It’s not very often I read an article and decide to I’d like to incorporate it into my practice. EMCrit covered this last month, but I reserved judgement until I had a chance to read the primary literature for myself.
This is the MOPETT trial – half-dose (?”safe dose”) tPA for “moderate” pulmonary embolism. We already know what to do for “massive” PE – full-dose thrombolytics when not otherwise contraindicated. However, the data for full-dose thrombolytics in “submassive” PE is less conclusive.
These authors enrolled relatively ill PE patients – tachypneic, hypoxic, tachycardic patients with >70% thrombotic occlusion of lobar or main pulmonary arteries – but did not apply regularly applied measures of “submassive” – RV dysfunction, elevated troponins, elevated BNP. Their primary outcome was long-term development of pulmonary hypertension, with mortality and bleeding as their secondary outcomes. They dosed tPA at 50mg, rather than 100mg – 10mg bolus and 40mg infusion.
Their two cohorts were rather well matched. Outcomes favored the thrombolysis group, with 16% subsequent pulmonary hypertension compared with 57% in the control group. Mortality, recurrent pulmonary embolism, and bleeding complications were similar and at rates too low to detect a difference given the power of the study.
I’d like to start doing this. I wish they published the troponin/BNP/RV dysfunction rates in the two cohorts to provide better context with the other submassive literature. I also would have preferred to see this study registered with clinicaltrials.gov. But, in a nice change, none of the authors declare any conflicts of interest!
“Moderate Pulmonary Embolism Treated With Thrombolysis (from the “MOPETT” Trial)”
Sadly, the jury is still out. Just months after Critical Care Medicine published the systematic review demonstrating an association between use of etomidate and mortality in sepsis, now they’re back with a retrospective data-mining expedition that draws the opposite conclusion.
This is a multi-center prospective registry of critically ill patients entered into a research database who were retrospectively data-mined for septic, intubated patients. Of the 42,000 patients in the database, approximately 2,000 met this definition, and about half were identified as receiving etomidate as their induction agent. In their cohort, there was no in-hospital mortality difference between the patients who received etomidate and the patients who received a different induction agent for intubation.
Unfortunately, as an observational, retrospective study of imperfectly matched cohorts, there are far too many uncontrolled confounders to base clinical practice on these findings. Studies such as these, even robust, prospective cohorts, are capable of doing little more than suggesting a hypothesis contrary to the findings of prior work.
If you believe etomidate has a chance to harm patients in sepsis, this doesn’t change your practice.
“Single-Dose Etomidate Is Not Associated With Increased Mortality in ICU Patients With Sepsis: Analysis of a Large Electronic ICU Database”
Mostly unrelated to Emergency Medicine – but an interesting descriptive study of a downstream phenomenon I see on a frequent basis.
For example, I’ll intermittently follow-up a patient to see how they fared as an inpatient. I’ll read the inpatient documentation, consultant reports, etc. – and find the tiny EM HPI perpetuated throughout the chart with minimal modification. This anecdotal experience is backed up by these authors who used text-compare software to identify copied passages in daily progress notes from an ICU setting. In this ICU at MetroHealth in Cleveland, 82% of resident notes copied at least >20% of the text from the previous days’ progress note – and copied 55% of the prior content on average. Attending notes were slightly less frequently copied (74%), but tended to copy more content (61%).
There’s no conclusive data regarding whether this copy/paste practice affects patient outcomes, but it’s an interesting symptom of evolving medical care and documentation in the EHR era. I hope that, as HIT evolves, documentation tools trend towards encouraging concise, effective communication, rather than this sort of (likely ineffective) chart bloat.
“Prevalence of Copied Information by Attendings and Residents in Critical Care Progress Notes”
If you’re still skeptical about the use of tPA in stroke patients – too bad. If you’re not on the bus, it would seem now you’re under it. ACEP has published their new Clinical Policy regarding tPA use in the most recent issue of Annals of Emergency Medicine. tPA should be offered to folks in the 0-3 hour window who meet NINDS criteria as a Level A recommendation. This is based on the following Class I evidence:
- Two studies that are negative for benefit (ECASS, ATLANTIS)
- The post-hoc analysis of ATLANTIS B with 61 patients,
The Level B recommendation is that tPA be considered for use off-label in the 3-4.5 hour window, based on ECASS III.
If you’ll travel backwards in time a couple days (by scrolling down), you’ll see I did a quick review of two articles concerning the “trustworthiness” of clinical practice guidelines. The Institute of Medicine names eight criteria – and, for the most part, this guideline does OK. It does, unfortunately, fare less well at the conflict of interests declared:
- Dr. Smith – Served on scientific advisory board for Genentech.
- Dr. Gronseth – Speakers’ bureau for, and honoraria from, Boehringer Ingelheim.
- Dr. Messe – Former speakers’ bureau for Boehringer Ingelheim.
Three out of eight guideline writers directly involved with the pharmaceutical manufacturer. As far as indirect support, however, if they wanted to be more transparent, Dr. Edlow, Dr. Jagoda, Dr. Stead, Dr. Wears, and Dr. Decker also ought to have disclosed their association with the Foundation for Education and Research in Neurologic Emergencies – supported by multitudinous pharmaceutical manufacturers, including Genentech.
If you’re irritated that pharmaceutical manufacturers are helping write our clinical guidelines, make your voice heard.
“Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department”
This short article from JAMA and corresponding study from Archives is concerned with advising practicing clinicians on how to identify which clinical guidelines are “trustworthy”. This is a problem – because most aren’t.
The JAMA article paraphrases the eight critical elements in the 2008 Institute of Medicine report required to generate a “trustworthy” article, such as systematic methodology, appropriate stakeholders, etc. Most prominently, however, several deal specifically with transparency, including this paraphrased bullet point:
- Conflicts of interest: Potential guideline development group members should declare conflicts. None, or at most a small minority, should have conflicts, including services from which a clinician derives a substantial proportion of income. The chair and co-chair should not have conflicts. Eliminate financial ties that create conflicts.
The Archives article cited by the JAMA article reviews over 100 published guidelines for compliance with the IOM. The worst performance, by far, was compliance with conflicts of interest, and notes that 71% of committee chairpersons and 90.5% of committee co-chairpersons declared COI – when declarations were explicitly stated at all. Overall, less than half of clinical guidelines met more than half of the IOM recommendations for “trustworthiness”.
Sadly, another dismal addition to the all-too-frequent narrative describing the rotten foundation of modern medical practice.
“How to Decide Whether a Clinical Practice Guideline Is Trustworthy”
“Failure of Clinical Practice Guidelines to Meet Institute of Medicine Standards”
Turns out – apparently, no!
Continuing the run on pulmonary embolism articles, we find that – in addition to all the things we know prognosticates increased mortality in PE patients – elevated plasma lactate levels also predict poor outcomes. This is generally unsurprising, because elevated lactate levels are associated with increased mortality, even in unselected ED patients. What is interesting, however, is that lactate levels >2 mmol/L were more associated with 30-day mortality than shock/hypotension, hypoxia, or right-ventricular dysfunction. It’s a small cohort, but it’s a reasonable finding, regardless.
However, what’s sort of odd regarding the Editor’s Summary for this article is that it specifically mentions the lactate level does not outperform a simplified pulmonary embolism severity index clinical tool. The “truth” is that an AUC of 0.84 is better than an AUC of 0.71 – but that (0.72 to 0.95) and (0.60 to 0.83) overlap. Rather than trash the lactic acid level compared with the PESI, it might have been more accurate to simply state the current study was underpowered to confirm the advantage of lactic acid over PESI, and further research is necessary.
Can you buy stock in lactate level assays? It’s clearly the new favorite all-purposes prognostication tool.
This study was featured in Academic Emergency Medicine as one of their CME articles – theoretically, an article with additional value presented with incentives to motivate a closer reading of the content. I don’t mean to imply this is somehow a bad article – but it’s just interesting to step back out of the tunnel vision of statistics and boggle at the inadequacy of the current state of medicine.
This is a prospective study of patients evaluated for pulmonary embolism attempting to evaluate how many patients were “inappropriately” scanned. This definition of “inappropriate” scanning was determined by patients who were either PERC negative or had low-risk Wells’ score followed by a negative d-Dimer. Overall, of 152 patients, 11.8% were ultimately diagnosed with PE. However, the authors state that application of the PERC rule might have eliminated 9.2% of these scans while Wells’/d-Dimer would have obviated 13.8%.
While I certainly don’t discount the beneficial effect of even small reductions in the number of individuals evaluated for pulmonary embolism, these are still terrible numbers. 90% of CT scans for PE are negative? And using these decision instruments gets us to ~75% negative scans? This would be comically wasteful performance and innovative performance improvement in any other industry.
We pretty clearly need to do better.
“Overuse of Computed Tomography Pulmonary Angiography in the Evaluation of Patients with Suspected Pulmonary Embolism in the Emergency Department”
There are still a few hold-outs on the 0 to 3 hour window, but most folks would agree that battle is lost – the best we can hope for is further clarifying the patients with the greatest likelihood of clinically significant benefit vs. those with the greatest level of potential harms.
But, greater than 3 hours is still a battlefield. This article in the January Annals uses the gloriously unbalanced ECASS III data for a cost-effectiveness analysis which, unsurprisingly, concludes in favor of tPA treatment. The problem is, of course, the assumption that ECASS III is infallible – a highly suspect position, considering the baseline differences between groups in ECASS III. Then, accounting for the the 1200 patients in IST-3 enrolled in the 3 to 4.5 window who did poorly with tPA, I’m guessing an updated meta-analysis wouldn’t look quite as favorable. But, I will give these authors a bit of a break, as this article was accepted for publication before IST-3 results were available.
Finally, in lieu of my usual rant, I’ll just copy and paste the disclosures portion of the article:
“This project was funded through a contract with Genentech, Inc. Drs. Boudreau and Veenstra and Mr. Guzauskas served as a consultant for Genentech, Inc. Ms. Villa is employed by Genentech, Inc. Dr. Fagan is a consultant for Genentech, Inc.”
“A Model of Cost-effectiveness of Tissue Plasminogen Activator in Patient Subgroups 3 to 4.5 Hours After Onset of Acute Ischemic Stroke”
This little letter, tucked away in the Correspondence section of Annals delves into the Pulmonary Embolism Rule-Out Criteria – a decision instrument of some controversy in Emergency Medicine. Specifically, this letter addresses a case report from a previous issue of Annals of, essentially, a large pulmonary embolus diagnosed in a young patient who was otherwise PERC negative.
The authors from Carolinas Medical Center have a registry of 1,880 PE+ patients with which to evaluation, and they performed a retrospective application of the PERC rule. Overall, 6% of this cohort was PE positive and PERC-negative. When compared with the patients with PE who were PERC-positive, there are a few statistically significant differences – pleuritic chest pain was more common in PERC-negative patients with PE, along with pregnancy or post-partum status. Unfortunately, these statistically significant relative differences reflect only small absolute differences of essentially clinically irrelevant magnitude. The only mildly interesting tidbit from the letter is the statistic that none of PERC-negative PEs died within 30 days, compared with 5.7% of the PERC-positive cohort.
The authors suggest a couple weak clinical implications from the data, but these are limited by the retrospective nature of the analysis. It is enough to remember that PERC-negative does not actually “rule-out” PE – it is simply a collection of negative likelihood ratios working against a pretest probability, resulting in clinical equipoise regarding the expect benefits vs. harms of CT pulmonary angiogram and the resultant harms of treatment in physiologically uninteresting PE.
“Clinical Features of Patients With Pulmonary Embolism and a Negative PERC Rule Result”
Just as relevant a year later, a quick re-post to the Cochrane Collaboration’s Tamiflu exposé:
“Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.”www.ncbi.nlm.nih.gov/pubmed/22258996
See what I wrote about it last year:
(spoiler alert: hardly worth the cost, at best; next to useless, more likely)