The existence of overdiagnosis in the pursuit of pulmonary embolism (PE) is undeniable. But the burden of clinically insignificant PEs diagnosed by our current hypersensitive, zero-miss culture is less apparent. The authors of a recent article ironically entitled RESPECT-ED, attempted to quantify the role in which overdiagnosis plays in the current incidence of PE.
Recently published in PLOS One, Mountain et al conducted a retrospective analysis of 14 hospital’s radiology reports of CT pulmonary angiograms (CTPA) ordered from the Emergency Department (1). Using a standardized data entry form, the authors examined both the frequency of CTPAs that were obtained at these various sites and the yield of positive findings. They then compared this diagnostic efficiency between sites, as well as to a prespecified standard of 15.3%. The hypothesis was that sites with an increased use of CTPA, and a low yield were undergoing the diagnostic workup for pulmonary embolism more frequently and would subsequently identify an increased rate of clinically insignificant PEs. The authors defined a clinically meaningless clot burden as a subsegmental filling defect identified by CTPA. Small PEs were categorized as subsegmental or isolated segmental clots, while large PEs were defined as any clot in a lobar vessel or larger.
Fourteen sites provided data from 7077 radiographic studies. Most of the sites utilized modern scanners (64-slice or greater), except for one which was still using a 16-slice scanner. The overall yield was 14.1% (ranging from 9.3%-25.3%). Subsegmental clots made up only 8.8% of the total PEs diagnosed. The various sites reported rates ranging from 2.0%-15.8% of their total PE burden. Likewise, the rates of small PEs ranged from 10.8%-21.1%.
In comparison, large PEs made up 55.2% of the total number diagnosed on CTPA. Between the sites, the variability ranged from 38.8%-66.0%. Neither the yield nor the number of subsegmental PEs diagnosed were found to be correlated with overall CT usage. The authors did however note that with an increasing utilization of CTPA (defined as number of CTPAs performed/1000 ED attendees), the total number of PEs diagnosed increased linearly.
The authors conclude that:
Higher CTPA utilization was positively correlated with PE diagnoses, but without evidence of increased proportions of small PE. This suggests that increased diagnoses seem to be of clinically relevant sized PE.
The major assumption of course with such a conclusion is that size alone determines the clinical importance of a PEs. And while larger clots are more likely to have clinically meaningful hemodynamic consequences, mere clot burden alone does not define clinical outcomes (2).
Den Exter et al examined 3769 patients from two prospective studies in an attempt to quantify the clinical relevance of anatomically defining clot burden in venothromboembolic disease (3). The authors compared patients with subsegmental clots, patients with either segmental or more proximal clots, and patients who were ruled out for pulmonary embolism using either a D-dimer or CTPA. The primary endpoint was the incidence of symptomatic (recurrent) VTE, major bleeding complications, and all-cause mortality during the 3-month follow-up period.
A total of 789 (21%) were diagnosed with a pulmonary embolism on CTPA. 41 patients were excluded from further analysis because the location of the PE could not be determined. Of the remaining 748 patients, 116 (15.5%) were diagnosed with a subsegmental PE and 632 had segmental or larger clot burdens. During the 3-month follow-up period, symptomatic recurrent VTE occurred in 4 patients with SSPE and in 14 patients with the more proximal PEs. The 3-month risk for recurrent VTE was 3.6% and 2.5%, respectively. When the authors controlled for confounding variables these risk burdens were unchanged. Additionally, 12 (10.3%) patients with SSPE and 40 (6.3%) patients with segmental or central PE died during follow-up. The cumulative mortality risks were 10.7% and 6.5%, respectively. The 3-month mortality in the patients who were originally ruled out for PE was shockingly high at 5.2%. The risk factors for death in all groups were malignancy, male gender, age, COPD, and heart failure.
If we are to believe the conclusions drawn by the authors of the RESPECT-ED data set than we would have to conclude that we are justified in our overzealous imaging practices in the hopes of identifying every PE. But these conclusions are likely erroneous. The rate of patients undergoing a workup for PE has skyrocketed over the past two decades. Unsurprisingly, the number of PEs diagnosed over that period has risen concordantly. With this we have seen a decrease in the case fatality rate while the overall mortality has risen only slightly (4). This does not definitively point to overdiagnosis, but rather is strongly suggestive of its existence. Similar to a black hole, the direct measurement of overdiagnosis is near impossible, and we can only garner evidence of its existence through examining the gravitational influences on surrounding celestial bodies.
The RESPECT-ED data set is not wrong. Rather our understanding of the clinical importance of anatomic disease burden is incomplete. Such analyses do not account for the physiologic turmoil surrounding the emboli. Without an understanding of the patients who experiences these embolic injuries, it is impossible to assign any clinical weight to their existence. And so the best that can be said from RESPECT-ED is the more PEs one endeavors to find the more one will be rewarded with anatomically definable disease. The clinical relevance of these findings is still unclear.
- Mountain D, Keijzers G, Chu K, et al. RESPECT-ED: Rates of Pulmonary Emboli (PE) and Sub-Segmental PE with Modern Computed Tomographic Pulmonary Angiograms in Emergency Departments: A Multi-Center Observational Study Finds Significant Yield Variation, Uncorrelated with Use or Small PE Rates. PLoS ONE. 2016;11(12):e0166483.
- Vedovati MC, Germini F, Agnelli G, Becattini C. Prognostic role of embolic burden assessed at computed tomography angiography in patients with acute pulmonary embolism: systematic review and meta-analysis. J Thromb Haemost. 2013;11(12):2092-102.
- Den exter PL, Van es J, Klok FA, et al. Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism. Blood. 2013;122(7):1144-9.
- Tapson VF. Acute pulmonary embolism: comment on “time trends in pulmonary embolism in the United States”. Arch Intern Med. 2011;171(9):837-9.