin assays, now we have a new entry: the Calculation of Myocardial Infarction Risk Probabilities to Manage Patients with Suspicion of Myocardial Infarction (COMPASS-MI) project.

This is not new data, but rather the power team of Roche and Abbott pooling the results of 15 prior studies to describe the diagnostic performance of their Elecsys and Architect high-sensitivity platforms. Then, there are really two parts of this article. There is an initial analysis looking at the performance characteristics of differing combinations of initial and serial sampling of each. After that, these authors pull in several age- and comorbidity-matched comparison populations and describe the long-term 1- and 2- year outcomes of patients with differing levels of troponin concentrations.

The main product of their work, however, boils down to a set of mildly confusing wheels of data regarding the negative predictive value of various combinations of initial troponin level and serial troponin change, divided up based on whether repeat sampling was performed early or late. These cut-offs are further divided on the wheel regarding the proportion of the population with a certain risk level for 30-ay MI or death.

The end result, combined with the various massive supplementary appendicies, are massive amounts of data to help systems using these assays tailor their practice patterns to their desired level of sensitivity and specificity. The authors are not specifically prescriptive in any one cut-off, but rather try to provide as much data as possible. Prevalence of nSTEMI in their population was about 14%, meaning the negative predictive values are only generalizable to to similar patient demographics.

If you’re using these assays, this is quite important work to help assist in interpretation. If not, considering there’s no comparative data to conventional assays, it seems to have limited utility.

It should finally be noted virtually all the listed authors of this work receive some financial support from the manufacturers of these assays.

“Application of High-Sensitivity Troponin in Suspected Myocardial Infarction”
https://www.nejm.org/doi/full/10.1056/NEJMoa1803377

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The Holy Grail in the evaluation of infants of less than 60 days remains safe discharge without a lumbar puncture. Boston, Philadelphia, Rochester, Step-by-Step and others have tried to achieve this noble goal over the years. And now, the Febrile Young Infant Research Collaborative has tossed their hat into the ring.

In this retrospective query of their Pediatric Health Information System and other electronic medical records, these authors identified 181 non-ill appearing patients across 11 Emergency Departments with invasive bacterial infection, defined as bacteremia in either blood or cerebrospinal fluid. Using 362 matched controls as a comparison cohort, these authors used the typical logistic regression route to tease out the strongest predictors of IBI – age in days, observed temperature, absolute neutrophil count, and urinalysis result. Subsequently, they condensed the continuous variables into cut-offs maximizing area under the curve. These cut-offs were then incorporated into a scoring system based on the strength of their adjusted odds ratio, and then the final output was validated on the derivation set using k-fold cross-validation with 10 sets.

The final result using their best cumulative score cut-off: sensitivity of 98.8% (95% CI 95.7-99.9) with 31.3% specificity. The two cases missed were that of a 3-day old and a 40-day old otherwise afebrile in the ED with normal UA and an ANC <5185. The authors ultimately conclude their score, if validated, may have best value as a one-way prediction tool primarily to reduce current routine invasive testing, owing to its poor specificity. Certainly, I agree it does not have much value in those who might otherwise not undergo testing; a more specific risk score may be better, if not clinician gestalt.

The other tidbit I might mention is whether there could be value in incorporating time-of-onset of fever into their evaluation. We’ve seen in other studies a few of the fallouts with regard to sensitivity of IBI stem from recency of illness onset, and it may be falsely reassuring to find a normal ANC early in an illness course. Furthermore, these authors do not specifically mention whether the lack of fever in the ED could have been associated with prehospital antipyretic use. Finally, their data collection does not appear to incorporate respiratory swab results; readily available respiratory viral panel results may also prove useful in ruling out IBI.

While these data are certainly alluring, considering the desire to avoid invasive procedures in young infants, substantial prospective work is still likely required.

As a sad aside, the authors state:

However, these criteria were developed >25 years ago, and the epidemiology of serious bacterial infections has changed considerably since that time.

Unfortunately, as vaccination frequency continues to decline, even since patients were enrolled for this study, our “modern” cohort may better begin to resemble that of 25 years ago.

“A Prediction Model to Identify Febrile Infants ≤60 Days at Low Risk of
Invasive Bacterial Infection”

https://www.ncbi.nlm.nih.gov/pubmed/31167938

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WBCs? Glucose? Gram stain? Next-generation genetic sequencing?

It’s the NEJM again, so you know the fingerprints of financial and professional conflict of interest pervade, but this study is still fairly typical of the types of infectious disease diagnostics on the horizon. Why wait for any specific organism to grow – over the course of days – when you can simply try and match DNA fragments floating around to those of various viral and bacterial pathogens?

The promise probably doesn’t quite meet the hype in this study, based out of UCSF, where many of those working on the project hold shares of the patent on the technology. In this prospective multicenter study, these authors recruited patients, ostensibly, who were diagnostic challenges – “idiopathic meningitis, encephalitis, or myelitis in patients who had not received a diagnosis at the time of enrollment”. The vast majority of those enrolled were ultimately encephalitis and meningitis. Then, this wasn’t specifically a formal trial as much as it was a collected case series with a 1-year convenience time frame, constrained by funding and testing capacity.

The authors screened 482 patients for a final study population of 204. Of these 204, their next-generation sequencing methods made a diagnosis in 32. Of these 32, 19 had already been made by further directed clinical evaluation. Of those final 13, then, in which the NGS assay was the only method of diagnosis, this information augmented clinical management in 7. The supplementary appendix details these specific impacts on management – although, in reality, few of the vignettes are terribly compelling. A handful of cases confirmed a suspected diagnosis, leading to clinicians to narrow antibiotic or antifungal therapy, while others “reassured” clinicians they were on the right course. The NGS assay did, however, occasionally detect clinically important pathogens and guide directed treatment, including Nocardia and S. mitis meningitis whose conventional testing was otherwise negative. Unfortunately, despite the addition of this testing, no conclusive final diagnosis was ever made in half their cohort.

At present, this sort of testing is not likely to be within the scope of the Emergency Department – these represent complex cases with low diagnostic yield, and even while this method picks up some new diagnoses, it also misses others established by conventional means. That said, this sort of technology will likely yet only improve, decrease in cost, and additional applications will edge closer to mainstream care.

“Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis”

https://www.nejm.org/doi/full/10.1056/NEJMoa1803396

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The Choosing Wisely campaign is quite popular in theory, if not in practice – ranging widely across the specialties from Pediatric Hospital Medicine to our own, beloved, Emergency Medicine.

This list is from the Canadian Association for the Study of the Liver, and two of their five recommendations are somewhat relevant to EM. Without further ado:

Statement 1: Don’t order serum ammonia to diagnose or manage hepatic encephalopathy

This was their most highly ranked recommendation when members were surveyed at their annual meeting. They cite multiple confounders regarding ammonia levels, factors affecting accuracy of the measurement, and state “elevated ammonia levels do not add any diagnostic, staging, or prognostic value.” The diagnosis, they feel, ought to be made based on clinical history and response to therapy alone.

Statement 2: Don’t routinely transfuse fresh frozen plasma, vitamin K, or platelets to reverse abnormal tests of coagulation in patients with cirrhosis prior to abdominal paracentesis, endoscopic variceal band ligation, or any other minor invasive procedures

This is another one of my favorite pet topics – transfusion intended to “restore normal hemostasis” in a dysfunctional, but somewhat already rebalanced coagulation system. As they say, “Routine tests of coagulation do not reflect bleeding risk in patients with cirrhosis and bleeding complications of these procedures are rare.” In fact, I’ve seen several articles approaching even liver resection in the context of elevated coagulation parameters absent any major bleeding complications – so this ought certainly apply to minor procedures, including those in the Emergency Department.

No doubt the uptake of these recommendations will be highly variable among hospitals and specialty groups, but lists like these are great tools with which to start the conversation.

“Choosing Wisely Canada-Top Five List in Hepatology”
https://www.ncbi.nlm.nih.gov/pubmed/30596626

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That is how the authors frame it, after all: “‘Vital signs are vital’ is a common refrain in emergency medicine.”

And, these authors add to the body of work further exploring this axiom. In this simple, retrospective data analysis, they evaluate all adult visits to their Emergency Department to determine the effect of abnormal vital signs at disposition on short-term outcomes.

For discharges, about 3% of their cohort returned to the same ED within 72 hours. Only a handful – a little less than 15% – had any vital sign abnormalities at discharge. And, yes, those with vital sign abnormalities were slightly more likely to return than those who did not, with relative risk ratios centered generally around 1.2. Then, a little more than a quarter of patients were admitted on their return visit – and, again, vital sign abnormalities increased the likelihood of subsequent admission by a small amount. In this case, fever was more likely than the other abnormal vital signs to tip the scales towards admission.

Similarly, an analysis of inpatient visits and subsequent escalations in care noted vital sign abnormalities exhibited a greater risk of upgrade, with RRs centered around 2.

Overall, however, the vast majority of patients who were either admitted or discharged with abnormal vital signs did well. Abnormal vital signs are always worth recognizing and dedicating a bit of cognitive effort, but the aren’t strong enough predictors of subsequent outcomes to drive changes in management.

“Association of Vital Signs and Process Outcomes in Emergency Department Patients”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526877/

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Did you miss the publication of EXTEND a couple weeks ago – a publication I helpfully labeled as “shenanigans“? Well, these same authors have wasted little time performing a systematic review and meta-analysis of individual patient data in the 4.5-9 hour timeframe. Their search, specifically limited to hemispheric stroke and pretreatment perfusion/diffusion evaluation, identifies: EXTEND, ECASS4-EXTEND, and EPITHET.

EXTEND we’ve already heard from – and, since most of the patients for this IPD meta-analysis come from EXTEND, it should be no surprise the overall results effectively mirror EXTEND. EPITHET, of which you may have some faint familiarity, has been pulled from the dusty archives of 2008. Then, there’s ECASS4-EXTEND, of which you probably hadn’t heard, since it was published with zero fanfare about a month ago.

So, what is ECASS4-EXTEND? These were again 4.5-9h patients screened with MRI and enrolled between 2014 and 2017, with early termination recommended by the Data Safety Monitoring Board when enrollment slowed to a trickle following publication of the endovascular trials. Before discontinuation, these authors enrolled 120 and analyzed 116, 60 receiving tPA and 56 placebo. Most of them were “wake up” strokes, and the “time-to-treatment” variable is again facetiously estimated by taking the midpoint between sleep onset and time of waking. There are small increases in patients with reduced disability in the tPA arm, but these unsurprisingly do not reach statistical significance. Likewise, deaths within 90 days are double – 11.5% versus 6.8% – another technically non-significant result. The authors, naturally, focus on the promise of the treatment if a sufficient sample were recruited, rather than the potential threat to patient safety.

And then there’s this all-too-familiar editorial failure:

Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

…in direct contradiction to the third author having this affiliation:

Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany

And this little snippet in the body of the article:

Role of the funding source
… The trial was supported with a restricted grant from Boehringer Ingelheim (Germany), the funder. The funder approved the study design…. Two employees of the funder were members of the steering committee and thus involved in data interpretation and preparation of the publication.

Finally, amusingly enough, ECASS4-EXTEND doesn’t technically meet criteria for their inclusion in the systematic review and IPD meta-analysis – they report they searched for trials “published in English between Jan 1, 2006, and March 1, 2019”, while ECASS4-EXTEND was published on April 4th.

Nitpicking aside, despite the relative frequency and prominence of these publications, this is mostly much ado about nothing – it should be obvious from the early termination of ECASS4-EXTEND these data primarily reflect a cohort we’re sending to endovascular therapy. Therefore, what we really need for these data to be relevant is a confirmatory trial performed specifically in the resource-austere settings thrombectomy might not be available.

“Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31053-0/fulltext

“Extending the time window for intravenous thrombolysis in acute ischemic stroke using magnetic resonance imaging-based patient selection”
https://www.ncbi.nlm.nih.gov/pubmed/30947642

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