Who Recanalizes with Just tPA?

The original argument: tPA helps all strokes, we must give it to everyone as quickly as possible!
The updated argument: tPA doesn’t not help all strokes, so it should still be given!

Specifically, as applies to the cohort of patients with large vessel occlusions being considered for mechanical thrombectomy. This small, pooled registry sample looked at cases from four centers, evaluating the rate and predictive characteristics for recanalization prior to cerebral angiography. The stated purpose of their study was to develop a predictive score, with the reasonable goal of reducing unnecessary tPA exposures prior to thrombectomy.

The numbers, in their score derivation and validation cohorts:

  • ICA: 6.4%/1.0%
  • M1 proximal: 16.1%/13.7%
  • M1 distal: 30.3%/30.7%
  • M2: 33.7%/34.0%

But, an even more powerful a predictor was thrombus length, as measured by T2 MRI susceptibility vessel sign. Recanalization was seen at over 80% for clots <5mm, 30% for 6-10mm, and below 10% for clots longer than 10mm, with particular futility for >20mm.

Interesting data – and a nice look at how not all sites of occlusion and clots are created equal. Whether, and how, we ought to treat them differently remains uncertain until the results of a prospective trial.

“Post-Thrombolysis Recanalization in Stroke Referrals for Thrombectomy”
https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.118.022335

Disutility, Thy Name is ANEXXA-4

About two and a half years ago, we were introduced to andexanet alfa (Andexxa), a modified recombinant form of factor Xa designed as a reversal option for factor Xa inhibitors. The mechanism of action is simple: andexanet mimics native factor Xa, providing the various Xa inhibitors (rivaroxaban, apixaban, edoxiban, betrixiban, and enoxaparin) an alternative target. When sufficient Xa inhibitor is bound to andexanet, the native version is freed to return to its normal work in hemostasis.

The problem, however, is the reversal is not durable. The half-life of andexanet is approximately 1 hour, after which point the factor Xa inhibitor levels rise and hemostasis is again impaired. This necessitates a bolus and an infusion. A bolus and infusion that costs ~$3,000 per 100mg vial – and requires 900mg for a “low dose” protocol or 1,800mg for a “high dose” protocol. And, it all vanishes to dust when the infusion completes.

The first NEJM publication regarding andexanet featured just the first 67 patients from ANNEXA-4, an open-label, single-arm descriptive study of patients given andexanet for major bleeding. Now, presented at the International Stroke Conference 2019 in Honolulu, we have the results from the full 352 patient cohort – and they’re every bit as uninspiring as the preview.

Nearly all patients were receiving rivaroxaban (half-life 7 to 13 hours) or apixaban (half-life 12 hours), with a handful on enoxaparin. As in the preview, the bolus of andexanet effectively dropped circulating levels of the factor Xa inhibitor down to negligible amounts. Again, as seen before, after cessation of the bolus, factor Xa levels returned to a level consistent with their terminal half-lives. Case in point: “At 4, 8, and 12 hours after andexanet infusion, the median value for anti–factor Xa activity was reduced from baseline by 32%, 34%, and 38%, respectively, for apixaban and by 42%, 48%, and 62%, respectively, for rivaroxaban.” This is just normal metabolism, not andexanet magic.

Death occurred in 14% of patients within 30 days, and there were thrombotic events in 10%. Hemostasis at 12 hours, their primary outcome, was 82% “in 204 of 249 patients who could be evaluated”. Specifically, they excluded a third of their population because they were effectively enrolled in error, as they met bleeding criteria but not Factor Xa inhibitor level criteria. This is similar to the idarucizumab open-label demonstration, in which many patients who were not actually coagulopathic were treated with anticoagulation reversal. This represents tremendous waste and cost.

Finally, the nail in the coffin, this admission in the abstract and the text: “Overall, there was no significant relationship between hemostatic efficacy and a reduction in anti–factor Xa activity during andexanet treatment.” The primary outcome wasn’t even correlated with their intervention!

As you can tell from the tone of this post, I am profoundly unimpressed with the value demonstrated here. There’s no evidence this is clinically useful, nor a potentially preferred strategy to use of prothrombin concentrate complexes to replete missing factor. The company and the FDA effectively admit the same:

The most important limitation of this trial is that it did not include a randomized comparison with a control group. At the time of study initiation, it was determined that a randomized, controlled trial would have logistic and ethical challenges, given the perceived risks of placebo assignment in this highly vulnerable population. However, continued use of unapproved agents, despite a lack of rigorous clinical data, has changed the equipoise for a trial. Thus, under the guidance of the FDA and as a condition of accelerated approval in the United States, the sponsor is conducting a randomized trial (ClinicalTrials.gov number, NCT03661528) that is expected to begin later this year.

I’m sure more will be made to unpack even further unfavorable details as time passes – and, until further reliable evidence can be presented, I’d pass on andexanet, as well.

“Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors”

https://www.nejm.org/doi/full/10.1056/NEJMoa1814051


Telehealth Triage for EMS

We’ve all seen non-emergency patients in our Emergency Departments. Further still, we’ve seen those same non-emergency patients arrive via emergency medical transport. Per these authors, the estimated burden of non-emergency or medically unnecessary ambulance transport ranges from 33-50%.

Houston, Texas, has a program of prehospital telehealth support provided by online board-certified Emergency Physicians. This article describes their retrospective cohort from 2015 through 2017, in which 15,067 patient encounters occurred from a total of 865,000 EMS incidents. Patients were eligible for telehealth if they met certain vital sign, chief complaint, and age criteria, and could be transported via non-ambulance alternative.

The good news: nearly everyone the EPs consulted with over telehealth was diverted from ambulance utilization. Only 11.2% of patients were ultimately transported by EMS –while basically the entire remainder utilized a taxi service. The bad news: nearly everyone was still transported to an Emergency Department. Only 5.0% of patients accepted same-day or next-day referral for follow-up at an affiliated outpatient health center. The primary advantage of this service, then, is increasing the availability of the limited ambulance services resource to respond to higher-acuity patients.

There are more than a few issues at play here in our current system with regard to providing, effectively, an unpaid, low-fidelity evaluation and assuming the liability risk. However, in systems with different structures and payment models where the overall costs to the system from ambulance utilization outweigh the other costs, this has a great deal of potential. Whether these results are generalizable is a reasonable concern, although the proportion of patients being referred to non-ambulance transport is not surprising. The entry criteria for telehealth consultation substantially narrowed the eligible population specifically to those whose complaints likely did not merit emergency transport. Finally, whether the EPs needed to be involved is another matter that could potentially be solved by more robust protocols in place to defer transport.

“Telehealth Impact on Primary Care Related Ambulance Transports”

https://www.ncbi.nlm.nih.gov/pubmed/30626250

Antibiotics & Hospitalization for Asthma

Reactive airway disease and asthma exacerbations. The mainstays of treatment are beta-agonist bronchodilators, systemic corticosteroids, and other adjunctive therapies as indicated. Conspicuously absent from treatment guidelines is any role for antibiotics – but that’s not stopping folks from using them.

In this retrospective data on inpatient hospitalizations comprised of 19,811 patients with acute asthma, 8,788 (44%) received antibiotics within the first two days of hospitalization. Patients receiving early antibiotics were mildly more ill than those who did not, and in their unadjusted analysis “treatment failure” was more common and length-of-stay was longer, as were antibiotic-associated adverse effects. The authors then performed a more evenly-matched propensity score analysis, featuring comparing 6,833 patients in each cohort – and find roughly the same associations, again favoring those who were not treated with antibiotics.

As usual, the limitations are the retrospective nature of a data-dredging exercise such as this, and potential for unmeasured confounders. I wouldn’t make much of the association between no-antibiotics and decreased length-of-stay, as it’s reasonable to expect confounding from selection bias at play for those receiving antibiotics and those who do not. Regardless, antibiotics were frequently used – and rather than wait for proof they are unhelpful, it seems more prudent to wait for proof they are.

There’s also been a fair bit of talk about the so-called anti-inflammatory effect of macrolides, specifically azithromycin. These represented about half the antibiotics used in these patients, and, obviously, there weren’t any further hypothesis-generating signals of benefit along that line of physiologic plausibility.

“Association of Antibiotic Treatment With Outcomes in Patients Hospitalized for an Asthma Exacerbation Treated With Systemic Corticosteroids”

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2721036

Again With The Value of CT-Diagnosed Rib Fractures

The elderly are more likely to fall. The elderly who fall are more likely to suffer rib fractures. The elderly who fall and suffer rib fractures are more likely to contract pneumonia and die. The chest x-ray is insensitive for rib fractures. So, we should always perform a CT in the elderly who fall and of whom we have suspicion for rib fractures?

This is a single-center retrospective study of 330 elderly patients, mean age 84, who presented after a fall. Each patient included in the study received a chest XR, followed by a CT of their chest. Overall, 96 patients had a rib fracture – 40 of which were seen on XR, the remainder only on CT. And, there are a number of interesting tidbits they describe in their population:

  • Neither hospital length-of-stay, ICU length-of-stay, or hospital mortality (10.3% vs. 7.3%) were (statistically) increased in those with occult rib fractures compared to those without any rib fractures.
  • These findings held true for the 63 patients with ≥2 occult rib fractures (both XR+ and XR-).
  • In patients with rib fractures seen on XR, the median number of additional rib fractures seen on CT was 2 (range 0-11).

Rates of in-hospital complications were similar between those hospitalized with rib fractures visualized on XR and those visualized only on CT. Then, in their case review, most adverse events occurring in those with occult rib fractures occurred due to associated injuries, events, or iatrogenic causes – not primarily due to the thoracic trauma itself.

This is only a small case series, and it is biased towards higher acuity – considering clinician judgement obtained CT imaging in all cases, and admission rates were nearly 90%. However, it does generally further demonstrate the low value in obtaining CT imaging to ensure no occult rib fractures are missed. An XR has low sensitivity, but these data do not support a premise of increased harm due to missed occult fractures.

“Chest CT imaging utility for radiographically occult rib fractures in elderly fall-injured patients”

https://journals.lww.com/jtrauma/Abstract/publishahead/Chest_CT_imaging_utility_for_radiographically.98414.aspx

Just Use the Slit Lamp

One is an unwieldy, medieval torture device. The other is a magnifying glass attached to a purple flashlight. In a busy Emergency Department, adapting to space requirements and patient flow needs, which one are you going to reach for?

Unfortunately – and rather obviously – the easy option is not equally effective. This small study pulled a convenience sample of anterior chamber-type eye complaints presenting to an eye urgent clinic, and evaluated them first with the Wood’s lamp, and then the slit lamp. Of the 73 patients included in the study, the overall sensitivity of the Wood’s lamp was 52% – missing, as the sensitivity might imply, about half of corneal abrasions, half of corneal ulcers, half of corneal foreign bodies, and most all of the keratitis or rust rings. Most of the provisional diagnoses given with the Wood’s lamp examination were different enough from the final diagnoses that the misses were clinically important.

Take a few minutes to re-familiarize yourself with the dials and widgets on your slit lamp – and use it. These data are hardly conclusive the slit lamp is, in fact, a “gold standard”, or that the Wood’s lamp is non-inferior in a general ED setting when used by emergency physicians. However, I’d rather put the onus on the evidence to demonstrate the effectiveness of the less-intensive diagnostic method, rather than base my practice on the assumption.

“Prospective study of the sensitivity of the Wood’s lamp for common eye abnormalities”
https://www.ncbi.nlm.nih.gov/pubmed/30630841

Bonus link: “What Really Glows” with the Wood’s lamp.

How Do Trauma Patients Die?

Comprised of 1,536 patients in an 18-center, prospective, observational study coordinated though the Western Trauma Association:

  • Traumatic brain injury – 45.0%
  • Exsanguination – 23.0%
  • “Late physiologic collapse” – 15.6%
  • “Early physiologic collapse.” – 9.7%
  • Pre-trauma medical event. – 3.8%
  • Airway issue. – 1.5%
  • Sudden unexpected event. – 1.0%

Unpacking the details, there are a handful of anticipated associations. Exanguination patients made up a much larger proportion of penetrating trauma patients. TBI proportion was actually only slightly higher in blunt trauma patients, but penetrating TBI was more likely to be deemed non-survivable on initial presentation. Almost half the deaths in penetrating trauma patients were in the Emergency Department – which also reflects a high proportion of pre-hospital arrest – followed by another quarter in the OR. Blunt trauma patients typically survived admission to the hospital. All patients for whom a pre-trauma medical event was determined to the causative factor were in the blunt trauma cohort, rather than penetrating.

There isn’t anything specifically prescriptive in this descriptive study, but it’s a building block for designing interventions in attempts to address the causes and timeframes of preventable death from trauma.

“The Why & How Our Trauma Patients Die: A Prospective Multi-center Western Trauma Association Study”
https://www.ncbi.nlm.nih.gov/pubmed/30633095

IDSA Influenza – Class A, Level III

The last time the IDSA updated their influenza practice guidelines, it was the time of the 2009 H1N1 influenza pandemic. Fittingly, we are entering another season of H1N1 – and we have new guidelines, incorporating all the new evidence gathered in the meantime.

And, unfortunately, that is to say: we don’t really have any new, high-quality evidence.

The grading system for their recommendations includes two categories. Strength of recommendation:

  • A: Good evidence to support a recommendation for or against use
  • B: Moderate evidence to support a recommendation for or against use
  • C: Poor evidence to support a recommendation

Quality of evidence:

  • I: Evidence from 1 or more properly randomized controlled trials
  • II: Evidence from 1 or more well-designed clinical trials, without randomization; from cohort or case-controlled analytic studies (preferably from >1 center); from multiple time-series; or from dramatic results from uncontrolled experiments
  • III: Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

It would follow, then, for an “A” strength recommendation, this ought to reflect I or II quality of evidence – but a bizarrely staggering number of their recommendations are A-III, effectively self-contradicting. Most of their “Which Patients Should Be Tested for Influenza?” recommendations are A-III. The critical “Which Patients With Suspected or Confirmed Influenza Should Be Treated With Antivirals?” section features another batch of A-III recommendations, followed by several C-I and C-IIIs.

A long story short, this is simply paradoxical, making level A recommendations from class III evidence in the form of manufacturer sponsored trials, indirectly-sponsored meta-analyses, and observational data. Many authors of this piece are neck deep in reported financial and professional conflicts of interest with industry, which almost certainly eases any pain felt by distributing such internally invalid recommendations. After decades of controversy and hundreds of millions of dollars in profit for Genetech/Roche, we’re still bumbling along with our original momentum lacking a full understanding of the effectiveness and value of these medications.

“Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza”
https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciy866/5251935

To COPD, or Not to COPD

This is yet another typically Canadian study, which is to say it’s Ian G. Stiell, et al, producing yet another high-quality risk-stratification profile for Emergency Department patients.

In this week’s episode, we find our heroes prospectively validating the Ottawa COPD Risk Scale (OCRS), a set of 10 criteria identifying COPD patients in the ED at highest-risk for short-term serious outcomes. Short-term serious outcomes, by their definition, was the occurrence of death, admission to a monitored unit, intubation, non-invasive ventilation, myocardial infarction, or hospital re-admission. Their target population was effectively patients with COPD who weren’t otherwise obviously ill, with a set of exclusion criteria for those who clearly necessitated admission on the index visit.

Within their 10 items, there are 16 points available to assign, and the expected risk of short-term outcomes ranged from 2.2% at a score of 0, up to 91.4% at a score of 10. Their validation, however, demonstrated potentially important differing results – with nearly two-fold greater risks for short-term poor outcomes in the lowest (and most common) strata. Then, at the high-end, there simply weren’t enough patients with scores >4 to come to any reliable consensus regarding the accuracy of the risk stratification. In fact, of the 65 patients with scores >4, the overall incidence of serious outcome was only 23% – while the expected risk from their derivation scale would probably be upwards of 40 or 50%. Their explanation: these higher-risk patients were all hospitalized at the index visit, thereby decreasing their expected rate of short-term serious outcome. This may, in fact, be true, but it is rather a hypothesis rather than a well-supported conclusion.

The other question, even assuming this tool is valid, is “what now?” The authors emphasize these data and risk levels are not necessarily prescriptive, but rather give the clinician an objective tool to supplement their decision-making. Will incorporating this tool this improve care delivery and outcomes? Unfortunately, it is impossible to tell. These authors have done the “easy” research, a data collection and number-crunching exercise. Determining its effect on clinical care is another, much harder step – and fraught with limitations due to generalizability from one practice setting to another. I would be wary of incorporating this into your clinical care until better data is available regarding its effect on patient-oriented and resource utilization outcomes – unless you’re ready to prospectively study it!

“Clinical validation of a risk scale for serious outcomes among patients with chronic obstructive pulmonary disease managed in the emergency department”

http://www.cmaj.ca/content/190/48/E1406

Who Are Buying Emergency Physicians?

It’s CMS Open Payments Database time again, updated for 2017. Sadly, it turns out you or at least one of your closest colleagues is a witting or unwitting puppet of the pharmaceutical industry: a full 35.4% of practicing U.S. emergency physicians received payments from industry last year.

The details:

  • The median payment was $18 – 90% of you just got lunch (or dinner)(or less).
  • Over 75% of emergency physicians in Mississippi were the recipient of some industry payment.
  • Ethicon Endo-Surgery and Janssen Pharmaceuticals were the largest of many contributors, and Xarelto, Eliquis, Activase, and Pradaxa were the most frequently cited products.
  • There were 35 EPs receiving industry sponsored research payments, primarily from device manufacturers – Covidien, Taro, and Zoll.

That said, these data also only scratch the surface of accountability, as about half of payments could not be associated with a product, and reporting to the OPD does not include other general grants and payments to organizations, rather than individuals.

And now you know, and knowing is half.

“Analysis of current financial relationships between emergency physicians and industry”
https://www.ajemjournal.com/article/S0735-6757(18)31001-5/abstract