Venous thromboembolism (VTE) is a single disease affecting the venous circulation. It has two distinct presentations, deep vein thrombosis (DVT) and pulmonary embolism (PE) (Anand 1998). A DVT is a venous thrombosis (blood clot) commonly found in the deep veins of the lower limb or pelvis. Thromboses may break off, or embolise, and travel through the veins to other parts of the body. If a thrombosis reaches the lungs it can cause PE by blocking one of the pulmonary arteries. DVT is more common than PE, affecting around 70,000 people each year in the UK, and it is potentially fatal if left untreated.
There are many risk factors associated with VTE but the incidence of the condition rises dramatically in people over the age of 60 years (White 2003). Major surgery, trauma, fractures or surgery to the hip or knee, malignancy, cardiac or respiratory failure, prolonged immobility, pregnancy, oestrogen therapy, previous DVT or PE, and obesity are all known to increase the likelihood of VTE (Anderson 2003). Affected individuals may have no symptoms but have a history of one or more risk factors, which creates a suspicion that a DVT is present, with subsequent testing confirming the presence of the blood clot (Goodacre 2006). Those with symptoms may have calf pain and swelling.
In general, symptomatic DVT is usually found proximally in the large veins of the thigh whereas non-symptomatic DVT is found more distally in the smaller veins of the calf. DVT in the large proximal veins is associated with poorer patient outcomes as these thromboses are more likely to embolise to the lungs and result in fatalities (NCGC 2012). Uncertainty exists about the most accurate method to diagnose DVT and this creates a great deal of variation in clinical practice (Goodacre 2006). Non-invasive tests to diagnose DVT include tests to detect D-dimer in plasma and duplex ultrasound. Clinical algorithms (clinical prediction rules) such as the Wells test are also recommended in clinical guidelines and are an important part of the patient pathway in routine clinical practice (NCGC 2012).
A systematic review of the clinical and cost effectiveness of non-invasive tests for DVT found that substantial heterogeneity was present in the studies included in the meta-analyses. The authors used meta-regression techniques to investigate sources of heterogeneity, but missing data prevented the analysis of covariates that could have explained some of this heterogeneity. The reviewers concluded that the observed heterogeneity is likely to have arisen from unreported differences between patient groups and the clinical probability of DVT (Goodacre 2006).
Non-invasive tests are generally considered to be less accurate than ascending venography, which has traditionally been the reference standard test for DVT (Goodacre 2006). For venography, the patient receives an injection of a contrast agent in one of the veins of the foot and then undergoes an x-ray. Venography allows the proximal and distal venous system to be clearly visualised but it is invasive, requires the use of an intravenous contrast agent, and delivers a dose of radiation. It is therefore contraindicated for certain groups of people such as pregnant women and those with renal failure, or an allergy to contrast. A further factor limiting availability is that its accuracy depends on the skill of the person conducting the test, and ascending venography should only be done by skilled radiologists with appropriate training, or similar. As ascending venography is not always readily available, other reference standards are also used.
Other acceptable reference standards include computed tomography (CT) venography and magnetic resonance (MR) venography. CT venography requires the administration of a nephrotoxic contrast agent to the patient who then undergoes CT scanning to produce images of the pelvic and lower limb veins. The CT scan uses x-rays and therefore delivers a dose of radiation to the patient. Like ascending venography, CT venography cannot be used on patients who are pregnant, have renal failure, or a contrast allergy. MR venography may or may not involve the use of a contrast agent but does not use additional radiation. Instead, MR imaging uses the magnetic properties of water particles in the body to form images. However, MR venography will not be suitable for patients who have metallic implants or suffer from claustrophobia. It is also not recommended for pregnant patients. If a contrast agent is used, then MR venography will also be contraindicated for patients with renal failure or a contrast allergy.
DVT is treated with anticoagulant therapy, which can be given for a period of between six weeks to six months during which time the patients require regular blood chemistry monitoring (Cundiff 2006; Watson 2004). The purpose of the treatment is to prevent recurrent episodes of DVT, post-thrombotic syndrome and the development of a PE. The accurate diagnosis of DVT is essential to avoid morbidity and mortality, and this review forms part of a programme of high priority systematic reviews in the diagnosis and treatment of peripheral vascular disease that is funded by the National Institute of Health Research (NIHR).
This protocol is complementary to the Cochrane protocol on the diagnosis of DVT in the upper extremity by ultrasound (Di Nisio 2011), however there is no overlap between the two protocols as they are concerned with different limbs.
Target condition being diagnosed
Deep venous thrombosis (DVT) of both proximal (thigh) and distal (calf) veins.
Duplex ultrasound is a non-invasive test which measures the flow of blood in the arteries and veins, and also allows the blood flow to be seen in real-time. It is considered to be the standard diagnostic test for clinically suspected DVT and is inexpensive but time-consuming to perform (Sampson 2005). Duplex ultrasound combines greyscale ultrasound with another Doppler ultrasound modality.
Traditional or greyscale ultrasound produces images that reveal the structure of the veins as two-dimensional (2-D) images. Other ultrasound modalities combined with greyscale ultrasound in the diagnosis of DVT include pulsed wave Doppler, colour Doppler ultrasound and power Doppler.
Pulsed wave Doppler ultrasound measures the velocity of blood flow and other flow features, and provides a waveform showing various attributes of the blood flow. Both colour and power Doppler are used to detect the patency of blood vessels. Colour Doppler ultrasound adds blue or red on top of the greyscale image to indicate the presence and direction of blood flow. Power Doppler is a version of colour Doppler that overcomes some of the technical difficulties that sometimes occur with directional colour Doppler, for example in distinguishing slow blood flow from background noise, but does not provide information on the direction of blood flow. Modern ultrasound scanners generally have all these modalities and the person testing for DVT may switch between modalities, as appropriate, to make a diagnosis.
The utility of a particular method will depend on the anatomy of the patient and the site of the DVT. Distal DVTs in the calf can be harder to image than proximal DVTs as the veins are smaller and more difficult to identify and image. If a DVT is above the groin in the pelvis, there may be bowel gas blocking the ultrasound beam. In such cases pulsed wave Doppler ultrasound at the groin may be more informative than the other kinds of duplex ultrasound.
The primary assessment of DVT diagnosis with ultrasound includes the use of vein compression. The person conducting the examination uses the ultrasound transducer to image the vein in the standard way with greyscale, and then tries to compress the vein with the transducer. Veins are normally highly compressible, and so any resistance to compression indicates the presence of a clot.
To enhance flow in the veins, manual compression of the calf muscle may also be used with colour Doppler ultrasound to help diagnose the presence of DVT. In this case the calf muscle is held and compressed with one hand while the transducer is used with the other hand to visualise the movement of blood flow, for example, no colour would indicate that a thrombus has occluded the vein.
There are, therefore, no explicit threshold criteria that are used when assessing the presence or absence of a DVT, as it is a judgement made by the person performing the ultrasound examination. They either see evidence for a DVT or they do not. A systematic review of the accuracy of ultrasound for detecting any DVT estimated the sensitivity to be 89.7% (95% confidence interval (CI) 88.8 to 90.5) and the specificity to be 93.8% (95% CI 93.1 to 94.4). However, there was significant heterogeneity and the accuracy of ultrasound varied according to whether DVT included both proximal and distal disease or not, and the type of ultrasound. These data were collected in 99 studies from patients who were managed in a variety of healthcare settings including as inpatients, outpatients and in hospital emergency departments (Goodacre 2005).
For the purpose of diagnosing DVT, the proximal segment includes the popliteal and more proximal veins, distal disease would involve the calf veins below the popliteal level.
Symptomatic patients generally undergo scoring by the DVT Wells test prior to any ultrasound (Wells 2006). The Wells test is a clinical prediction rule that gives the patient a point for each criterion met (for example pitting oedema in the symptomatic leg, previous known DVT), and subtracts two points if an alternative diagnosis is considered just as likely. The maximum score is nine points. Current NHS guidance recommends that patients with a score of 2 or more undergo ultrasound testing within four hours, and those with a score of 1 or less or without access to ultrasound within four hours undergo D-dimer testing (NCGC 2012). Patients with a Wells score of 1 or less but a positive D-dimer test are also recommended to undergo ultrasound within four hours of request.
This NHS guidance has been available for less than one year, and so we do not expect that all studies will have dichotomised the Wells score at 1 or less and 2 or more. For example, some studies will have used three subgroups where a patient is graded as low risk if he or she has a score of 0 or less, moderate risk if the score was 1 or 2, and high risk if the score was 3 or more, as this is the categorisation used by the developers of the Wells score (Wells 1997). In addition, the availability of other clinical prediction rules means that studies may have used other scores to screen for DVT.
Symptomatic patients thought to be at low risk by the clinical prediction rule will generally undergo D-dimer testing. Doctors will look for non-DVT causes of the symptoms if a low risk score is combined with a negative D-dimer test. Patients with a low risk score but a positive D-dimer test will be referred for ultrasound imaging. Patients with a high risk score may not receive a D-dimer test but be referred straight to ultrasound imaging. Furthermore, patients may be offered anticoagulation treatment prior to the ultrasound if rapid access to ultrasound is not available and they are either classed as high risk by the clinical prediction rule or have a positive D-dimer test.
In this review, we will consider studies that use a clinical prediction rule with or without D-dimer testing to screen patients for ultrasound testing in secondary care. Specifically, we will use studies that recruited symptomatic outpatients with the following.
1. A low risk score but a positive D-dimer test.
2. A high risk or medium risk score without a D-dimer test.
3. A high risk or medium risk score with a negative D-dimer test.
4. A high risk or medium risk score with a positive D-dimer test.
The probability of DVT will differ between these four groups. All four groups will have a higher probability of DVT than a group of untested patients with symptoms of DVT. This is because the patients who are least likely to have a DVT, that is those with a low risk score and a negative D-dimer test, are not included in any of the four groups.
If possible, we shall also group patients according to whether they received anticoagulant treatment or not, and the specific clinical prediction rule.
Patients with indeterminate or conflicting test results may undergo repeat imaging, but the review will be restricted to studies investigating the diagnostic accuracy of the initial ultrasound only.
Duplex ultrasound is commonly used in the detection of DVT and is non-invasive, convenient and readily available. A non-Cochrane systematic review (search date April 2004) found that ultrasound demonstrated good overall sensitivity (89.7%; 95% CI 88.8 to 90.5) and specificity (93.8%; 95% CI 93.1 to 94.4), but these varied according to ultrasound type and other factors (Goodacre 2006). There is a need for non-invasive tests for DVT given the lack of widespread applicability of ascending venography.