Dr Henry Watson discusses how the SIGN recommendations will help to improve identification of patients with venous thromboembolism and provision of prophylactic treatment

SIGN launched guideline 122 on Prevention and management of venous thromboembolism (VTE) in December 2010.1 The guideline was developed over 2 years by a multidisciplinary group, which included lay representatives and was chosen to represent relevant specialties and disciplines from a spread of different Scottish geographical areas.

The guideline was produced following the SIGN methodology, which emphasises the development of recommendations that are graded to reflect the quality of the evidence supporting them. It runs to 100 pages, contains 108 recommendations, 54 practice points, and 425 references. In fitting with SIGN's new aim of encouraging implementation of its guidelines, the document also contains several protocols and information sheets for patients to help health boards provide a more uniform approach to the prevention and management of VTE.1

Need for the guideline

SIGN has published two previous guidelines on the prevention of VTE—the first in 1995 and the second in 2002—and so awareness of this clinical issue has never been a problem in Scotland. This 2010 update was produced following:

  • an increased awareness of the very high level of risk of VTE associated with both surgical and medical hospital admission
  • validation of new approaches to the diagnosis of suspected pulmonary embolism (PE) and deep vein thrombosis (DVT), which are poorly understood and inappropriately implemented by many physicians
  • the licensing of novel anticoagulants with proven efficacy in the prevention of post-operative VTE.

The increased awareness, particularly of the magnitude of the problem of hospital-acquired VTE, and the interest of Parliament in VTE-associated morbidity and mortality, also acted as catalysts for the development of this guideline.

Hospital-acquired VTE

The association between hospital admission and subsequent development of VTE has long been recognised, particularly for patients undergoing surgery:

  • If all VTE events are considered, 50% are related to hospital admission2
  • Almost half of all hospitalised patients are considered to have a risk factor for development of VTE3
  • In a study based on 7.45 million US hospital discharge abstracts, the post-operative development of VTE was a common cause of prolonged inpatient stay and excess mortality4
  • The magnitude and duration of the VTE risk associated with surgery in the UK was recently demonstrated in a cohort study from Oxford based on data from over 900,000 women: the results showed a relative risk of VTE post-operatively in middle-aged women of nearly 70 in the first 6 weeks following an operation and a relative risk of 20 in weeks 7–12.5

Although the risk between surgery and VTE has been well recognised for some time, the extent of the risk associated with medical admission has until recently been less emphasised. The data, however, indicate that this is a major problem—indeed the majority of patients dying of PE related to hospital admission are medical patients.6,7 As such, many experts now consider hospital-acquired VTE to be as much of a problem in medical patients as it is in surgical patients. In spite of this, the ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study found that in the UK, only 50% of all patients at risk of hospital-acquired VTE received appropriate thromboprophylaxis.3

Inclusion of recommendations on management

While previous SIGN guidelines have concentrated solely on prevention of VTE, it was decided that this version should also include recommendations on management. There were several reasons for this:

  • Many large observational studies of groups of patients presenting with suspected DVT or PE have clarified the role of clinical decision rules (CDR) in management strategies.8 The main change is in the investigation of community based patients presenting with suspected DVT and PE.8 While previously all patients were assessed by an imaging method it has now become clear that for appropriately selected patients, the combination of a 'low-risk' or 'unlikely' CDR score combined with a negative D-dimer result excludes VTE with as much certainty as formal imaging
  • There were several instances where the diagnostic process of suspected VTE has failed indicating that clarification of diagnosis, its management, and issues relating to patient communication were required
  • Recent studies on new drugs such as rivaroxaban and dabigatran, have shown that they may have a role in prophylaxis of VTE9–13 and these new data need to be considered alongside the evidence for other antithrombotic drugs.

Assessment of risk

In response to the 2007 report of the Independent Expert Working Group for the prevention of VTE in hospitalised patients,14 the Chief Medical Officer for England encouraged the development of a national strategy of risk assessment for VTE of all hospitalised patients saying that: 'This simple step has the potential to save thousands of lives each year.'15 In order to support clinical assessment of VTE, the SIGN Guideline Development Group included an algorithm for assessing risk, which has been developed and piloted in one of the Scottish Health Boards.1 It identifies patients who might benefit from thromboprophylaxis and those who are at increased risk of bleeding and who might develop unacceptable complications from pharmacological prophylaxis for that reason.1 Both patient and procedural factors are taken into consideration when assessing risk. The provision of this algorithm should aid the development of a standardised method of assessment throughout Scotland. It will hopefully improve the appropriate provision of thromboprophylaxis for those who are likely to benefit from it.

Use of the risk-factor tables in the SIGN guideline should improve identification of those at risk with a view to providing appropriate thromboprophylaxis.1

Pregnancy
The SIGN guideline recommends that all pregnant women be assessed for risk factors for VTE. The guideline contains a chapter on recommendations for the prevention and management of VTE during pregnancy.1 The rationale for this is fairly obvious: pregnancy is associated with an increased risk of VTE of around 101 and although maternal death is rare, fatal pulmonary embolism still features as one of the most common causes in each confidential enquiry into maternal death.16

Prophylaxis

The recommendations on offering appropriate thromboprophylaxis for surgical and medical patients generally reflect:

  • the data in favour of combined mechanical and pharmacological thromboprophylaxis for surgical patients
  • the paucity of data supporting mechanical thromboprophylaxis in medical patients especially those who have sustained a stroke.

Prophylactic measures commonly used are mechanical compression usually using hosiery and pharmacological methods based on antithrombotic drugs.

The available evidence on the new antithrombotics, rivaroxaban and dabigatran, were incorporated into the recommendations on prophylaxis following major lower limb orthopaedic surgery. One issue that has recently been clarified relates to the duration of prophylaxis following this procedure. Studies confirm a benefit in post-discharge prophylaxis for up to approximately 30 days following total hip replacement and hip fracture and 14 days following total knee replacement.12,13,17,18 This may impact on primary care, through the need for nurses to perform injections and to monitor blood counts for developing thrombocytopenia, for example. However, where treatment is given in an oral (rivaroxaban or dabigatran) as opposed to an injectable form (low molecular weight heparin [LMWH]), there are fewer resource issues.

The SIGN guideline includes recommendations on providing thromboprophylaxis to surgical (e.g. general, laparoscopic, bariatric) and medical (e.g. acute stroke, acute coronary syndromes) patients.1

Management of VTE

Diagnosis
All appropriate patients with suspected DVT and PE should be initially assessed using a CDR to allow the most appropriate strategy for investigation to be followed.1 This recommendation has been put in place to allow stratification of risk and to ensure that patients do not have inappropriate investigations, the results of which might be misleading and the costs of which are effectively wasted. Widespread development of local protocols based on these recommendations would almost certainly improve the effectiveness of investigating suspected VTE.

One barrier to the implementation of these methods of diagnosis (exclusion) is a lack of understanding of the role of the D-dimer test among many clinicians. It should be emphasised that this test is only of value in excluding a diagnosis of DVT or PE in appropriate low-risk groups and should not be used otherwise. Deep vein thrombosis should be diagnosed by ultrasound and PE by ventilation perfusion scanning or computed tomography pulmonary angiography, where they are clinically suspected and are not excluded by appropriate use of CDR combined with a negative D-dimer test.

The SIGN guideline includes advice on re-evaluation of patients with a previous negative or inadequate compression ultrasound scan. Further investigation is indicated for these individuals if symptoms persist.1 Examples of patient information that should be given out following initial negative investigation of a suspected episode are provided in Annex 6 and 7.1

Preliminary assessment
Clinical evaluation of patients should be performed to detect underlying causes for thrombosis and to assess suitability for anticoagulant therapy.1 Examples of this include a history that:

  • is suggestive of inflammatory bowel disease as a trigger for development of thrombosis
  • suggests a patient is likely to have a high risk of bleeding on receiving warfarin.

Routine testing for thrombophilia and extensive screening for cancer in the initial management of a patient is not recommended.1

Choice of anticoagulant
Patients without cancer and diagnosed VTE should normally receive at least 5 days of LMWH and a minimum of 3 months of warfarin, although this may change in the next year or so if the new oral anticoagulants receive their licence for this indication.

Low molecular weight heparin is recommended over warfarin in patients with VTE and malignancy. This is based on the findings of the CLOT (Comparison of Low-molecular-weight heparin versus Oral anticoagulant therapy for the prevention of recurrent venous Thromboembolism in patients with cancer) study, which demonstrated a lower rate of recurrence of VTE in patients with cancer treated with LMWH rather than warfarin for 6 months.19 This recommendation may bring additional work to primary care following patient discharge, but in general, most patients can administer their own LMWH at home after simple training prior to discharge.

Duration of anticoagulation therapy
Studies on treatment to prevent recurrent VTE indicate that all patients with proximal DVT or PE should receive at least 3 months of anticoagulation treatment.20,21 In general, patients who develop thrombosis in the context of a concurrent risk factor, such as recent surgery or use of the combined oral contraceptive pill, have a much lower rate of thrombosis recurrence after discontinuation of therapy than patients who have unprovoked events. Long-term anticoagulation after a first event in these patients is rarely indicated. In comparison patients who sustain unprovoked events have a rate of recurrence of around 20% in 2 years following discontinuation of warfarin,22 and increasingly the case is being made for consideration of long-term anticoagulation in these individuals.

There is no absolute consensus on providing long-term anticoagulation therapy, but there are several markers and clinical features that can aid decision-making:

  • Gender23
  • Pulmonary embolism presentation24
  • Severe post-thrombotic syndrome25
  • Good anticoagulant control
  • Low risk of bleeding
  • The presence of other co-morbidities may predict a higher risk of VTE recurrence and more severe consequences.

Adverse effects of VTE prophylaxis and treatment

Bleeding is the main adverse effect of prophylaxis and treatment with heparins and warfarin. Bleeding that requires re-operation for control as a result of the use of thromboprophylaxis is seen in approximately 0.7% of patients treated with heparin or LMWH.26 Warfarin for treatment of VTE is associated with a risk of major bleeding up to 7% per annum.27

Heparin-induced thrombocytopenia (HIT) is a rare, but severe and often life-threatening complication of all heparin therapy (unfractionated or low molecular weight),1,28 which presents with thrombocytopenia and paradoxical thrombosis in either the arterial or venous circulation. Patients receiving LMWH as therapy for VTE need to have serial platelet counts up to day 14 of treatment to exclude the development of HIT.28 Details of the process of monitoring for HIT by checking platelet counts are included in the SIGN recommendations.1

Role of primary care

Patients receiving thromboprophylaxis post-hospital stay
Primary care will need to know about thromboprophylactic methods and anticoagulant therapies and their planned duration following discharge. Patients who are receiving heparin will need to be monitored for platelet counts. General practitioners will also need to know about patient follow up in secondary care if appropriate.

Patients discharged on therapeutic doses of anticoagulation
Primary care needs to be informed of a diagnosis of VTE, the target International Normalised Ratio (INR), INR range, and proposed duration of therapy. Provision of anticoagulant care varies from region to region and should follow locally developed protocols. Patients who have been investigated for VTE with a negative outcome should be supplied with information informing them of the process, individual risk of thrombosis, and what to do in the context of ongoing symptoms. The SIGN guideline includes versions of various types of documents for use by health boards across Scotland.1

Conclusion

The SIGN guideline provides an evidence-based approach to the prevention and management of VTE. It emphasises the detection of patients at high risk of hospital-associated thrombosis. It gives evidence on appropriate thromboprophylaxis for different clinical situations and offers advice on the appropriate duration of thromboprophylaxis following major surgery (e.g. major orthopaedic surgery). With regard to major orthopaedic surgery, the recommendations include advice on the use of recently licensed new oral anticoagulant drugs. The guideline emphasises new approaches to the clinical assessment and diagnosis of DVT and PE using appropriate clinical decision rules and negative D-dimer testing to exclude the diagnosis in low risk individuals.

However, guidelines only work if they are implemented and to assist with this process, SIGN has provided a series of useful questions as appendices in the guideline.1


  • The SIGN guideline is designed for use in Scotland, but NICE has produced similar guidance for England and Wales
  • GP commissioners should ensure quality standards for VTE prophylaxis that are built into contracts with hospital providers (including community hospitals)
  • In England, Commissioning for Quality and Innovation payments can be paid against successful performance on pre-agreed clinical standards for VTE prophylaxis and outcomes
  • Most potential cases of DVT presenting in primary care can be evaluated using clincal decision rules (Wells Score) and use of a D-dimer test against a local protocol
  • This can avoid many hospital admissions or outpatient assessments in hospital for ultrasound imaging
  • In the future, commissioners should consider fitness-for-referral schemes with local GPs where VTE risk assessment is initiated in primary care at the point of referral alongside fitness-for-anaesthesia checks
  • Tariff prices:a
    • Ultrasound (RA23Z-non mandatory) = £49
    • Pulmonary embolus (DZ09C) emergency admission = £1645.
  1. Scottish Intercollegiate Guidelines Network. The prevention and management of venous thromboembolism. SIGN 122. Edinburgh: SIGN, 2010. Available at:www.sign.ac.uk/guidelines/fulltext/122/index.html nhs_accreditation_1cmyk.eps
  2. Heit J, O'Fallon W, Petterson T et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population based study. Arch Int Med 2002; 162 (11): 1245–1248.
  3. Cohen A, Tapson V, Bergman J et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross sectional study. Lancet 2008; 371 (9610): 387–394.
  4. Zhan C, Miller M. Excess length of stay, charges and mortality attributable to medical injuries during hospitalization. JAMA 2003; 290 (14): 1868–1874.
  5. Sweetland S, Green J, Liu B et al; Million Women Study collaborators. Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study. BMJ 2009; 339: b4583.
  6. Alikhan R, Peters F, Wilmott R, Cohen A. Fatal pulmonary embolism in hospitalized patients: a necropsy review. J Clin Pathol 2004; 57 (12): 1254–1257.
  7. Baglin T, White K, Charles A. Fatal pulmonary embolism in hospitalised medical patients. J Clin Pathol 1997; 50 (7): 609–610.
  8. Ten Cate-Hoek A, Prins M. Management studies using a combination of D-dimer test result and clinical probability to rule out venous thromboembolism: a systematic review. J Thrombosis Haemostasis 2005; 3 (11): 2465–2470.
  9. Eriksson B, Dahl O, Rosencher N et al. RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370 (9591): 949–956.
  10. Eriksson B, Dahl O, Rosencher N et al; RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5 (11): 2178–2185.
  11. Eriksson B, Borris L, Friedman R et al. RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358 (26): 2765–2775.
  12. Lassen M, Ageno W, Borris L et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358 (26): 2776–2786.
  13. Kakkar A, Brenner B, Dahl O et al; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372 (9632): 31–39.
  14. Department of Health. Report of the independent expert working group on the prevention of venous thromboembolism in hospitalized patients. London: DH, 2007. Available at: www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_073944
  15. All-Party Parliamentary Thrombosis Group. Venous thromboembolism prevention: a patient safety priority. King's Thrombosis Centre, 2009. Available at: www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_101398
  16. Royal College of Obstetricians and Gynaecologists. Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Green-top Guideline No. 37a London: RCOG, 2009.
  17. Hull R, Pineo G, Stein P et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med 2001; 135 (10): 858–869.
  18. Eriksson B, Lassen M; PENTasaccharide in HIp-FRActure Surgery Plus Investigators. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med 2003; 163 (11): 1337–1342.
  19. Lee A, Levine M, Baker R et al. Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349 (2): 146–153.
  20. Pinede L, Ninet J, Duhaut P et al. Investigators of the "Durée Optimale du Traitement AntiVitamines K" (DOTAVK) Study. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001; 103 (20): 2453–2460.
  21. Campbell I, Bentley D, Prescott R et al. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. BMJ 2007; b (7595): 674.
  22. Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362 (9383): 523–526.
  23. McRae S, Tran H, Schulman S et al. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet 2006; 368 (9533): 371–378.
  24. Baglin T, Douketis J, Tosetto A et al. Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis. J Thromb Haemost 2010; 8 (11): 2436–2442.
  25. Rodger M, Kahn S, Wells P et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008; 179 (5): 417–426.
  26. Leonardi M, McGory M, Ko C. The rate of bleeding complications after pharmacologic deep venous thrombosis prophylaxis: a systematic review of 33 randomized controlled trials. Arch Surg 2006; 141 (8): 790–797.
  27. Linkins L, Choi P, Douketis J. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139 (11): 893–900.
  28. Keeling D, Davidson S, Watson H; Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The management of heparin-induced thrombocytopenia. Br J Haematol 2006; 133 (3): 259–269.G