It is quite uncommon that while reading the results of a clinical trial one feels the universal gasp of sorrow released from the hearts and minds of Emergency Physicians worldwide. Maybe it was my own personal anguish at the realization of the disastrous consequences the results of a recent trial published in the NEJM will have on the practice of Emergency Medicine, but I am almost certain it was a unique moment of shared consciousness. In fact, with the release of the Pulmonary Embolism in Syncope Italian Trial (PESIT) examining the prevalence of pulmonary embolism in patients admitted to the hospital with syncope, the global wince of practicing Emergency Physicians was almost palpable (1).
Prandoni et al examined 560 patients presenting to 11 hospitals in Italy admitted after an initial syncopal episode regardless of the suspected cause of the event. All 560 patients underwent a protocolized assessment for pulmonary embolism, including risk stratification via the Well’s score, a D-dimer when appropriate, and either a CTPA or V/Q scan in high-risk patients and those with a positive D-dimer assay.
The authors reported that of the 560 patients prospectively enrolled, 97 (17.3%) were found to have a pulmonary embolism. Now these results, if true, are practice changing. In fact, the NEJM’s twitter quote read “1 in 6 patients with syncope (+) for PE after ER presentation”. 1 in 6 is an impressive and terrifying figure. But these results are so discordant from what we all observe in day-to-day clinical practice, that they fly in the face of our communal experience.
The most obvious concern is whether these pulmonary emboli identified on CT and V/Q scan were responsible for the patients’ syncopal events, or were just unfortunate incidental bystanders. Previous data has consistently demonstrated the majority of patients admitted to the hospital for syncope do not undergo evaluation for pulmonary embolism and do well. In these cohorts, patients were not subjected to universal screenings for pulmonary embolism, and experienced minimal adverse events (2,3). The few that experienced adverse events were typically not due to pulmonary emboli. Does this mean we are missing pulmonary embolism in 17% of the patients we admit to the hospital for syncope? Likely, no. The PESIT results are in a large part likely due to over-diagnosis. I think even the authors of this manuscript realize this potential source of bias, as the entire supplemental appendix which supports this manuscript is full of radiographic proof of the cohorts’ clot burden, as if such evidence will convince us of the clinical importance of these anatomic findings. But radiographic filling defects do not directly translate into clinical pathology. In fact, in the accuracy defining study, PIOPED-2, in low risk patients who underwent CT-imaging for pulmonary embolism, almost half of the positive CTPAs were deemed to be false positive findings (4).
But over-diagnosis aside, let us for a moment suppose these results actually represent clinically important pulmonary emboli. This still does not justify a global diagnostic strategy to identify an embolic cause of syncope in every patients presenting to the Emergency Department. Unfortunately, it is impossible to discern from the published manuscript, but it seems the patients who presented with syncope due to a true physiologically relevant pulmonary embolism are clinically distinguishable from those without an embolic etiology. The patients in the PESIT trial with pulmonary embolisms found on radiographic imaging had significantly more episodes of tachycardia, tachypnea, hypotension, obvious signs of lower extremity DVT, and more often presented with cancer than the patients with a negative workup for pulmonary embolism.
Furthermore, it is important to note, this is not a cohort of 97 pulmonary embolisms in 560 patients as it will inevitably be portrayed. Rather this was 97 (3.8%) radiographic pulmonary embolisms in 2584 patients presenting to the Emergency Medicine for a syncopal event. Only the patients admitted to the hospital after an Emergency Department workup for syncope were enrolled into the PESIT cohort. The majority of patients presenting to the Emergency Department were discharged home without further workup. This means 1 in 26 patients presenting to the Emergency Department will have a pulmonary embolism found on imaging. The large majority of these will be incidental findings and the remainder will be clinically obvious.
There are times when our clinical experience is misleading. When empiric evidence should call into question our long standing practice patterns. But there are times when the evidence is in such conflict with our shared experience, there is nothing to be done but to questions its validity. There is no doubt that these results will be misinterpreted over the next few days, weeks and years. We will now be tasked with performing invasive diagnostic workups in patients with no clinical signs or symptoms of pulmonary embolisms. Any Emergency Physician will tell you not to order a CTPA on a patient in whom you do not wish to know the results. Likewise, do not order a D-dimer in a patient who you have no intention of acquiring further imaging. Prandoni et al have perpetrated the systematic equivalent of this diagnostic absurdity. To translate these results into meaning that all patients presenting to the Emergency Department after a syncopal event require a work-up for pulmonary embolism is not only statistical hoodwinkery, but is just bad medicine. These patients will be exposed to needless and harmful downstream workups, radiation and anticoagulation. We have chased the ghost of Pulmonary Embolism far beyond the reaches of good clinical practice. And this quixotic quest has left a path of over-diagnosis and unnecessary treatments in its wake. At some point someone has to stop this madness. I offer that time is here and now.
Sources Cited:
- Prandoni, Paolo et al. Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope. New England Journal of Medicine,375,16;1524-1531 2016
- Quinn J, Mcdermott D, Stiell I, Kohn M, Wells G. Prospective validation of the San Francisco Syncope Rule to predict patients with serious outcomes. Ann Emerg Med. 2006;47(5):448-54.
- Birnbaum A, Esses D, Bijur P, Wollowitz A, Gallagher EJ. Failure to validate the San Francisco Syncope Rule in an independent emergency department population. Ann Emerg Med. 2008;52(2):151-9.
- Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med. 2006;354(22):2317-27.
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I too was surprised by the apparently high rate of PE in these patients admitted for syncope. As someone who agrees we search for too many PEs, I am not sure what to do with this result. However, as I’ve said elsewhere, this 3.8% number is a lie. Since the patients discharged were not systematically screened for PE, we have no idea of their rate. It may be closer to the usually background risk or it may be closer to the high rate observed in their inpatients. It is very unlikely zero, which is what you are implying when you… Read more »
Hey Jordan,
Thank you for writing. Completely agree. I don’t think we have a true grasp the rate of PE in patients presenting with syncope. Nor do we truly understand how to discern which are clinically important emboli and which are over-diagnosis. The best I can say is patients with syncope and a clinical presentation concerning for syncope should have a work up for syncope. But universal screening in all patients admit for syncope will be a disaster.
Notable what the study was missing was a control group of healthy individuals and a true patient centered outcome such as mortality. Perhaps our testing is becoming too sensitive and there is a “physiologic” amount of pulmonary embolism that we have yet to learn about. Similarly, up to 50% of nursing home residents can have a bacteriuria but certainly not all have UTIs which require antibiotics. Overtesting causes real harm. To look at these results another way – If you look for PE chances are you will find it but should you?
Your fist sentence could but be more true. As I read the abstract my wife asked me,”what’s wrong?” As I had apparently groaned something that may have rhymed with an expletive.
Interested to know your thoughts on biological plausibility of small PE causing syncope. If we are expectd to believe that the PE was the cause of the syncope – what’s the mechanism for a very small PE to cause an interruption to cardiac output that is sustained long enough to cause collapse.
http://stemlynsblog.org/prevalence-of-pe-in-patients-with-syncope-st-emlyns/
S
40% of the PEs were pretty large. And we have no idea of the moment-to-moment natural history of PEs; perhaps they are more dynamic than we assume. I do seem to remember textbooks claiming syncope can be a presentation of PE…
Brilliant stuff Rory.
This reminds me a bit of the background rate of PE in ICU patients. Depending on your case mix, the incidence of unsuspected PE in the ICU may be roughly 15%. But that doesn’t mean that randomly scanning ICU patients is a smart idea.
My question would be: how likely is it to miss a clinically significant PE despite a thoughtful H&P, EKG, and clinician echocardiography?
Thanks Josh!! I don’t think we no for sure but my personal opinion and the SF syncope rule data would support, not very often. Certainly testing everyone on the rare occasion you will detect a clinically important clot that is not picked up on history and physical exam is not worth the statistical noise gained by this small increase in sensitivity. I think this boils down to what we do as Emergency Physicians. So much of it is looking at a patients and getting a gestalt of how sick they really are. Its hard to quantify this but there is… Read more »
I appreciate the time and effort put into the post. That said, I strongly disagree. First, methodologically, this is a well done study. Inclusion and exclusion are reasonable, the coordination of standardized protocols in 11 different hospitals is impressive, and the primary outcome – clearly stated – prevalence of PE in admitted syncope patients – is straightforward and derived without the use of complicated statistics. As a fellow researcher, I respect the years it took to design, implement and publish this study – there is a reason it is published in NEJM. Second, the numbers are not a “lie”. For… Read more »
No need to apologize, and thank you for the wonderful response. These post are met to stimulate discussion, not suppress it. Your thoughts are well taken. I think the FOAM community has been so vocal on this article because the major message this study is promoting is that all patients admitted to the hospital for syncope require a workup for PE independent of their clinical appearance. Like you said elderly patients, with abnormal vital signs and cancer are at high risk for having a pulmonary embolism. But these patients will be clinically apparent. To take this cohort and state all… Read more »
Hi Bill and Rory, I haven’t seem the design of the study criticised that much to be honest. I think it’s been methodologically constructed well, and the approach to diagnosis is reasonable, pragmatic and achievable. In fact the study is not the issue at all really, it’s what we do with the results and that is where we are seeing all sorts of claims knocked about both for and against the study findings. Articles with headlines such as 1:6 patients with syncope have a PE are just as misleading to ED docs. Similarly, ignoring these results completely would be just… Read more »
I truly value going through your thinking. Although the study is far from perfect, I think it just raised an important yellow flag in syncopal patients : have I really considered PE for this case ? What are his risk factors? Is he a little tachypneic? How looks his EKG and FAST echo? This study won’t help in the prognosis and outcomes of treatment… but I feel it is also too early to dismiss. I also note that once again, prodromal symptoms are useless to discriminate. Thank you for allowing us to question our practices, Frédéric Picotte, MDCM HCM, Shawinigan,… Read more »
Clearly these patients weren’t THAT clinically apparent since they were admitted without the diagnosis of PE beeing made.. I know, I admitted at least some of them as an Emergency Physician in one of the main contributory hospital of this paper (although I’m in no way related to the study).
I think that the paper itself raise some important questions, just not for the EPs community but for the internal medicine one. Don’t discount PEs in your admitted syncope patients…
Appreciate the replies – these are the type of thoughtful analyses that furthers our understanding beyond the news cycle / initial reaction. I agree our clinical gestalt is paramount – indiscriminate test ordering wastes time, resources and is poor patient care. Further, the data presented does suggest that the majority of patients had a clinical sign – the old residency mnemonic ” syncope +” holds true- in this case, tachycardia, hypotension, tachypnea, signs of DVT, etc. Further cofactor analysis, including symptoms, past history, labs including cardiac biomarkers, would help ED providers like myself better understand the prevalence of PE in… Read more »
As the headline from this article now seems to be “1-in-6 patients with syncope have a PE”, and the gut reaction from clinicians now seems to be something along the lines of “my gosh, my numbers are nowhere near that, I must be missing a buck load of PE:s”. This could very well result in a knee-jerk reaction to say use a routine D-Dimer assay in the ER for patients presenting with syncope, which is something I think Rory fears with the increased number of false positives and increased radiation burden on the population. While this study looks quite impressive… Read more »
Thank you for your comment, Dr Magagnotti. I was also curious about the patients admitted without a primary diagnosis. In the Italian model of Emergency Medicine, would it be usual to do a very thorough work-up in the ED, or, is it more usual to refer to inpatient units, once it is apparent that an admission is required for physiological reasons?
I think the response is partly related to the patient we are talking about. These were very old, mostly high comorbidity pts; I would personally be more reluctant to ask for a D-dimer than with younger, more fit folks. As for the general model of Italian EDs, it is expected that the primary diagnosis be made before admission.
If you have a big enough PE to give you syncope, I suggest you would probably not spontaneously wake up again. Sometimes common sense helps.
Are you suggesting that PE cannot be a cause of syncope at all? That doesn’t seem like common sense to me. Many physiologic processes are dynamic. We know very little about the moment to moment behavior of PEs. Why could a person not have a saddle embolus that causes severe hypotension, then breaks up and partially lyses resulting in normalization of vitals prior to presentation?
It seems like this implies that PE cannot be a cause of syncope. I don’t think that’s common sense, and in fact it contradicts most teaching on the subject. We know very little about the moment to moment behavior of PEs. It seems quite possible that one could have a saddle embolus resulting in severe hypotension and syncope, but then breaks up and partially lyses, with normalization of vitals.
Hi Rory, I am not a medical professional, so I realize that I’m not the audience you’re going for here. However, I am a bit of a literary critic, and I really enjoy your analysis and your writing style As a huge Poe fan, I also love your titles. I recently became fascinated with the FOAMed community, and you’re by far my favorite contributor that I’ve found so far. Would you mind if I shared some of your posts to my company Twitter page? I think that my clients would really enjoy your content. Thanks for a fun and informative… Read more »
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I don’t think there is anything terribly wrong with the study design or the finding that 1 in 6 has PE. The problem is the potential fearmongering that every uncomplicated syncope with no clinical evidence of PE needs D dimer or CTPA. Those people included in the study do have those clinical signs (no matter how subtle) and in the end if symptoms persist and you cannot find other causes working up for PE (whether it is clinically relevant or actually do explain their symptoms) is not entirely unreasonable. After all, those patients are admitted to hospital for a reason… Read more »