Month: April 2019

The CT and Syncope

The Choosing Wisely Campaign lists non-contrast CT of the head as one of their low-value procedures for low-risk patients presenting with syncope. However, despite these recommendations, these authors voice concerns up to two-thirds of patients still undergo advanced imaging.

In this systematic review looking at both practice patterns and yield, the authors identify 17 studies of both hospitalized and Emergency Department patients addressing this topic. Pooling together 1,669 ED patients, 55% underwent CT with a yield of 3.8%. Pooling 1,289 hospitalized patients, CTs were performed 45% of the time with a yield of 1.2%. Considering the general morbidity and mortality associated with intracranial conditions, these are not fantastic yield numbers, but are not entirely unreasonable.

There is a bit of trouble with these numbers, however: even though their systematic review went up to 2017, most of the included studies were published before 2011. Even their citation of “two-thirds receiving head CTs” was published in 2009, well before the 2014 Choosing Wisely statement. Then, the bulk of the included studies were retrospective, blurring the reliability of their inclusion and outcomes measurement.

I think these data probably effectively illustrate the rarity of serious outcomes in syncope, but provide little insight into the current scope of the problem with respect to overuse. An intracranial process or intracranial injury associated with syncope ought to be considered in each case, but better data describing features predictive of underlying intracranial injury is needed to better separate high-risk from low-risk.

“The Yield of Computed Tomography of the Head Among Patients Presenting With Syncope: A Systematic Review”
https://www.ncbi.nlm.nih.gov/pubmed/31006937

Add Clopidogrel to Aspirin, Temporarily

In the Emergency Department, we’re not necessarily spending a lot of our time sending home patients with minor stroke or high-risk transient ischemic attack – or, even if we are, we’re usually not doing it independently. That said, our scope of practice always seems to be expanding, observation units are frequently run by emergency physicians, and hospitals are looking to take advantage of opportunities to discharge patients rather than admit.

Regardless, this is a meta-analysis supporting the findings of CHANCE, looking specifically at the short-term use of aspirin and clopidogrel after a minor stroke or high-risk TIA. CHANCE enrolled 5,170 patients, while this meta-analysis effectively combines these with POINT, while also tossing in the patients from FASTER.

The main takeaway here is the combination of the evidence from the long-term treatment observing it was effectively a wash between stroke prevention and bleeding complications, and the observation that stroke risk was highest immediately following the index event. A reasonable interpretation, as highlighted by the guidelines, is to use dual-antiplatelet therapy short-term after the index event. The evidence does not specifically describe the optimal duration, but anywhere between 10 and 21 days seems reasonable.

Just wanted to toss this one out there with a little more prominence, as this isn’t particularly new, but I also wouldn’t want it to be overlooked.

“Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high risk transient ischaemic attack: systematic review and meta-analysis”
https://www.bmj.com/content/363/bmj.k5108

“Guideline: Starting dual antiplatelet therapy ≤ 24 h after high-risk TIA or minor ischemic stroke is recommended.”
https://www.ncbi.nlm.nih.gov/pubmed/30986828

Levetiracetam vs. Phenytoin

The epic, classic showdown from time immemorial: new vs. old.

But, more specifically, these are two trials set to determine relative utility of each in pediatric seizures, vying for the coveted “second-line” therapy recommendation once benzodiazepines have failed. The thought and hope is, of course, the newer agent – levetiracetam – is at least as efficatious, if not moreso, as it can be infused more quickly. The authors then propose levetiracetam is associated with fewer long-term adverse effects and medication interactions during oral maintenance, and, as such, allows for convenient continuation after intravenous initiation.

Generally speaking, these two trials are very similar – both open-label trials randomizing pediatric patients with ongoing seizures, both analyzing about 250 patients … and both demonstrating effectively similar results by different routes. EcLiPSE, interestingly, was designed as a superiority trial, with a primary outcome of time from randomization to seizure cessation. Median time to seizure cessation not statistically different at 35 minutes for fosphenytoin and 45 minutes for levetiracetam, with similar numbers of treatment failures for additional anticonvulsants or intubation. In ConSEPT, the primary outcome was cessation of seizure activity within 5 minutes of the end of the infusion, and here results favored phenytoin at 60% versus 50% for levetiracetam.

Effectively, however, the sample sizes are small enough, the types of patients heterogenous enough, and the differences small enough, the Bayesian interpretation is probably a wash. These are both fine second-line options, but these trials do not provide any data supporting levetiracetam as a superior option.

“Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30724-X/fulltext

“Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30722-6/fulltext

Back Pain is a Pain

The authors’ bottom line:

“Adding baclofen, metaxalone, or tizanidine to ibuprofen does not appear to improve functioning or pain any more than placebo plus ibuprofen by 1 week after an ED visit for acute low back pain.”

There were 320 patients with atraumatic back pain randomized to one of four arms in a 1:1:1:1 manner at two urban Emergency Departments, with follow-up one week later. As noted above, the differences in improvement on the Roland-Morris Disability Questionnaire were similarly scattershot across groups. The waterfall graph probably shows this best:

Notes:

  • The prescribed dose of ibuprofen was only 600mg every eight hours. I’m more a 500mg naproxen twice daily sort of guy, but this wouldn’t necessarily obscure differences between groups.
  • Half of patients continued to complain of back pain at seven days, including a third for whom it was moderate or severe.
  • Adverse events were rare in all groups.

Pretty dismal and disappointing, as so many of our patients in the ED are coming in because they’re already taking some over-the-counter analgesic without perceived relief. There is clearly an unmet need for something to fill the void, hence our attempted use of all these unproven adjuncts. Unfortunately, these folks are stuck – it’s going to be 2-3 days until they will be able to return to their usual activities, if not more, and none of these are adding any value.

“A Randomized, Placebo-Controlled Trial of Ibuprofen Plus Metaxalone, Tizanidine, or Baclofen for Acute Low Back Pain”

https://www.ncbi.nlm.nih.gov/pubmed/30955985

A Brief BRUE Follow-Up

The “apparent life-threatening event” has long since been replaced by the “brief resolved unexplained event – an event occurring in an infant <1 year of age with:

  • Cyanosis or pallor
  • Absent, decreased or irregular breathing
  • Marked changes in tone
  • Altered level of responsiveness.

This is just a brief, single-center, retrospective chart review identifying children hospitalized for BRUE and their outcomes up to 5 years. These authors identified 120 hospitalized infants under one year of age meeting criteria for BRUE, and performed telephone follow-up at least 6 months after the event. Most children hospitalized were less than 1 month of age, and about half were hospitalized for apnea or breathing issues. Of the 87 they were able to contact, none had died or developed chronic medical illness, 71 had developed normally, and the remainder developed either a global or verbal developmental delay.

This is a small sample, to be sure, but these data suggest children hospitalized for BRUE are not specifically at risk for long-term poor neurologic or cardiac outcomes above the baseline population level.

“Long-Term Follow-Up of Infants After a Brief Resolved Unexplained Event–Related Hospitalization”

https://www.ncbi.nlm.nih.gov/pubmed/30951030

A (Mostly) Unnecessary Antivenin

We’re something of experts in spider bites in the Emergency Department. Black widow-type spider bites, however, are a little more exceptionally interesting than the average patient encounter. Latrodectism is usually nonfatal and easily managed with conservative treatment in the ED, although an immunoglobulin-based antivenom exists. Adverse effects from this antivenom are likely high-risk than any symptomatic benefit.

Now, a new antibody-fragment antivenom is vying for space on your formulary. In this study, 64 patients with clinical lactrodecism and significant baseline pain were randomized to either up to two doses of antivenin thirty minutes apart, or matching saline placebo. The primary outcome was “treatment failure”, a composite endpoint of failure to sufficiently decrease pain on the VAS scale, provision of a prescription analgesic, or a dose of the currently available antivenin.

Overall, the intervention met their predefined primary outcome – although, interestingly, half the antivenin cohort still had “treatment failure”. Then, almost a quarter of patients in the placebo cohort achieved full recovery. This remaining sliver of patients represents the measured effect size of the intervention – but the question remains the value and clinical relevance of their composite outcome. Mortality from lactrodectism is vanishingly low, and this intervention is not touted as being protective. Then, if the concern voiced by the authors is of short-term morbidity and ED recidivism in those whose pain is not adequately controlled without antivenom, then their primary, or at least a secondary outcome, ought to address this. Finally, the sample size is too small to draw any conclusion regarding safety.

This will undoubtedly be expensive and may likely expire in your hospital pharmacy prior to use. This trial gives us a small amount of information regarding its utility, but there’s little clear value demonstrated here.

“The Efficacy of Antivenin Latrodectus (Black Widow) Equine Immune F(abʹ)2 Versus Placebo in the Treatment of Latrodectism: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial”

https://www.sciencedirect.com/science/article/pii/S019606441930109X

More Cardiac Stress Test Futility

Once upon a time, it was believed important to perform cardiac stress testing in patients with chest pain and potential acute coronary syndrome. Intuitively, this makes little sense – a stress test may identify obstructive coronary disease, but this is rarely the culprit for acute coronary syndrome, and certainly only rarely the cause of chest symptoms in a patient at low-risk for coronary artery disease. Unfortunately, the American College of Cardiology/American Heart Association have had a nonsensical recommendation for noninvasive testing within 72 hours of an index visit on the books for quite some time – leading, to put it mildly, to a test or two.

This observational data set evaluates the outcomes of patients in the Kaiser Southern California system who were referred for outpatient stress testing following an encounter in the Emergency Department. They tracked 7,988 patients for a month after their ED encounter, 2,497 of whom underwent stress testing within 3 days, 4,695 within 4 to 30 days, and 796 who never showed up for their referred testing. Most stress tests were exercise or pharmacologic stress ECG, with the minority stress echocardiograms or myocardial perfusion imaging.

Patients undergoing testing were not devoid of risk factors: an average age of 55 years, most were overweight, and over half had at least one risk factor for coronary artery disease. Within 30 days, fewer than 1% were diagnosed with an acute MI, and a handful of those underwent PCI or CABG. There were tiny differences between groups, as none of the patients who skipped their stress test underwent subsequent revascularization. There were no deaths in any cohort.

The narrow view here in this article is there is no apparent benefit to undergoing stress testing within 72 hours as compared with a longer timeframe. The wider view is yet another piece of information showing the general disutility of stress testing. These are not randomized cohorts, nor is 30-days a long enough window to detect any potential benefits to the stress test – as measured by decreased morbidity or mortality as relating to a timelier PCI or CABG. However, even these interventions were rare enough the effect size from any benefit is bound to be so small as to represent low-value care. It is absolutely reasonable to suggest the Bayesian pendulum for the valuation of stress testing is swinging the other direction – and those who advocate for stress tests ought to generate data to support its targeted use, rather than for the opposition to generate data contrary to its assumed routine utility.

“Evaluation of Outpatient Cardiac Stress Testing After Emergency Department Encounters for Suspected Acute Coronary Syndrome”

https://www.sciencedirect.com/science/article/pii/S019606441930054X

Any Troponin is Bad Troponin – Gender-Specific Edition

High-sensitivity troponins mean a lower limit of detection. Picking up these lower quantitative values for circulating troponin – and new reference limits for the 99th percentile of normal – has required an adjustment in perspective with respect towards making the diagnosis of acute coronary syndrome. Now, the question with these more sensitive assays becomes: should we adjust our clinical considerations to incorporate sex-specific reference intervals?

This brief analysis from the UTROPIA study looks specifically at the downstream MACE in patients whose serial troponin measurements fall between the limit of detection and the sex-specific 99th percentile intervals. For this Abbott assay, that means 34 ng/L for men and 16 ng/L for women. In their 180-day follow-up period, they found the incidence of major adverse cardiac events was vanishingly small for those with undetectable levels of circulating troponin. However, those with any circulating troponin – even below the 99th percentile reference interval – were vastly more likely to experience an event within the next 180 days, reaching about 10% incidence of MACE. Importantly, however, the distributions of probability for downstream MACE were similar with regard to the measured value with respect to the sex-specific 99th percentile.

This confirms some of what we already knew: any troponin is bad troponin, even if it’s lower than the 99th percentile. Then, this also validates sex-specific 99th percentiles, as percentile levels conveyed similar risk between men and women.

Just another insight into the next level of sophistication for use of these assays in assessing patients with potential ACS, and for downstream anatomic assessment and preventive interventions.

“Clinical Features and Outcomes of Emergency Department Patients With High- Sensitivity Cardiac Troponin I Concentrations Within Sex-Specific Reference Intervals”

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.038284