Broader definition using clinical probability and D-dimer identifies more subjects with low PE risk

Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability

Literature - Kearon C, de Wit K, Parpia S, et al. - N Engl J Med 2019;381:2125-34. DOI: 10.1056/NEJMoa1909159

Introduction and methods

Chest imaging with computed tomographic pulmonary angiography to diagnose pulmonary embolism (PE) has disadvantages, such as radiation exposure, contrast reactions, high costs, and can be time-consuming and should therefore be avoided when possible. A method to rule out PE includes assessment of clinical pretest probability (C-PTP) [1-3] and measurement of D-dimer levels. Blood D-dimer levels correlate with the probability of patients’ risk of having pulmonary embolism [4,5], and use of a threshold level of 500 ng/mL gives a high negative predictive value.

It has been established that PE can be ruled out in patients with a low C-PTP and D-dimer level<500 ng/mL [1-3,6,7], but this occurs in only 30% of outpatients. To possibly increase this number, two definitions were used to rule out PE: a D-dimer level <1000 ng/mL in patients with low C-PTP and a D-dimer <500 ng/mL in patients with a moderate C-PTP.

In the Pulmonary Embolism Graduated D-dimer (PEGeD) study, the strategy consisting of two definitions was used to rule out PE. Outpatients with symptoms or signs suggestive of PE were eligible for this prospective management study. Exclusion criteria included anticoagulant therapy for 24 hrs, major surgery within 21 days, known D-dimer level before C-PTP assessment, undergoing chest imaging, ongoing need for anticoagulant therapy. C-PTP was determined by seven item Wells prediction rule and categorized as low (Wells score 0-4.0), moderate (4.5-6.0), or high (≥6.5). D-dimer was measured in patients with a low or moderate C-PTP. The PEGeD algorithm was as follows: patients with low C-PTP and D-dimer<1000 ng/mL or with moderate C-PTP and D-dimer <500 ng/mL had no further testing for PE and did not receive anticoagulant therapy. All other patients underwent chest imaging and received anticoagulant therapy in case of PE. Study outcomes were assessed at 90 days after first diagnostic testing. Primary outcome was symptomatic venous thromboembolism (VT), including PE or deep-vein thrombosis. 2017 Patients were included from Dec 2015 and May 2018.

Main results

  • 86.9% had a low C-PTP, 10.8% a moderate C-PTP, and 2.3% had a high C-PTP.
  • Of 1970 patients who had low (1285) or moderate (40) C-PTP, 1325 (67.3%) had a negative D-dimer test <1000 or 500 ng/mL, respectively). None of these patients (95%CI: 0.00-0.29%) had VT during follow-up.
  • Of 1863 patients who did not have a diagnosis of PE and no anticoagulant therapy, 1 patient (with low C-PTP and high D-dimer [1200 ng/mL] and negative findings on imaging) had VT (95%CI: 0.01-0.30).
  • None of 1285 patients with low C-PTP and negative D-dimer test (<1000 ng/mL) and no anticoagulant therapy had VT during follow-up (95%CI: 0.00-0.30), including those with low C-PTP and D-dimer level between 500-999 ng/mL.
  • 40 Patients had a moderate C-PTP, a negative D-dimer test (<500 ng/mL) and did not receive anticoagulant therapy. None of these patients had VT (95%CI: 0.00-8.76).
  • The use of the PEGeD algorithm resulted in use of chest imaging in 34.3% patients. Standard strategy (low C-PTP and D-dimer <500 ng/mL) would have resulted in chest imaging in 51.9% (difference, -17.6% points, 95%CI: -19.2 to -15.9), a relative difference of -33.9%.
  • PEGeD strategy resulted in testing D-dimer in 97.7% patients, whereas standard strategy would have resulted in testing D-dimer in 86.9% patients.


This prospective management study of patients with suspected PE showed that applying a strategy of low C-PTP and D-dimer<1000 ng/mL identified a group of individuals with low risk of PE. Also, the strategy of moderate C-PTP and D-dimer level <500 ng/mL to rule out PE was associated with low risk of PE. Moreover, use of the PEGeD algorithm reduced the use of chest imaging.


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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: 701-11.

3. Hendriksen JM, Geersing GJ, Lucassen WA, et al. Diagnostic prediction models for suspected pulmonary embolism: systematic review and independent external validation in primary care. BMJ 2015;351: h4438.

4. Linkins LA, Bates SM, Ginsberg JS, Kearon C. Use of different D-dimer levels to exclude venous thromboembolism depending on clinical pretest probability. J Thromb Haemost 2004; 2: 1256-60.

5. Kohn MA, Klok FA, van Es N. D-dimer interval likelihood ratios for pulmonary embolism. Acad Emerg Med 2017; 24: 832-7.

6. Lim W, Le Gal G, Bates SM, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism. Blood Adv 2018; 2:3226-56.

7. van Es N, van der Hulle T, van Es J, et al. Wells rule and d-dimer testing to rule out pulmonary embolism: a systematic review and individual-patient data metaanalysis. Ann Intern Med 2016; 165: 253-61.

Find this article online at N Engl J Med

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