Probability Adjusted D-Dimer for Pulmonary Embolism

The Gist: Kearon and colleagues found that the PEGeD strategy, which employs an elevated D-dimer threshold of 1000 ng/mL in patients with a Wells score of ≤4, resulted in less imaging than the standard approaching using Wells, age-adjusted D-Dimer with Wells, or the YEARS algorithm while  “missing” ≤2% of venous thromboembolic events (VTE) at 90 days [1]. This multi-center study indicates that this approach is likely safe in low-prevalence settings such as the US and Canada and could dramatically reduce the burden of imaging.

The background: Risk stratification is the first step in the evaluation of pulmonary embolism (PE) and this can be assessed using gestalt or a risk stratification tool such as the Pulmonary Embolism Rule Out Criteria (PERC), Wells Score, Revised Geneva Score, or the YEARS algorithm. In conjunction with the age-adjusted d-dimer, these are recommended in guidelines to reduce imaging in patients with suspected PE [2-4]. While provider gestalt yields similar estimates of the probability of PE, risk stratification tools have demonstrated benefit in improving imaging yield (and reducing unnecessary imaging) [5].

The problem: Unfortunately, the lack of specificity of the D-Dimer renders many patients who are low or intermediate risk requiring imaging. Literature has increasingly supported elevated D-Dimer thresholds in certain patients (such as those > 50 years old) and in pregnant patients [2-4, 6, 7]. However, studies have recently examined, with success, risk adjusting the D-dimer to use higher thresholds in low probability patients [8-10]. 

This study is an evaluation of a modified Wells + D-Dimer pathway, allowing for patients with a Wells score of ≤4 to have a D-dimer threshold of 1000 ng/mL. 

The study basics are depicted below.

This study found that VTE at 90 days, a surrogate for "missed PE" was very uncommon. This occurred in 0 patients with a D-Dimer <1000 ng/mL (double the typical threshold!). Two patients, both with low pretest probability and d-dimer >1000 ng/m, had VTE at 90 days. One patient, initially diagnosed with PE on imaging, was also diagnosed with a PE on day 77. This is obviously not a "miss" of the algorithm. Another patient, with active malignancy, was diagnosed with a DVT on day 4. 

Assuming the worst-case scenario, VTE at 90 days still occurred in <2% of patients. Unfortunately, 9 of the 1285 patients with a Wells ≤4 and D-Dimer <1000 ng/mL were lost to follow up. Assuming all of these patients had VTE (which is quite unlikely), 0.7% (95% CI 0.32,1.33) would have had VTE at 90 days with an exact binomial confidence interval below the test threshold of 2%. Treating ALL patients, including those who got imaging for PE who were lost to follow up, as having 90-day VTE, would result in 0.7% (95% CI 0.4,1.2) with VTE, again well within the safe testing margins.

MANY (253) patients were excluded because they received imaging despite a Wells  ≤ 4  and D-Dimer <1000 ng/mL.  It is interesting that these patients weren't handled as "protocol violation" and were simply excluded. There are several possible reasons patients received imaging despite their Wells score and low D-Dimer, including something about the patient's clinical course changed or, perhaps, providers just couldn't' help themselves.  Data were available for 127 of these patients (from 2 of the centers) who would otherwise have been eligible for the study, and only 2 had PE on imaging (D-Dimer 720 ng/mL and 650ng/mL), resulting in an overall event rate of 0.19% (95%CI 0.05,0.48%) not accounting for those lost to follow up. Assuming all patients lost to follow up had VTE at 90 days, 0.8% (95% CI 0.47,1.25) of patients would have VTE events, still below the 2% threshold. 

The outcome is quite conservative but is a proxy for "missed PE," which is likely lower. Throughout the PE literature, 90-day deep vein thrombosis (DVT) or PE has been used as a surrogate for missed PE. This is an overly conservative measure that attempts to account for not all patients receiving confirmatory testing (which would be unethical in low-risk patients). This is interesting, though, because this treats risk stratification, D-Dimer, and imaging as a fortune-telling test rather than markers of a disease process at point of time it is tested. Patients with risk factors necessitating testing, will continue to have these risk factors.

This study is also interesting because the "low risk" group in the Wells score is ≤ 4 and the intermediate group is 4.5-6 The Wells scoring systems are complex, with both dichotomous (≤ 4 as "Unlikely, > 4 as "Likely) and trichotomous (<2 as "Low", 2-6 as "Intermediate", or >6 as "High") scoring systems. The major appeal to this cut point is that a patient can still have "Alternative diagnosis less likely than PE," (3 points) and still be classified as "low risk" and have the <1000 ng/mL D-Dimer threshold. While overall 21% of patients in this study met this criterion, most of these patients were in the Wells >4 group and only 11% of patients in the "low risk group" met this criterion. The PEGed algorithm may perform less optimally in a cohort where more low risk patients satisfy this criterion; however, I suspect that this is indicative of the less conservative evaluation in Canada compared with the US (but this is strictly conjecture).

While this study has limitations, it is a multicentered trial in many centers in Canada, the findings are consistent with other findings suggesting the acceptability and safety of higher D-Dimer thresholds. These findings may not be generalizable to settings in Europe and Asia where PE prevalence is higher than the 7.4% in this study. However, in the United States where the prevalence of PE in those evaluated is less than in Canada, these findings likely apply. Additionally, the PEGeD approach is similar to the YEARS algorithm which has been studied in Europe and the United States with many D-Dimer assays.

No algorithm or test will result in 0% miss rate. Further, the harms caused by excess testing and treatment if the likelihood is <2% would outweigh the benefit (5-25% false positive rate of CTPA for PE, anticoagulation, harms from contrast, etc). Given the frequency of PE evaluation and the incremental benefit in reducing imaging, the potential to reduce imaging could be profound.

References:
1. Kearon C, De Wit K, Parpia S, et al. Diagnosis of Pulmonary Embolism with D-Dimer Adjusted to Clinical Probability. N Engl J Med 2019;381(22):2125–34. 
2. Raja AS, Greenberg JO, Qaseem A, Denberg TD, Fitterman N, Schuur JD. Evaluation of patients with suspected acute pulmonary embolism: Best practice advice from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med 2015;163(9):701–11.
3.Wolf SJ, Hahn SA, Nentwich LM, Raja AS, Silvers SM, Brown MD. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Suspected Acute Venous Thromboembolic Disease. Ann Emerg Med. 2018;71(5):e59–109. 
4. Fesmire FM, Brown MD, Espinosa JA, et al. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Ann Emerg Med.  2011;57(6):628-652.e75. 
5. Wang RC, Bent S, Weber E, Neilson J, Smith-Bindman R, Fahimi J. The Impact of Clinical Decision Rules on Computed Tomography Use and Yield for Pulmonary Embolism: A Systematic Review and Meta-analysis. Ann Emerg Med. 2016;67(6):693–701. 
6. van der Pol LM, Tromeur C, Bistervels IM, et al. Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism. N Engl J Med [Internet] 2019;380(12):1139–49. 
7. Kline JA, Williams GW, Hernandez-Nino J. D-Dimer concentrations in normal pregnancy: New diagnostic threshold are need. Clin Chem 2005;51(5):825–9. 
8. Kabrhel C, Van Hylckama Vlieg A, Muzikanski A, et al. Multicenter Evaluation of the YEARS Criteria in Emergency Department Patients Evaluated for Pulmonary Embolism. Acad Emerg Med [Internet] 2018;25(9):987–94. 
9. van der Hulle T, Cheung WY, Kooij S, et al. Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study. Lancet 2017;390(10091):289–97. 
10. Kline JA, Hogg MM, Courtney DM, Miller CD, Jones AE, Smithline HA. D-dimer threshold increase with pretest probability unlikely for pulmonary embolism to decrease unnecessary computerized tomographic pulmonary angiography. J Thromb Haemost. 2012;10(4):572-81.
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