It was October 2016 when the authors of the now infamous PESIT trial carelessly tossed a symbolic wrench into the already-indecisive diagnostic workup of patients presenting to the ED following a syncopal event. (N Engl J Med 2016;375:1524; http://bit.ly/2Sxs2Hl.)
The study by Prandoni, et al., enrolled patients who were admitted to the hospital following a syncopal event and engaged in what can only be described as diagnostic insanity. The authors evaluated all patients for pulmonary embolism, risk-stratifying them and conducting serum screening using a D-dimer assay or radiographic imaging. This diagnostic pathway led to 17.3 percent of the cohort being diagnosed with a PE. If these results were true, it would mean the underlying epidemiology of syncope had swiftly and drastically changed or we have been missing an unacceptably high number of PEs.
A far more likely explanation for these authors' unbelievable results is that they are simply not to be believed. In truth, they represent the natural consequence of the empiric use of a D-dimer assay in an elderly population and the overdiagnosis that follows. Despite the PESIT results being an extreme outlier from all the previous data examining syncope and its underlying causes, there has been a dearth of high-quality evidence directly disputing PESIT's claims. A recent publication by Thiruganasambandamoorthy, et al., finally provided evidence directly contradicting the findings presented by the PESIT authors. (Ann Emerg Med 2019; Jan 25. doi: 10.1016/j.annemergmed.2018.12.005.)
The authors performed a secondary analysis of two large prospective cohorts and sought to quantify the proportion of patients presenting to the ED with syncope, in which a PE was ultimately found responsible for their transient loss of consciousness. The first was a large trial in 17 Canadian EDs that enrolled patients older than 16 presenting after a syncopal event. The second was an equally large study performed in multiple U.S. EDs enrolling patients over 60 who presented with syncope or a near-syncopal episode. The authors collected demographics, medical history, serological and radiological investigations for PE that occurred during the initial syncope presentation, and 30-day outcome data.
Looking Harder for PE
A total of 9091 patients were included in the final analysis of the 9374 who were enrolled over six years. Six percent of the entire cohort underwent investigations for pulmonary embolism, and only 56 patients (0.6%) had a PE as the cause of their syncopal event. Four deaths were attributed to PEs, and 52 patients (0.6%) died within 30 days due to an unknown cause.
These results fall in stark contrast to the 17.3 percent observed in the PESIT cohort. How do we reconcile these differences? It could be that we are comparing two different cohorts. Thiruganasambandamoorthy, et al., enrolled all patients who presented to the ED with syncope while the PESIT authors only enrolled patients who were being admitted to the hospital because of their syncopal event. Only 560 (21.7%) of the 2584 who presented with syncope in the PESIT cohort were enrolled in the study. Do the results of these two cohorts diverge from each other so drastically because they represent two very different patient populations?
Even if you examine the subset of patients in the Thiruganasambandamoorthy study who were admitted to the hospital (39.1% of the entire cohort) for their syncopal event, only 1.2 percent were diagnosed with a PE.
The PESIT cohort was an older population at higher risk of PE. Was this the reason for the contrasting rates of PE? The mean age was 76 in the PESIT cohort and 66 in the Thiruganasambandamoorthy cohort. But if you examined the subset of patients enrolled in the U.S. study where the enrollment criteria demanded patients be over 60, the mean age was 71. PE in this subset of patients was determined to be the cause of their initial presentation in 1.3 percent.
Clearly the differences in the rates of pulmonary embolism between these two cohorts are not simply due to patient selection. The most likely reason the PESIT authors found a much higher incidence of PE was simply because they looked harder. The questions are how much of this represents true clinically meaningful disease and how much is simply overdiagnosis? To make the claim that the large majority of the additional PEs identified in the PESIT cohort were clinically important disease, one has to assume that there would be clinical consequences for missing these diagnoses if the large majority of these PEs had gone unidentified, and in turn, untreated in Thiruganasambandamoorthy, et al. This is not the case.
Only six percent of the entire Thiruganasambandamoorthy cohort underwent testing for PE. And only 0.2 percent of the patients who did not undergo initial testing for PE in the ED and who were admitted to the hospital went on to be diagnosed with a PE as an inpatient. None of the patients who did not undergo testing for PE during their initial presentation was subsequently diagnosed with PE, and only 0.5 percent died due to an unknown cause within the 30-day follow-up period. One would have to imagine the clinical consequences of missing such diagnoses would be more apparent than what these authors observed if 17 percent of these patients were secretly concealing pulmonary emboli that went undiagnosed on their initial presentation.
Following the publication of the Thiruganasambandamoorthy study, it is apparent that the results of the PESIT trial were immensely inflated. The vast majority of the PEs diagnosed in the PESIT cohort fell into one of two categories: clinically important PEs that were identified because they presented with signs and symptoms consistent with PE or radiological diagnoses of no clinical import, simply the natural consequence of a diagnostic strategy that divorces itself from clinical reasoning.
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Dr. Spiegel is a clinical instructor in emergency medicine and a critical care fellow in the division of pulmonary and critical care medicine at the University of Maryland Medical Center. Visit his blog at http://emnerd.com, follow him on Twitter @emnerd_, and read his past articles at http://bit.ly/EMN-MythsinEM.Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.