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Anticoagulant management of DVT.

Introduction (1-5)

The current options for therapeutic anticoagulation are unfractionated heparin (UFH), warfarin and low molecular weight heparin (LMWH). Although warfarin and UFH are effective anticoagulants, both drugs have safety problems. Warfarin has been the only oral anticoagulant since 1940; it has a narrow therapeutic window and requires monitoring. There is a high risk of bleeding and its action is affected by diet and many drugs. The introduction of newer oral anticoagulants such as dabigatran and rivaroxoban has led to promising prophylactic studies that are likely to change prophylaxis protocols in the future. Over the next 5 years these drugs will be extensively investigated as therapeutic agents. For now LMWH and warfarin are the 'gold standard' therapeutic agents for established venous thromboembolism. Fondaparinux and hirudin need to be considered when heparin-induced thrombocytopenia has been diagnosed.

Initial therapy with LMWH (1-3), (6)

The primary objectives of treatment for DVT are to prevent clot extension, fatal and non-fatal pulmonary embolism (PE) and to reduce the risk of recurrent thrombosis. The long-term objective is to reduce the incidence of pulmonary hypertension and the risk of developing complications of chronic venous hypertension. LMWH has replaced UFH to initiate anticoagulation; compared with UFH, LMWH has been shown to be more effective and is associated with a lower incidence of major bleeding, and has a mortality benefit. It is mandatory to begin LMWH as soon as possible in the acute phase of DVT. Clot propagation and the development of pulmonary emboli need to be 'arrested' rapidly. Other benefits of using LMWH include a reduced incidence of heparinreduced thrombocytopenia (HIT) and hospital stay. LMWH should continue for at least 5 days and evidence suggests that even a longer period of 7 -10 days may decrease the risk of long-term chronic venous hypertension. Although the risk of HIT is lower when using LMWH, platelet count still needs to be monitored. A platelet count should be obtained at 72 hours after LMWH has been started. If the platelet count drops below 100 000 cells/[MU]l or 50% of its initial value, heparin should be stopped and substituted with a hirudin derivative.

Use of warfarin (1-3), (6)

Initial therapy with warfarin alone is associated with a high rate of recurrence. In most patients 5 mg of warfarin should be given immediately after the first dose of LMWH. The INR is monitored from 72 hours onwards anticipating a therapeutic range of 2 - 3. LMWH should be stopped after 5 days provided the INR remains in the therapeutic range for at least 2 consecutive days.

Very careful monitoring of the INR is mandatory, particularly in high-risk groups. These include patients who have a bleeding tendency, are malnourished or debilitated, in heart failure, have liver disease, or are elderly. In these patients it may be necessary to decrease the initial warfarin dose early in therapy and subsequent target INR should also be adjusted. If warfarin is contraindicated, inconvenient or if therapeutic ranges have not been achieved, long-term therapy with LMWH should be considered.

Monitoring LMWH (1-3), (6-11)

LMWH anticoagulant activity is measured using an anti-Xa activity assay. Anti-Xa monitoring is indicated in pregnancy, renal failure or morbidly obese patients in whom larger doses are anticipated. It is important to realise that the various LMWHs are distinct drug products. They require clinical validation for specific indications. Each LMWH must be dosed according to the manufacturer's recommendations. The dose recommended for each product has optimum benefit/risk ratio as shown by clinical trials.

Duration of warfarin therapy (1), (2), (12-14)

In the modern era the duration of therapy should be individualised. Generally it is a balance between the risk of recurrence, the risk of haemorrhage, the patients' state of health and whether there are transient or persistent predisposing factors. The following recommendations need to be considered:

* Isolated calf vein thrombosis associated with transient risk factors: duration of therapy 3 months

* Idiopathic calf vein thrombosis: duration of therapy >3 - 6 months

* First episode proximal vein thrombosis: duration of therapy at least 6 - 12 months

* In relatively mild thrombophilic disorders (anti-phospholipid antibodies, factor V Leiden, prothrombin 20210 gene mutation): duration of therapy at least 12 months

* In severe thrombophilic disorders (antithrombin III, protein C and S deficiencies): continue therapy indefinitely

* In patients with recurrent thrombosis not induced by trauma or surgery: continue therapy indefinitely.

Graduated compression stockings (15), (16)

Patients should be mobilised immediately with a class II compression stocking. This reduces pain and swelling and decreases the incidence of the post-thrombotic syndrome.

LMWH as an alternative to warfarin (1-3), (12-14)

Therapeutic doses of LMWH are as safe and effective as warfarin (for 3 - 6 months). Thus LMWH is an alternative option in patients in whom INR control is difficult. LMWH also appears to be more effective than warfarin in reducing recurrent DVT in patients with cancer. In pregnant patients who require anticoagulation, LMWH is the current treatment of choice because it does not cross the placenta. Women who become pregnant while on warfarin should immediately change to LMWH.

JAY PILLAI, Senior Surgeon, Vascular Unit, University of the Witwatersrand

MARTIN VELLER, Head of Dept of Surgery, University of the Witwatersrand

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(2.) Jacobson B, et al. Venous thromboembolism--prophylactic and therapeutic practice guideline. S Afr Med J 2009; 99: 187-192.

(3.) Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed.). Chest 2008; 133; 141-159S.

(4.) Gomez-Outes, et al. New anticoagulants: Focus on venous thromboembolism. Curr Vasc Pharmacol 2009; 7: 309-329.

(5.) Merli G, et al. Use of emerging oral anticoagulants in clinical practice: translating results from clinical trials to orthopaedic and general surgical patient populations. Ann Surg 2009; 250: 219-238.

(6.) Clexane[R] prescribing information.

(7.) Fareed JW, et al. Are all low molecular weight heparins equivalent in the management of venous thromboembolism? Clin Appl Thrombosis/Hemostasis 2008; 14: 385-392.

(8.) Fareed J, Ma Q, Florian M, et al. Differentiation of low-molecular-weight heparins; impact on the future of the management of thrombosis. Semin Thromb Hemost 2004; 30(Suppl 1): 89.

(9.) Bick RL, Fareed J. Low molecular weight heparins; differences and similarities in approved preparations in the United States. Clin Appl Thrombosis/Hemostasis 1995; (Suppl 1): S63.

(10.) Nightingale SL. From the FDA. Appropriate use of low-molecular-weight heparins (LMWHs). JAMA 1993; 270: 1672.

(11.) Nicolaides AN, et al. Prevention and treatment of thromboembolism. Int Angiol 2006; 25: 101-161.

(12.) Hull RD, Pineo GF, Brant RF, et al., for the LITE Trial Investigators. Long-term lowmolecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119: 1062-1072.

(13.) Bates S, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed.). Chest 2008; 133: 884-886S

(14.) Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology Guidelines: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25: 5490-5495.

(15.) Partsch H, Blatter W. Compression and walking versus bed rest in the treatment of proximal deep venous thrombosis with low molecular weight heparin. J Vasc Surg 2000; 32: 861-869.

(16.) Prandoni P, Lensing AW, Prins M, et al. Belowknee elastic compression stockings to prevent post-thrombotic syndrome: a randomized, controlled trial. Ann Int Med 2004; 141: 249-256.
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Author:Pillai, Jay; Veller, Martin
Publication:CME: Your SA Journal of CPD
Date:Jun 1, 2010
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