D-dimer for excluding pulmonary embolism in hospital outpatient and accident and emergency populations

Review question

To investigate the ability of the D-dimer test to rule out a diagnosis of acute pulmonary embolism (PE) in patients treated in hospital outpatient and accident and emergency (A&E) departments.

Background

Pulmonary embolism (PE) is a serious, potentially fatal condition that occurs when a blood clot becomes lodged in the blood vessels of the lungs. When people arrive to hospital A&E departments reporting difficulty breathing, breathlessness and chest pain, several explanations are possible but a quick diagnosis is needed. Tests that are available to detect blood clots in the lungs can be invasive and time-consuming, can carry a radiation burden and may be costly. Quick, easy-to-use and inexpensive tests that can be used to rule out the diagnosis would be very valuable.

One such test is the D-dimer test, which is so named because it detects small pieces of protein in the blood, which are called D-dimer. When someone with symptoms of breathlessness and chest pain arrives to the hospital A&E department, the staff conducts an examination and asks questions about the patient's medical history and lifestyle. This helps them to calculate a score for the patient's risk that symptoms are due to a PE.

If the score shows that they are at high risk of a blood clot in the lungs, patients undergo diagnostic scanning immediately (or are treated while test results are awaited). A D-dimer test can be ordered for people in low or moderate (or unlikely) risk groups; a negative D-dimer result might rule out the diagnosis of PE without the need for imaging.

Study characteristics

This review considered all evidence provided by studies that assess the ability of D-dimer to rule out PE in people attending hospital outpatient and A&E departments.

We assessed all available reports from a wide search of databases of medical literature. Two review authors independently assessed studies that met the review criteria, including use of a study design called a cross-sectional study; inclusion of people with symptoms of PE who attended hospital outpatient and A&E departments; use of a risk score and then a D-dimer test; and comparison of results of the D-dimer test against the results of the very best available tests - ventilation/perfusion scanning (V/Q scanning), pulmonary angiography, computerised tomography pulmonary angiography, and magnetic resonance pulmonary angiography.

Key results

Four studies met our criteria, and data from 1585 patients were available. We found evidence that negative (disease absent) D-dimer tests are very good at ruling out PE and identifying people without PE, but high numbers of false-positive test results suggest that people with a raised D-dimer may not in fact have a PE; therefore, a positive result needs to be followed by imaging. In one study, false-positives were more common among people older than 65 years of age.

Quality of the evidence

The flow of patients and the timing of D-dimer and reference standard tests were of greatest methodological concern; no study authors provided a flow diagram to show the flow of patients throughout their study, and only one study clearly reported the time between administration of index and reference standard tests. In the remaining three studies, timing between conduct of the index test and completion of the reference standard was not clearly reported, leading to an unclear classification of bias.

Conclusions

Limited evidence from the studies included in this review suggests that quantitative D-dimer tests used in emergency departments have few false-negatives but very high levels of false-positive results, with a high level of sensitivity consistently evident across all age groups. This makes the test useful as a rule-out test but means that a positive result requires diagnostic imaging.

Authors' conclusions: 

A negative D-dimer test is valuable in ruling out PE in patients who present to the A&E setting with a low PTP. Evidence from one study suggests that this test may have less utility in older populations, but no empirical evidence was available to support an increase in the diagnostic threshold of interpretation of D-dimer results for those over the age of 65 years.

Read the full abstract...
Background: 

Pulmonary embolism (PE) can occur when a thrombus (blood clot) travels through the veins and lodges in the arteries of the lungs, producing an obstruction. People who are thought to be at risk include those with cancer, people who have had a recent surgical procedure or have experienced long periods of immobilisation and women who are pregnant. The clinical presentation can vary, but unexplained respiratory symptoms such as difficulty breathing, chest pain and an increased respiratory rate are common.

D-dimers are fragments of protein released into the circulation when a blood clot breaks down as a result of normal body processes or with use of prescribed fibrinolytic medication. The D-dimer test is a laboratory assay currently used to rule out the presence of high D-dimer plasma levels and, by association, venous thromboembolism (VTE). D-dimer tests are rapid, simple and inexpensive and can prevent the high costs associated with expensive diagnostic tests.

Objectives: 

To investigate the ability of the D-dimer test to rule out a diagnosis of acute PE in patients treated in hospital outpatient and accident and emergency (A&E) settings who have had a pre-test probability (PTP) of PE determined according to a clinical prediction rule (CPR), by estimating the accuracy of the test according to estimates of sensitivity and specificity. The review focuses on those patients who are not already established on anticoagulation at the time of study recruitment.

Search strategy: 

We searched 13 databases from conception until December 2013. We cross-checked the reference lists of relevant studies.

Selection criteria: 

Two review authors independently applied exclusion criteria to full papers and resolved disagreements by discussion.

We included cross-sectional studies of D-dimer in which ventilation/perfusion (V/Q) scintigraphy, computerised tomography pulmonary angiography (CTPA), selective pulmonary angiography and magnetic resonance pulmonary angiography (MRPA) were used as the reference standard.

• Participants: Adults who were managed in hospital outpatient and A&E settings and were suspected of acute PE were eligible for inclusion in the review if they had received a pre-test probability score based on a CPR.

• Index tests: quantitative, semi quantitative and qualitative D-dimer tests.

• Target condition: acute symptomatic PE.

• Reference standards: We included studies that used pulmonary angiography, V/Q scintigraphy, CTPA and MRPA as reference standard tests.

Data collection and analysis: 

Two review authors independently extracted data and assessed quality using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). We resolved disagreements by discussion. Review authors extracted patient-level data when available to populate 2 × 2 contingency tables (true-positives (TPs), true-negatives (TNs), false-positives (FPs) and false-negatives (FNs)).

Main results: 

We included four studies in the review (n = 1585 patients). None of the studies were at high risk of bias in any of the QUADAS-2 domains, but some uncertainty surrounded the validity of studies in some domains for which the risk of bias was uncertain. D-dimer assays demonstrated high sensitivity in all four studies, but with high levels of false-positive results, especially among those over the age of 65 years. Estimates of sensitivity ranged from 80% to 100%, and estimates of specificity from 23% to 63%.

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