Pharmacological prophylaxis for venous thromboembolism

Transcription

1 Pharmacological prophylaxis for venous thromboembolism Essence of this ArticleFor more than 20 years, routine preventive anticoagulant therapy has been the standard of care after major orthopaedic surgery. It has been shown to be both effective and associated with a low risk of postoperative bleeding complications. Thromboprophylaxis has proven to be cost-effective in moderate- and high-risk general surgery patients. In acutely ill, hospitalized medical patients, pharmacological prophylaxis is also recommended. Anticoagulant drugs are designed to inhibit the coagulation cascade to modulate the formation of thrombi. Traditional agents tend to target multiple factors in the cascade. Since 2008, a number of single-target novel oral anticoagulants have become available. Pharmacological prophylaxis for venous thromboembolismbookmark this page For more than 20 years, routine preventive anticoagulant therapy has been the standard of care for major orthopaedic surgery: [59] Pharmacologic measures to prevent venous thromboembolism (VTE) in surgical patients are both effective and associated with a low risk of postoperative bleeding complications Thromboprophylaxis has proven to be cost-effective in moderate- and high-risk general surgery patients In acutely ill, hospitalized medical patients, pharmacological prophylaxis is also recommended, although the optimal duration of therapy is not known. [63] Despite the well-recognized risks of VTE, the rate of provision of appropriate prophylaxis remains low in general hospital patients. A multinational, cross-sectional audit including 32 countries the ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) survey revealed that: [64] 64% of surgical patients were at risk for VTE, but only 58.5% of these received recommended prophylaxis 41.5% of medical patients were also at risk, but only 39.5% of these received recommended prophylaxis Only half the patients deemed to be at risk of VTE received appropriate thromboprophylaxis, although this percentage varied between countries #IMG src="/static/media/images/upload/proportions_of_patients.jpg" alt="pharmaco Proportions of patients (A) at risk of VTE and (B) receiving recommended prophylaxis. Data from the ENDORSE survey. [64] VTE, venous thromboembolism. These findings suggest a need for hospital-wide strategies to ensure appropriate preventive care for all patients at risk. The optimal duration of anticoagulation needed to prevent VTE is an important aspect of care: In surgical patients, the risk of VTE remains high and persists after hospital discharge, particularly after total hip replacement surgery [ The 2012 American College of Chest Physicians (ACCP) guidelines recommend thromboprophylaxis for a minimum of 10 14

2 days after total hip or knee replacement surgery and suggest extending thromboprophylaxis in the outpatient period for up to 35 days from the day of surgery [ In non-surgical patients thromboprophylaxis is usually administered for 6 14 days and, although there is evidence that the risk of VTE may persist beyond this time, the benefits of extended thromboprophylaxis have not been shown to outweigh the risks of bleeding. [ renewed focus on identifying at-risk groups of medically ill patients who would benefit from extended-duration thromboprophylaxis for more information, click Anticoagulants and their targets. VKAs inhibit the synthesis of Factors II, VII, IX and X. The heparins inhibit Factor Xa and thrombin indirectly through AT, and fondaparinux indirectly inhibits Factor Xa alone via AT. Rivaroxaban, apixaban and edoxaban directly inhibit Factor Xa and several anticoagulants, including dabigatran, directly inhibit thrombin. AT, antithrombin; TF, tissue factor; VKA, vitamin K antagonist. Approved anticoagulants for the prevention of venous thromboembolism Anticoagulant drugs are designed to modulate the coagulation cascade by inhibiting the conversion of fibrinogen to fibrin and preventing the subsequent formation of a thrombus. Traditional agents tend to target multiple factors in the cascade, but more recently a number of single-target agents have become available. Antiplatelets for the prevention of VTE Although acetylsalicylic acid (ASA; aspirin) is more effective than placebo in preventing VTE in high-risk patients, it appears to be less effective than low molecular weight heparin (LMWH). [69] There are insufficient data comparing ASA with warfarin or unfractionated heparin for VTE prophylaxis, and no comparative studies with the novel oral anticoagulants. [69] The 2012 ACCP guidelines recommend ASA, among other antithrombotics, over no prophylaxis at all, but LMWH or oral anticoagulants are preferred. [65] The benefits of ASA for VTE prevention are, therefore, unclear. Approved anticoagulants for VTE prophylaxis Drug Target Dose/regimen Supporting data Major orthopaedic surgery UFH Factor Xa and thrombin (indirect via AT) Subcutaneous weight-based doses or fixed dose of 5000 IU bid or tid LMWH Factor Xa and thrombin (indirect via AT)

3 E.g. enoxaparin: subcutaneous injection, 40 mg od given for 7 10 days [70]

4 Meta-analysis [71] Meta-analysis [72]

5 Fondaparinux Factor Xa (indirect via AT) Subcutaneous injection, 2.5 mg od given for 5 9 days (hip and knee replacement surgery), up to 33 days (hip fracture surgery) [73] EPHESUS [74] (hip replacement surgery) PENTATHLON [75] (hip replacement surgery) PENTAMAKS (knee replacement surgery) PENTH [77] (hip fracture surgery) Meta-analysis of the four studies [78] VKA Vitamin K (inhibits synthesis of Factors II, VII, IX and X) Oral, od dosing to maintain a target international normalized ratio of Meta-analysis following elective hip replacement surgery [79] Rivaroxaban Factor Xa (direct) Oral, 10 mg od started 6 10 hours (provided that haemostasis has been established) after elective hip or knee replacement surgery and given for 2 weeks (knee replacement surgery) or 5 weeks (hip replacement surgery) [80] RECORD1 [81] (hip replacement surgery) RECORD2 [82] (hip replacement surgery) RECORD3 [83 (knee replacement surgery) RECOR [84] (knee replacement surgery) Pooled analysis of all four studies [85] Apixaban Factor Xa (direct) Oral, 2.5 mg bid started hours after hip or knee replacement surgery and continued for days (knee replacement surgery) or days (hip replacement surgery) [86] ADVANCE-1 [87] (knee replacement surgery) ADVANCE-2 [ (knee replacement surgery) ADVAN [89] (hip replacement surgery) Pooled analysis of ADVANCE-2 and ADVANCE-3 [90] Edoxabana] Factor Xa (direct) Oral, 30 mg od for days after hip replacement surgery Dabigatran Thrombin (direct) Initiated orally within 1 4 hours of completed surgery with a single capsule (110 mg), continuing with 220 mg od thereafter for 10 days (knee replacement surgery) or days (hip replacement surgery) [91] STARS J-V [97] RE-MODEL [92] (knee replacement surgery) RE MOBILIZE (knee replacement surgery) RE-NOV [94] (hip replacement surgery) RE NOVATE II [95] (hip replacement surgery) Pooled analys of RE-MODEL, RE MOBILIZE and RE-NOVATE [96] Immobilized medical patients UFH Factor Xa and thrombin (indirect via AT) bid or tid dosing [63]

6 LMWH Factor Xa (indirect via AT) Enoxaparin 20 mg or 40 mg od given for 6 14 days MEDENOX trial [98] Fondaparinux Factor Xa (indirect via AT) 2.5 mg fondaparinux or placebo subcutaneously od for 6-14 days ARTEMIS trial [99] a] Approved in Japan. AT, antithrombin; bid, twice daily; LMWH, low molecular weight heparin; od, once daily; PE, pulmonary embolism; tid, three-times daily; UFH, unfractionated heparin; VTE, venous thromboembolism. 54 Geerts WH, Bergqvist D, Pineo GF et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:381S 453S. 59 Kakkar AK. Prevention of venous thromboembolism in general surgery. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th edn. Colman RW, Clowes AW, George JN et al. (editors). Philadelphia: Lippincott, Williams & Wilkins; p Kahn SR, Lim W, Dunn AS et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e195S e226s. 64 Cohen AT, Tapson VF, Bergmann JF et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008;371: Falck-Ytter Y, Francis CW, Johanson NA et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e278S e325s. 66 Hull RD, Schellong SM, Tapson VF et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010;153: Goldhaber SZ, Leizorovicz A, Kakkar AK et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011;365: Karthikeyan G, Eikelboom JW, Turpie AGG, Hirsh J. Does acetyl salicylic acid (ASA) have a role in the prevention of venous thromboembolism? Br J Haematol 2009;146: sanofi-aventis US LLC. Lovenox (enoxaparin sodium) Prescribing Information Available at: [accessed 22 December 2014]. 71 Nurmohamed MT, Rosendaal FR, Büller HR, et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992;340: Koch A, Ziegler S, Breitschwerdt H, Victor N. Low molecular weight heparin and unfractionated heparin in thrombosis prophylaxis: meta-analysis based on original patient data. Thromb Res 2001;102: European Medicines Agency. Arixtra (fondaparinux sodium 2.5 mg/0.5 ml injection) Summary of Product Characteristics Available at: [accessed 12 December 2014]. 74 Lassen MR, Bauer KA, Eriksson BI, Turpie AGG. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002;359: Turpie AGG, Bauer KA, Eriksson BI et al. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002;359: Bauer KA, Eriksson BI, Lassen MR, Turpie AGG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345: Eriksson BI, Bauer KA, Lassen MR et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001;345: Turpie AGG, Bauer KA, Eriksson BI et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002;162:

7 79 Freedman KB, Brookenthal KR, Fitzgerald RH, Jr. et al. A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty. J Bone Joint Surg Am 2000;82-A: Bayer Pharma AG. Xarelto (rivaroxaban) Summary of Product Characteristics Available at: June 2015]. 81 Eriksson BI, Borris LC, Friedman RJ et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358: Kakkar AK, Brenner B, Dahl OE et al. 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: Lassen MR, Ageno W, Borris LC et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358: Turpie AGG, Lassen MR, Davidson BL et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009;373: Turpie AGG, Lassen MR, Eriksson BI et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011;105: Bristol-Myers Squibb, Pfizer. Eliquis (apixaban) Summary of Product Characteristics Available at: [accessed 28 April 2015]. 87 Lassen MR, Raskob GE, Gallus A et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009;361: Lassen MR, Raskob GE, Gallus A et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010;375: Lassen MR, Gallus A, Raskob GE et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363: Raskob GE, Gallus AS, Pineo GF et al. Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint Surg Br 2012;94: Boehringer Ingelheim International GmbH. Pradaxa (dabigatran etexilate) Summary of Product Characteristics Available at: [accessed 28 April 2015]. 92 Eriksson BI, Dahl OE, Rosencher N et al. 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: The RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009;24: Eriksson BI, Dahl OE, Rosencher N et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007;370: Eriksson BI, Dahl OE, Huo MH et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, non-inferiority trial. Thromb Haemost 2011;105: Friedman RJ, Dahl OE, Rosencher N et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: A pooled analysis of three trials. Thromb Res 2010;126: Fuji T, Wang CJ, Fujita S et al. Safety and efficacy of edoxaban, an oral Factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: The STARS E-3 trial. Thromb Res 2014;134: Samama MM, Cohen AT, Darmon JY et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999;341: Cohen AT, Davidson BL, Gallus AS et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006;332: