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NIHR Signal Rapid blood test helps exclude pulmonary embolism for low risk patients

Published on 25 October 2016

doi: 10.3310/signal-000320

An inexpensive blood test can help quickly rule out pulmonary embolism for low risk patients attending hospital outpatient or emergency departments, especially in people with early symptoms.

This review looked at the accuracy of a simple blood test called a D-dimer added to the usual diagnostic pathway and a clinical prediction rule. The test is already used to indicate the likelihood of related blood clots in the legs.

Findings from four studies suggest that a negative D-dimer result effectively rules out the diagnosis, particularly for patients with few risk factors. A positive result is less reliable and may pick up people without the condition, especially in over 65’s.

People who test positive will still need diagnostic imaging. Overall a change in the management pathway for suspected pulmonary embolism (PE) have potential to be cost saving and provide better care. Commissioners, will be interested in the overall pathway costs but unfortunately these were not researched here.

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Why was this study needed?

In the UK, 47,734 cases of PE were reported between 2014 and 2015. Emergency admissions for PE increased by 30% between 2008 and 2012.

A pulmonary embolism is a blockage in a blood vessel in the lungs and is often caused by a blood clot travelling up from one of the deep veins in the legs. It is potentially fatal but can be difficult to diagnose because it causes symptoms that are shared by other conditions. These include breathlessness and chest pain which may be relatively mild at first. Scans of the lungs and blood vessels are usually required to confirm the diagnosis. These may involve exposure to X-rays or other radiation.

Clinical predication rules have been developed and are widely used to assess the likelihood of PE based on risk factors such as age, prolonged inactivity, or past clot. Many people nevertheless have to have complex scans before the condition can be safely ruled out.

The D-dimer blood test measures a protein found in the blood when clots break down and if the level is low blood clots are unlikely. While the test is widely used to diagnose blood clots in the legs it is less certain how accurate this is for diagnosis of pulmonary embolus.

This review examined evidence for the accuracy of the D-dimer test in suspected pulmonary embolus.

What did this study do?

This systematic review included four cross-sectional studies published 2004 to 2012. None was from the UK.

The studies included 1,585 adults attending outpatient and A&E departments with symptoms of PE and risk assessed using a score. Three used the Wells clinical predication rule; the fourth study used the Geneva rule.

D-dimer test results were compared against one of the “gold standard” diagnostic scans used to confirm the diagnosis, such as computed tomography pulmonary angiography.

Limitations of this review include the small number of studies and the fact it was not possible to pool the results in meta-analysis. This was because of differences between the studies, such as the timing of the D-dimer test, thresholds used to define a positive result, and the diagnostic scan used.

What did it find?

  • All studies found that a D-dimer test was highly sensitive; meaning in people with PE it was reliable in identifying them correctly. Three studies found test sensitivity at 91%, 94% and 100%, which suggests few false negatives, who might be falsely reassured.
  • This and the linked negative predictive value, means that a negative test result effectively rules out a diagnosis of PE, especially for low risk patients scored by the clinical rule.
  • The authors were unable to combine the results together as there were too few studies.
  • All four studies reported high numbers of false-positives. Specificity in three studies was 45%, 49% and 63%, which was low suggesting that in people without PE a positive result might be caused by something else.
  • Only one study reported the linked “positive predictive value” of 61% directly. This gives a better idea of the consequences for all people who test positive. It means that roughly 4 in ten people testing positive, initially thought to have a PE, won’t have it confirmed after a scan. This reinforces the idea that further diagnostic testing is required in people who test positive on the blood test.

What does current guidance say on this issue?

The NICE 2012 guideline on venous thromboembolic diseases states that patients with suspected PE and a “likely” two‑level PE Wells CPR score should be offered either immediate computed tomography pulmonary angiogram or anti-clotting therapy in the interim until angiography if not carried out immediately. A D‑dimer test is recommended for people in whom PE is suspected and who have an “unlikely” two‑level PE Wells score. If this is positive, then immediate angiogram (or interim anti-clotting therapy) is advised.

If the subsequent angiogram is negative, an ultrasound of the leg veins may be needed to exclude deep vein thrombosis.

What are the implications?

The serious consequences of undiagnosed PE and the difficulties of diagnosis make the D-dimer test a useful tool in emergency settings. A negative D-dimer result can reliably rule out a diagnosis of PE, particularly those at low risk according to a prediction rule. This means that these patients can be assessed for other conditions without being subjected to further costly and unnecessary scans for PE.

The review supports recommendations to choose the diagnostic test based on the suspected probability of PE. If the person is at low risk, a D-dimer is a quick and simple way of ruling this out in most situations.

Citation and Funding

Crawford F, Andras A, Welch K, et al. D-dimer test for excluding the diagnosis of pulmonary embolism. Cochrane Database Syst Rev. 2016;(8):CD010864.

Cochrane UK and the Cochrane Vascular Group are supported by NIHR infrastructure funding.

Bibliography

British Lung Foundation. Pulmonary embolism statistics. London: British Lung Foundation; 2016.

NHS Choices. Deep vein thrombosis. London: Department of Health; 2016.

NHS Choices. Pulmonary embolism. London: Department of Health; 2015.

NHS Digital. Hospital Episode Statistics, Admitted Patient Care, England - 2014-15. Leeds: NHS Digital; 2015.

NICE. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. CG144. London: National Institute for Health and Care Excellence; 2012.

Why was this study needed?

In the UK, 47,734 cases of PE were reported between 2014 and 2015. Emergency admissions for PE increased by 30% between 2008 and 2012.

A pulmonary embolism is a blockage in a blood vessel in the lungs and is often caused by a blood clot travelling up from one of the deep veins in the legs. It is potentially fatal but can be difficult to diagnose because it causes symptoms that are shared by other conditions. These include breathlessness and chest pain which may be relatively mild at first. Scans of the lungs and blood vessels are usually required to confirm the diagnosis. These may involve exposure to X-rays or other radiation.

Clinical predication rules have been developed and are widely used to assess the likelihood of PE based on risk factors such as age, prolonged inactivity, or past clot. Many people nevertheless have to have complex scans before the condition can be safely ruled out.

The D-dimer blood test measures a protein found in the blood when clots break down and if the level is low blood clots are unlikely. While the test is widely used to diagnose blood clots in the legs it is less certain how accurate this is for diagnosis of pulmonary embolus.

This review examined evidence for the accuracy of the D-dimer test in suspected pulmonary embolus.

What did this study do?

This systematic review included four cross-sectional studies published 2004 to 2012. None was from the UK.

The studies included 1,585 adults attending outpatient and A&E departments with symptoms of PE and risk assessed using a score. Three used the Wells clinical predication rule; the fourth study used the Geneva rule.

D-dimer test results were compared against one of the “gold standard” diagnostic scans used to confirm the diagnosis, such as computed tomography pulmonary angiography.

Limitations of this review include the small number of studies and the fact it was not possible to pool the results in meta-analysis. This was because of differences between the studies, such as the timing of the D-dimer test, thresholds used to define a positive result, and the diagnostic scan used.

What did it find?

  • All studies found that a D-dimer test was highly sensitive; meaning in people with PE it was reliable in identifying them correctly. Three studies found test sensitivity at 91%, 94% and 100%, which suggests few false negatives, who might be falsely reassured.
  • This and the linked negative predictive value, means that a negative test result effectively rules out a diagnosis of PE, especially for low risk patients scored by the clinical rule.
  • The authors were unable to combine the results together as there were too few studies.
  • All four studies reported high numbers of false-positives. Specificity in three studies was 45%, 49% and 63%, which was low suggesting that in people without PE a positive result might be caused by something else.
  • Only one study reported the linked “positive predictive value” of 61% directly. This gives a better idea of the consequences for all people who test positive. It means that roughly 4 in ten people testing positive, initially thought to have a PE, won’t have it confirmed after a scan. This reinforces the idea that further diagnostic testing is required in people who test positive on the blood test.

What does current guidance say on this issue?

The NICE 2012 guideline on venous thromboembolic diseases states that patients with suspected PE and a “likely” two‑level PE Wells CPR score should be offered either immediate computed tomography pulmonary angiogram or anti-clotting therapy in the interim until angiography if not carried out immediately. A D‑dimer test is recommended for people in whom PE is suspected and who have an “unlikely” two‑level PE Wells score. If this is positive, then immediate angiogram (or interim anti-clotting therapy) is advised.

If the subsequent angiogram is negative, an ultrasound of the leg veins may be needed to exclude deep vein thrombosis.

What are the implications?

The serious consequences of undiagnosed PE and the difficulties of diagnosis make the D-dimer test a useful tool in emergency settings. A negative D-dimer result can reliably rule out a diagnosis of PE, particularly those at low risk according to a prediction rule. This means that these patients can be assessed for other conditions without being subjected to further costly and unnecessary scans for PE.

The review supports recommendations to choose the diagnostic test based on the suspected probability of PE. If the person is at low risk, a D-dimer is a quick and simple way of ruling this out in most situations.

Citation and Funding

Crawford F, Andras A, Welch K, et al. D-dimer test for excluding the diagnosis of pulmonary embolism. Cochrane Database Syst Rev. 2016;(8):CD010864.

Cochrane UK and the Cochrane Vascular Group are supported by NIHR infrastructure funding.

Bibliography

British Lung Foundation. Pulmonary embolism statistics. London: British Lung Foundation; 2016.

NHS Choices. Deep vein thrombosis. London: Department of Health; 2016.

NHS Choices. Pulmonary embolism. London: Department of Health; 2015.

NHS Digital. Hospital Episode Statistics, Admitted Patient Care, England - 2014-15. Leeds: NHS Digital; 2015.

NICE. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. CG144. London: National Institute for Health and Care Excellence; 2012.

D-dimer test for excluding the diagnosis of pulmonary embolism

Published on 6 August 2016

Crawford, F.,Andras, A.,Welch, K.,Sheares, K.,Keeling, D.,Chappell, F. M.

Cochrane Database Syst Rev Volume 8 , 2016

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 METHODS: 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 x 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%. 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.

  • Sensitivity is the proportion of people with a disease who are correctly identified as having that disease by the diagnostic test. For example, if a test has a sensitivity of 90%, this means that it correctly identified 90% of the people with the disease, but missed 10% (these people were ‘false negatives’ on the test).
  • Specificity is the proportion of people without a disease who are correctly identified as not having that disease by the diagnostic test. For example, if a test has a specificity of 95%, this means that it correctly excludes the diagnosis in 95%, but 5% of people have incorrect tests results indicating that they have the disease when they do not (these people were ‘false positives’ on the test).
  • The positive predictive value of a test is how well the test identifies people who have a disease. It is the proportion of people with a positive test result who truly have the disease. For example, if a test has a positive predictive value of 99%, this means that 99% of the people who test positive will have the disease, while 1% of those who test positive will not have the disease (false positives). It varies depending on how common the disease is in the population being tested.

Expert commentary

In the emergency department, it is often hard to balance the harms of testing for blood clots in the lung against the benefits of early detection and treatment. We know that in symptomatic patients who are unlikely to have disease, a simple blood test can provide reassurance. However, this blood test is often positive for reasons other than blood clots; further invasive tests are then needed.

This issue gets worse with age. We need to continue research on improving the accuracy of this blood test in older patients, to avoid the inconvenience, harm and cost associated with unnecessary invasive testing.

Dr Daniel Horner, Consultant in Emergency Medicine and Intensive Care, Salford Royal NHS Foundation Trust