Pulmonary embolism (PE) is a common, potentially life-threatening yet treatable condition. Prompt diagnosis and expeditious therapeutic intervention is of paramount importance for optimal patient management. Our objective was to systematically review the accuracy of D-dimer assay, compression ultrasonography (CUS), computed tomography pulmonary angiography (CTPA), and ventilation-perfusion (V/Q) scanning for the diagnosis of suspected first and recurrent PE. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. 2 investigators screened and abstracted data. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 61 studies. The pooled estimates for D-dimer sensitivity and specificity were 0.97 (95% confidence interval [CI], 0.96-0.98) and 0.41 (95% CI, 0.36-0.46) respectively, whereas CTPA sensitivity and specificity were 0.94 (95% CI, 0.89-0.97) and 0.98 (95% CI, 0.97-0.99), respectively, and CUS sensitivity and specificity were 0.49 (95% CI, 0.31-0.66) and 0.96 (95% CI, 0.95-0.98), respectively. Three variations of pooled estimates for sensitivity and specificity of V/Q scan were carried out, based on interpretation of test results. D-dimer had the highest sensitivity when compared with imaging. CTPA and V/Q scans (high probability scan as a positive and low/non-diagnostic/normal scan as negative) both had the highest specificity. This systematic review was registered on PROSPERO as CRD42018084669.

In summary, PE can be excluded without further testing in patients presenting with symptoms of PE who meet none of the 8 clinical items of PERC. In patients with low or intermediate clinical probability, PE can be excluded without imaging studies if there is a low likelihood for PE and D-dimer level of less than 1000 ng/mL or if there is not a low likelihood for PE and a D-dimer below the age-adjusted threshold (Figure 1).

A computed tomographic (CT) pulmonary angiogram is the imaging study of choice for the diagnosis of PE because it has high diagnostic performance and identifies alternative diagnoses such as pneumonia or pleural effusions. In a systematic review and meta-analysis of 16 studies including 6 clinical trials and a total of 4392 patients, evidence of an intraluminal filling defect in the pulmonary arterial tree on chest imaging had a sensitivity of 94% for PE.

The ventilation/perfusion lung scintigraphy (V/Q scan) is a radiologic test for diagnosing PE that has several limitations. V/Q scans are less readily available than CT pulmonary angiograms, have a relatively low sensitivity for PE (56%-98%), and lack the ability to identify alternative diagnoses. Pulmonary angiography, the former criterion standard for diagnosing PE, is performed by injecting intravenous contrast directly into the pulmonary arteries via a percutaneous catheter advanced through the heart under fluoroscopic guidance. Pulmonary angiography is rarely used to diagnose PE because it has a diagnostic performance similar to CT pulmonary angiogram, which is a less invasive and less labor-intensive imaging study.

In patients with a suspected PE and hemodynamic instability (defined by a systolic blood pressure <90 mm Hg and end-organ hypoperfusion), bedside echocardiography can detect nonspecific signs of PE such as right ventricular dilatation and a flattened intraventricular septum. Rarely, bedside echocardiography can diagnose PE by detecting a thrombus moving between the heart and the pulmonary artery. However, bedside echocardiography has a negative predictive value of 50% and therefore a normal examination cannot exclude PE.

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.

Although pulmonary embolism (PE) due to thrombotic occlusion of the main or branching pulmonary arteries is common ( 1 ), it remains difficult to diagnose owing to the nonspecific signs, symptoms, and risk factors with which it is associated ( 2, 3 ). Acute PE can lead to significant morbidity and mortality ( 4, 5 ), and patients presenting to their physicians or to an emergency department (ED) with cardiopulmonary symptoms are often evaluated for the disease.
Because no individual risk factor, patient symptom, or clinical sign can definitively diagnose or exclude PE ( 6 ), clinical decision tools have been developed to help guide clinicians during their evaluation of patients with suspected acute PE. These decision tools (discussed below) are meant to help physicians stratify patients into groups for whom different diagnostic strategies are appropriate: those for whom PE is so unlikely that they need no further testing, those for whom plasma d-dimer testing can provide additional risk stratification, and those who are at high enough risk that imaging is indicated.
Highly sensitive plasma d-dimer tests (those that measure the level of this fibrin degradation product by using enzyme-linked immunosorbent assays) can be used to rule out PE in patients with low or intermediate pretest probability of PE, whereas older latex or erythrocyte agglutination assays can only rule out PE in patients with low pretest probability ( 7, 8 ). For the purposes of these guidelines, we will assume that highly sensitive d-dimer assays are being used.
Computed tomography (CT) has become the predominant imaging modality used for the diagnosis of PE. Although the use of CT for the evaluation of patients with suspected PE is increasing in the inpatient, outpatient, and ED settings ( 9–14 ), no evidence indicates that this increased use has led to improved patient outcomes. In fact, evidence suggests that many of the PEs diagnosed with increasing use of CT may be less severe ( 15–17 ). As a result, although the incidence of PE has risen significantly with the use of CT, there has been minimal or no associated change in mortality ( 9, 10 ).

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.