D-dimer is a fibrin degradation protein fragment created when fibrin undergoes endogenous fibrinolysis. Blood D-dimer levels are increased in the presence of thrombosis. With a threshold of 500 ng/mL, this D-dimer testing has a 97% to 100% negative predictive value for PE and is often part of diagnostic strategies to rule out PE without the need for unnecessary chest imaging. However, depending on a patient’s risk of PE, D-dimer can have low specificity (in patients with low probability) and can be insufficiently sensitive (in patients with high probability). Therefore, a bayesian approach is recommended to reduce the use of chest imaging while avoiding an unacceptable high rate of missed PE diagnosis. The scientific and standardization committee of the International Society on Thrombosis and Hemostasis recommends that a diagnostic strategy can be considered safe if it is associated with missing less than 1.85% to 2% of patients with PE.

Standard diagnostic strategies for PE consist of 3 steps: evaluating clinical probability, D-dimer testing when indicated, and chest imaging if indicated (Figure 1). The first step of the diagnostic strategy is estimating the clinical probability of PE as low, moderate, or high. The PE prevalence within these 3 categories varies across different clinical prediction rules but is approximately less than 15% among persons with low clinical probability, 15% to 40% among persons with moderate clinical probability, and greater than 40% among persons with high clinical probability. Two structured scores have been validated for identifying the clinical probability of

Pe: the Wells score, and the revised Geneva score (Table 1). These scores include consideration of predisposing factors (recent immobilization, malignancy, and history of VTE) and clinical characteristics at presentation (age, heart rate, signs of DVT, hemoptysis). The revised Geneva score includes only objective components, whereas the Wells score also includes 1 subjective item—PE is the most likely diagnosis. In addition to these 2 structured scores, the clinical probability can be estimated by clinical gestalt: an unstructured clinical impression of whether the probability of PE is low (<15%), moderate (15%-40%), or high (>40%).

Figure 1:
Caption: Diagnostic Strategy for Pulmonary Embolism
Description: aPE is unlikely if the Wells score is less than or equal to 4 or if there are no YEARS criteria (ie, no hemoptysis, no clinical sign of deep venous thrombosis, aand no opinion from the clinician that PE is the most likely diagnosis).Although PERC and YEARS criteria have been validated in randomized clinical trials, this overall algorithm has not been validated in randomized clinical trials.

Table 1:
Caption: Clinical Prediction Rules for the Diagnosis of Pulmonary Embolism

Both the Wells and Geneva tools have been externally validated, but neither has been found to be superior to the other or to risk stratification by using clinician gestalt ( 6, 32, 42 ).
Earlier data had suggested that d-dimer testing was appropriate only for risk stratification of the lowest-risk patients, and that patients at intermediate risk for PE need imaging ( 34 ). However, 3 more recent studies have demonstrated that a normal high-sensitivity d-dimer level can be used to further risk-stratify patients at both low and intermediate risk for PE. The first study, by Perrier and colleagues ( 43 ), enrolled 674 non–high-risk patients (at either low or intermediate risk for PE). Those with normal d-dimer levels were followed for 3 months, and no thromboembolic events were noted.
The latter 2 studies both looked specifically at intermediate-risk groups: Warren and Matthews ( 44 ) used the Wells criteria, and Gupta and colleagues ( 45 ) used the revised Geneva score. They evaluated 1679 and 330 patients, respectively, who were determined to be at intermediate risk for PE and found that a normal d-dimer level was 99.5% and 100% sensitive, respectively, for excluding PE on CT.
The most recent decision tool was developed in response to growing use of d-dimer testing (a test with known low specificity) among patients with the wide range of signs and symptoms potentially suggestive of PE. The Pulmonary Embolism Rule-Out Criteria (PERC) ( Table 1 ) were specifically developed to help guide clinicians in identifying low-risk patients in whom the risks of any testing, including a plasma d-dimer level, outweigh the risk for PE (about 1%) ( 46–49 ). The PERC are not a screening tool for all patients, but rather are meant to be applied to patients in whom a clinician has a genuine concern about PE and whose initial risk stratification identifies them as being at very low risk.

Background/Objectives: Acute pulmonary embolism (PE) remains a leading cause of cardiovascular morbidity and mortality. Although computed tomography pulmonary angiography (CTPA) is the gold standard for diagnosis, electrocardiography (ECG) is a widely available, non-invasive tool that may provide diagnostic clues. This study aims to estimate the pooled prevalence of specific ECG abnormalities in patients with confirmed acute PE. Methods: We conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines. We searched PubMed, Embase, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials until April 2024 for studies reporting prevalence data on ECG abnormalities in confirmed acute PE cases. Pooled prevalence estimates were calculated using a random-effects model, and heterogeneity was assessed using the I2 statistic. Publication bias was evaluated through funnel plots and Egger's test. Results: Twenty-four studies with 7467 patients were included. The most common ECG abnormalities were sinus tachycardia (31%, 95% CI 22-40%), clockwise rotation (28%, 95% CI 12-45%), T-wave inversion in leads V1-V3 (18%, 95% CI 13-23%), S1Q3T3 pattern (15%, 95% CI 11-19%), and right bundle branch block (14%, 95% CI 10-17%). High heterogeneity was observed across studies, with an I2 value exceeding 95%. Publication bias was detected for both S1Q3T3 and right bundle branch block. Conclusions: Sinus tachycardia and the S1Q3T3 pattern are frequently observed in acute PE, supporting their potential use in clinical recognition. However, significant heterogeneity and publication bias highlight the need for larger, higher-quality studies with standardized ECG protocols to understand ECG's diagnostic and prognostic role in PE.

In practice, however, implicit estimation typically overestimates the probability of pulmonary embolism, which can limit the use of the PERC rule. Physicians should be familiar with a validated decision rule to guide the use of d-dimer testing. Among patients with a low structured clinical probability score — a Wells score of 4.0 or less (found in 80% of patients tested in North America), a revised Geneva score of 10 or less (on a scale ranging from 0 to 22, with higher scores indicating a greater probability of pulmonary embolism), and a simplified Geneva score of 4 or less (on a scale ranging from 0 to 9, with higher scores indicating greater probability of pulmonary embolism) — pulmonary embolism can be safely ruled out on the basis of d-dimer levels when manufacturer-recommended cutoffs were used (sensitivity, 98 to 99%; specificity, 37 to 40%). Additional details of the scoring systems and their use are provided in Figure 1. Older data from a different d-dimer assay suggested that a d-dimer level of less than 500 ng per milliliter could be used to rule out pulmonary embolism without consideration of clinical risk factors, but more data are needed to confirm the usefulness of this approach with current assays and relative to currently recommended strategies. The diagnostic accuracy of d-dimer testing in patients with coronavirus disease 2019 (Covid-19) remains unchanged.

Newer approaches have adjusted the d-dimer threshold for ruling out pulmonary embolism and are validated for d-dimer assays for which the manufacturer-recommended cutoff is equivalent to 500 ng per milliliter. These strategies include d-dimer levels that are adjusted for age, (reported sensitivity for the age-adjusted approach ranges from 97 to 99%, and specificity ranges from 42 to 47%) or that are adjusted to the YEARS algorithm for ruling out pulmonary embolism (sensitivity, 96 to 98%; specificity, 54 to 61%) or the Wells score (sensitivity, 93 to 97%; specificity, 61 to 67%). Randomized trials that compare various d-dimer strategies in patients with pulmonary embolism are lacking.

Figure 1:
Caption: Overview of Testing for Pulmonary Embolism in Outpatients or Patients in the Emergency Department.
Description: Physicians may use Pulmonary Embolism Rule-out Criteria (PERC) to rule out pulmonary embolism if their implicit sense suggests there is less than 15% probability that the patient has pulmonary embolism. Otherwise, physicians should use a d-dimer assay to rule out pulmonary embolism in patients who have a low structured clinical probability score (a Wells score of ≤4.0 on a scale of 0 to 12.5, a revised Geneva score of ≤10 on a scale ranging from 0 to 22, or a simplified Geneva score of ≤4 on a scale of 0 to 9; on all three scales, higher scores indicate a greater probability of pulmonary embolism) or should use the YEARS algorithm. Each circled number refers to a different clinical decision rule, and each circled letter to a distinct d-dimer strategy. Imaging can be avoided in patients with clinical probability scores at or below the given cutoff and d-dimer level below the given cutoff. Computed tomography (CT) and ventilation–perfusion single-photon-emission computed tomography (SPECT) are reserved for patients with a clinical probability score above the preset cutoff for the chosen score or a d-dimer at or above the preset cutoff for the chosen d-dimer option. The adjusted d-dimer thresholds have been validated for assays with a manufacturer-recommended cutoff of 500 ng per milliliter. DVT denotes deep-vein thrombosis.

According to our experience the 12-lead electrocardiogram (ECG) may be used to estimate the pretest probability of acute pulmonary embolism (acPE). To this end, we devised a novel ECG score (nECGs) composed of 5 known ECG criteria, best characterizing the key pathogenetic steps of acPE. A retrospective derivation cohort including 136 patients with acPE and a prospective validation cohort including 149 consecutive patients were used to devise and validate the nECGs. The latter cohort consisted of 76 patients with acPE and 73 controls presenting with characteristic symptoms of acPE, in whom the work-up ruled out acPE. We compared the diagnostic value of our nECGs with those of another ECG score (Daniel-ECG-score) and of the best prediction rules (3 Wells score and 2 Geneva score variants). The sensitivity (98.7%), negative predictive value (98%), test accuracy (84.4%) and the negative likelihood ratio (LR) (0.019) of the nECGs were superior to those of all other investigated methods. There was no between-groups difference in the positive LR. The specificity (69%) of the nECGs was inferior to those of the Daniel-ECG-score and Wells scores and did not differ or was superior to those of the Geneva score variants. The positive predictive value (77.3%) of the nECGs was superior to those of the 2 Geneva scores and did not differ from those of the other methods. In conclusion, the nECGs due to its superior sensitivity, negative predictive value, test accuracy, and negative LR estimated the pretest probability of acPE better than the Daniel-ECG-score and the prediction rules.