Adriano Sala Tenna, Scott Harrison, Liz Avital, and Gerard Stansby discuss how the NICE guideline aims to improve identification and management of DVT and PE
- Timely and accurate diagnosis of VTE is essential as delayed or missed diagnoses can result in longer-term complications or death
- Patients with suspected DVT should initially undergo a pretest probability two-level DVT Wells score. Depending on the pretest probability Wells score they should then either proceed to two-point ultrasound scanning or D-dimer testing
- Patients with suspected PE should undergo a two-level PE Wells score and receive a CTPA if scored 'likely' or D-dimer testing if there is a low pretest probability score. If the D-dimer test is positive, patients should undergo CTPA. A V/Q SPECT scan should be considered in place of CTPA if the patient has an allergy to contrast media or renal impairment
- Immediate interim parenteral anticoagulant therapy should be offered in cases of suspected DVT and PE if appropriate diagnostic tests cannot be carried out immediately
- Treatment with LMWH or unfractionated heparin in those with renal failure or increased risk of bleeding should be carried out as soon as possible; monitoring of INR and continuation of heparins for 5 days or until the INR is ?2 for 24 hours is recommended
- LMWH should be continued for 6 months in those with active cancer as a cause of VTE; its continuation should then be reassessed. (NB Not all LMWH therapies have UK marketing authorisation for 6 months of treatment in patients with cancer, and none have authorisation for treatment over 6 months; informed consent for off-label use should be obtained and documented)
- Offer below-knee compression stockings (ankle pressure ?23 mmHg) to patients a week after diagnosis of proximal DVT. These should be replaced two or three times a year and be worn for a period of 2 years
- Patients aged ≥40 years with unprovoked DVT should be investigated for cancer, including a full examination, blood tests, chest radiography, and urinalysis; abdomino-pelvis computed tomography should be considered if these investigations are negative
- Thrombophilia testing should:
- not be offered to those who are continuing anticoagulation or those with provoked VTE
- be offered to those with an unprovoked VTE where there is a first-degree relative with previous VTE
- not be routinely offered to first-degree relatives of people with a history of VTE and thrombophilia.
VTE=venous thromboembolism; DVT=deep vein thrombosis; PE=pulmonary embolism; CTPA=computed tomography pulmonary angiogram; V/Q SPECT=ventilation/perfusion single photon emission computed tomography; LMWH=low molecular weight heparin; INR=international normalised ratio
|NICE Clinical Guideline 144 on Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing has been awarded the NHS Evidence Accreditation Mark.
This Mark identifies the most robustly produced guidance available. See evidence.nhs.uk/accreditation for further details.
Venous thromboembolism (VTE) is a term covering a wide spectrum of conditions but which mainly consist of deep vein thrombosis (DVT) and pulmonary embolism (PE). Venous thromboembolism is an important cause of death and its prevention has recently been made a priority for the NHS.1
Venous thromboembolism causes over 500,000 deaths in Europe2 and it is estimated that 25,000 people in the UK die from avoidable hospital-acquired VTE every year.3 If left untreated, proximal DVT can lead to a 30%–50% risk of PE and a 12% mortality rate.4
Timely and accurate diagnosis is essential in the primary care setting as the consequences of acute VTE can result in death or the considerable morbidity associated with:
- post-thrombotic syndrome (PTS)—this affects 20%–40% of patients following DVT of the lower limb; it can be debilitating and have a significant impact on their quality of life5
- chronic thromboembolic pulmonary hypertension (CTEPH):
- CTEPH is less common and is caused by obstruction of large pulmonary arteries due to PE. 6
Need for the guideline
The diagnosis of VTE is not always straightforward as other conditions may have similar symptoms; this highlights the need for guidance on diagnostic pathways that can be used for the assessment of possible DVT and PE, and subsequent management. Failure to diagnose a case of VTE correctly could lead to incorrect treatment, with the patient potentially sustaining a fatal PE as a result.7
The most clinically and cost-effective diagnostic pathway needs to be established from a combination of results from clinical diagnostic scores (such as the Wells score), D-dimer measurement, and ultrasound and radiological imaging. It is important to identify the subset of patients in which VTE can safely be excluded in the primary care setting to prevent unnecessary hospital admission, imaging, and patient anxiety.
Anticoagulation is the current standard treatment for VTE; however this is not without risk, and guidance is needed on identifying patients who require prolonged therapy beyond 3–6 months and how any potential monitoring should be performed.7
The remit of NICE Clinical Guideline 144 (CG144) was to facilitate clinical guidance on the management of venous thromboembolic diseases, including thrombophilia testing and the association with cancer. The NICE recommendations were developed based on systematic reviews of the current best-available evidence of clinical and cost effectiveness. Where there was minimal evidence, the Guideline Development Group proposed recommendations based on the group’s experience and opinion of what constitutes best practice.
The guideline was developed to stratify the management of adults (aged 18 years and older) with a suspected or confirmed DVT or PE in primary, secondary, and tertiary healthcare settings. The recommendations also cover the following special-risk groups:7
- people with cancer (as they are at higher risk of developing VTE and may need special advice on its management)
- intravenous drugs users
- residents of nursing homes
- people with physical disabilities who have restricted movement following VTE
- people with learning disabilities who require long-term treatment.
The guideline does not cover: prophylaxis against VTE; thrombosis in arm veins, splanchnic, cerebral vein, and retinal vein thrombosis; DVT in the arms, or in children aged <18 years or pregnant women.7
Assessment and investigation
A patient who presents to primary, secondary, or tertiary care with signs and symptoms of VTE should have a full history taken and an examination to exclude other causes. An analysis of risk factors and clinical signs and symptoms showed that 80% of patients with DVT had one risk factor, 40% had two, and 10% had three. A history of previous DVT, malignancy, and bed rest had a positive predictive value (PPV) of 67% for DVT.8 Clinical examination alone is unreliable for diagnosis of DVT.
Deep vein thrombosis
A pre-test probability two-level DVT Wells Score (see Table 1),9 which can be performed easily in primary care, stratifies patients into two categories of ‘likely’ (score ?2) and ‘unlikely’ (score ?1).7
The NICE guideline recommends that people with a ‘likely’ score (?2 points) should be offered a 2-point proximal leg ultrasound scan within 4 hours of request and a D-dimer test if the scan is negative. If the ultrasound scan cannot be carried out within 4 hours, a D-dimer test and interim 24-hour dose of a parenteral anticoagulant should be given and a leg ultrasound performed within 24 hours of request. Any patient who has a negative ultrasound scan, but a positive D-dimer test should have the scan repeated 6–8 days later.7
The sensitivity and specificity of all types of available D-dimer tests10 imply that this diagnostic method can be considered to rule out DVT in conjunction with another test, but D-dimer alone is not sufficient to rule out DVT in those with a high likelihood of DVT, as suggested by pretest probability scores.11 It can, however, be used to rule out DVT in patients with an unlikely pretest probability score if they test negative. NICE recommends that patients with a low likelihood of DVT (score of ?1 point) and who have a positive D-dimer test should be offered a 2-point leg ultrasound within 4 hours; if this is not possible, an interim 24-hour dose of a parenteral anticoagulant and a leg ultrasound scan should be performed within 24 hours of being requested.7
The NICE guideline will help to increase the accuracy of diagnosis of DVT, as use of the D-dimer test alone will omit 9–10 in every 100 people with the condition.10
Pulmonary embolism is a potentially fatal condition and accounts for 10% of in-hospital deaths; and despite advances in diagnosis, the mortality from recognised PE is 8.6%.12 As subjective assessment of pretest probability of PE has been shown to be unreliable,13 NICE has put forward its strategy: pretest clinical probability scores should be used in the diagnostic management of patients with suspected PE, such as the modified two-level PE Wells score (see Table 2).7,14
Patients who have a ‘likely’ score (>4) for PE should be offered a computed tomography pulmonary angiogram (CTPA); if this is not available immediately, the patient should receive interim parenteral anticoagulation followed by a CTPA.7
Patients who have an ‘unlikely’ score (?4 points) for PE should be offered D-dimer testing and if the result is positive, CTPA. Again, if CTPA cannot be performed immediately, interim parenteral anticoagulation followed by CTPA should be offered.7 If the D-dimer test is positive, patients should undergo CTPA. A ventilation/perfusion single photon emission computed tomography (V/Q SPECT) scan should be considered in place of CTPA if the patient has an allergy to contrast media or renal impairment.7
|Active cancer (treatment ongoing, within 6 months, or palliative)||1|
|Paralysis, paresis, or recent plaster immobilisation of the lower extremities||1|
|Recently bedridden >3 days or major surgery within 12 weeks requiring general or regional anaesthesia||1|
|Localised tenderness along the distribution of the deep venous system||1|
|Entire leg swollen||1|
|Calf swelling 3 cm larger than asymptomatic side||1|
|Pitting oedema confined to the symptomatic leg||1|
|Collateral superficial veins (non-varicose)||1|
|Previously documented DVT||1|
|Alternative diagnosis at least as likely as DVT||-2|
|Clinical probability simplified score|
|Clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the deep veins)||3|
|An alternative diagnosis is less likely than PE||3|
|Heart rate greater than 100 beats per minute||1.5|
|Immobilisation (for >3 days) or surgery in the previous 4 weeks||1.5|
|Malignancy (on treatment, treated in the last 6 months, or palliative)||1|
|Clinical probability simplified score|
Consideration of initial treatment for confirmed VTE should include a choice of low molecular weight heparin (LMWH) or fondaparinux depending on patient co-morbidities, drug costs, and contraindications (unfractionated heparin can be used under certain circumstances, as described in the guideline). Treatment should be started as soon as possible and continued for at least 5 days or until the international normalised ratio (INR), adjusted by a vitamin K antagonist, is ?2 for at least 24 hours (whichever is longer).7
Patients who have active cancer and confirmed VTE should be considered for 6 months of therapy with LMWH, with the risks and benefits of treatment reassessed after this time. NB At the time of publication of CG144 (June 2012) some types of LMWH did not have a UK marketing authorisation for 6 months of treatment of DVT or PE in patients with cancer. Prescribers should consult the summary of product characteristics for the individual LMWH and make appropriate adjustments for severe renal impairment or established renal failure. Informed consent for off-label use should be obtained and documented. Although this use is common in UK clinical practice, at the time of publication of the guideline none of the anticoagulants had a UK marketing authorisation for the treatment of DVT or PE beyond 6 months in patients with cancer. Informed consent for off-label use should be obtained and documented.
Vitamin K antagonists should be started within 24 hours of diagnosis in line with NICE and should be continued beyond 3 months in those patients with an unprovoked PE or proximal DVT, again depending on the risks and benefits of recurrence versus bleeding.7
Primary care healthcare professionals should be aware of the possibility of thrombolysis for symptomatic ilio-femoral DVT, as well as the placement of inferior vena cava filters in patients who cannot have anticoagulant treatment or who have recurrent VTE despite adequate anticoagulation, although these methods are not part of routine care for VTE.7
The NICE guideline suggests that below-knee graduated compression stockings should be prescribed a week after diagnosis of DVT (or once swelling has settled) and these should be worn on the affected leg for 2 years. Although this may result in adverse events, such as skin conditions or patient inconvenience, compression is considered to have a significant impact on improving patient outcomes leading to more efficient use of NHS resources and more importantly, prevention of post-thrombotic syndrome (PTS).7
Investigations for cancer
Although the investigation of cancer in patients aged over 40 years with unprovoked VTE is not recommended by current international guidelines, the association of cancer with VTE is well known and 10%–12% of patients with unprovoked VTE have an undiagnosed cancer, which is usually detected within 2 years of their VTE.13 Patients with VTE should receive a full physical examination, blood tests, chest X-ray, and urinalysis. If the above investigations are negative abdomino-pelvic CT scanning (and mammogram for women) in all patients aged over 40 years should be considered.7 These recommendations aim to improve diagnosis and therefore survival if cancers are diagnosed at an earlier stage; they will also help to identify patients who require modified anticoagulation treatment.
Although an undiagnosed thrombophilia can be a cause of VTE, the NICE guideline does not recommend testing in patients who are currently on long-term anticoagulation or have provoked DVT or PE.7 Testing for antiphospholipid antibodies should be considered in patients with an unprovoked VTE if the cessation of treatment is being considered, and in those who have an unprovoked VTE and a first-degree relative with VTE.7
NICE CG144 will hopefully help to make the diagnosis and management of VTE within the primary care setting easier and more structured. It provides clear algorithms for management, which in the confines of a busy GP practice is invaluable. There are, however, some important factors in their implementation. General practices will need to have access to D-dimer testing and results, coupled with timely access to early ultrasound scanning. It may also identify a need to develop a bridging anticoagulation service
Challenges to implementation
Any diagnosis that relies on tests will encounter delays when, for example, access to imaging is needed out of hours or at weekends (for example to a GP on call). The NICE guideline has built-in delays that take this into account, whereby anticoagulation is given prior to any formal diagnostic imaging if the combination of the clinical Wells score and a D-dimer test suggest a likely diagnosis.7 It may be necessary for local referral patterns to change for those patients deemed suitable for thrombolysis.
The guideline suggests that patients with cancer should receive subcutaneous injections of LMWH throughout the 6 months;7 this would have economic implications as patients may not be able to administer injections themselves, and would require district nurses for regular treatment. It is proposed that patients should be taught to self administer wherever possible.
The increased cost impact of investigations for potential occult cancer in its suggested sequence has been shown to be cost effective and leads to an increased detection rate; whether this will make an impact on survival remains to be seen.
NICE has developed a tool set to support implementation of the guideline, which can be found later in this article and is available at: www.nice.org.uk/guidance/CG144
The NICE guideline on VTE provides structured and comprehensive algorithms, which can be followed in the primary care setting. The guideline is based on the current best available evidence and expert opinion and will hopefully provide for early diagnosis and rapid treatment of what is still a potentially fatal condition.
NICE implementation tools
NICE has developed the following tools to support implementation of Clinical Guideline 144 (CG144) on Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. The tools are now available to download from the NICE website: www.nice.org.uk/CG144
NICE support for commissioners
Baseline assessment tool
baseline assessment is an Excel spreadsheet that can be used by organisations to identify if they are in line with practice recommended in NICE guidance and to help them plan activity that will help them meet the recommendations.
Costing reports are estimates of the national cost impact arising from implementation based on assumptions about current practice, and predictions of how it might change following implementation of the guideline.
NICE support for service improvement systems and audit
Clinical audit tools
Audit tools aim to assist organisations with the audit process, thereby helping to ensure that practice is in line with the NICE recommendations. They consist of audit criteria and data collection tool(s) and can be edited or adapted for local use.
NICE support for education and learning
Clinical case scenarios
Clinical case scenarios are an educational resource designed to improve and assess users’ knowledge of the venous thromboembolic diseases clinical guideline (CG144) and its application in practice.
The slides provide a framework for discussing the NICE guideline with a variety of audiences and can assist in local dissemination. This information does not supersede or replace the guidance itself.
Training plans have been developed to provide the framework for a workshop designed to support education and learning about the diagnosis and management of deep vein thrombosis and pulmonary embolism.
Two-level Wells score templates
This document provides templates for local adaptation to allow the two-level Wells scores for deep vein thrombosis or pulmonary embolism to be calculated and recorded in a format suitable for filing in the patient record.
|NICE support for commissioners||
|NICE support for service improvement systems and audit||
|NICE support for education and learning||
- The VTE guideline offers simple advice that can be adapted into local care pathways
- Commissioners should ensure they commission a rapid-access DVT-assessment service that can provide a response within 24 hours and includes leg ultrasoundâ€”ideally this would be an outpatient service to avoid expensive emergency admission tariff charges and relieve pressure on hospital emergency departments for patients who present outside hospital settings
- Primary care services should be supported with educational programmes and simple flow charts for the use of Wells scores and D-dimer testing (and referral guidelines where these are positive) for both in-hours and out-of-hours settings
- Commissioners should ensure direct access to CT scanning for unprovoked DVT in older patients; a proforma request form could ensure that other necessary tests have been completed first as CT scanning is not without risk
- Primary care physicians may need to access specialist advice in determining whether to continue anticoagulation beyond 6 months and should ensure such advice is available and accessible
- Commissioners may need to consider particular challenges to local implementation (e.g. frail patients in community hospitals without access to ultrasound services on site).
VTE=venous thromboembolism; DVT=deep vein thrombosis; CT=computed tomography
- House of Commons Health Committee. The prevention of venous thromboembolism in hospitalised patients: second report of session 2004–05 (HC99). House of Commons, 2005. Available at: www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/99/99.pdf
- Cohen A, Agnelli G, Anderson F et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98 (4): 756–764.
- Department of Health, Chief Medical Officer. Report of the independent expert working group on the prevention of venous thromboembolism in hospitalised patients. London: DH, 2007. Available at: www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_073950.pdf
- Anderson F Jr, Wheeler H, Goldberg R et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Archiv Intern Med 1991; 151: 933–938.
- Prandoni P, Lensing A, Cogo A et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125 (1): 1–7.
- Goldhaber S, Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet 2012; 379 (9828): 1835–1846.
- National Institute for Health and Care Excellence. Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Clinical Guideline 144. London: NICE, 2012. Available at: www.nice.org.uk/guidance/CG144
- Markel A, Manzo R, Bergelin R, Strandness D. Acute deep vein thrombosis: diagnosis, localization, and risk factors. J Vasc Med Biol 1991; 3: 432–439.
- Wells P, Anderson D, Rodger M et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349: 1227–1235.
- Goodacre S, Sampson F, Stevenson M et al. Measurement of the clinical and cost-effectiveness of noninvasive diagnostic testing strategies for deep vein thrombosis. Health Technol Assess 2006; 10: 1–168, iii–iv.
- Tenna A, Kappadath S, Stansby G. Diagnostic tests and strategies in venous thromboembolism. Phlebology 2012; 27 (Suppl 2): 43–52.
- Hogg K, Thomas D, Mackway-Jones K et al. Diagnosing pulmonary embolism: a comparison of clinical probability scores. Br J Haematol 2011; 153: 253–258.
- Rodger M, Maser E, Stiell I et al. The interobserver reliability of pretest probability assessment in patients with suspected pulmonary embolism. Thromb Res 2005; 116: 101–107.
- Wells P, Anderson D, Rodger M et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000; 83 (3): 416–420.
- Piccioli A, Lensing A, Prins M et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J Thromb Haemostat 2004; 2: 884–889.G