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Anticoagulant Therapy for Venous Thromboembolism Prevention
This section details the mechanisms of actions and guideline recommendations of anticoagulation in patients with VTE
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. A number of orally available and parenteral (i.e. infused or injected) drugs are available for the prevention of VTE.
Anticoagulants and their targets. VKAs inhibit the synthesis of Factors II, VII, IX and X. The heparins inhibit Factor Xa and thrombin indirectly through antithrombin, and fondaparinux indirectly inhibits Factor Xa alone via antithrombin. Rivaroxaban, apixaban and edoxaban directly inhibit Factor Xa and dabigatran directly inhibits thrombin
- LMWHs, such as enoxaparin and dalteparin, are commonly used for short-term prophylaxis; they are more practical to administer in most patients than UFH1,2
- Fondaparinux is also administered by injection and has shown similar or improved efficacy to LMWH for VTE prevention after hip replacement,3,4 knee replacement5 and hip fracture surgery6
- Warfarin has been shown to reduce the risk of VTE after hip replacement surgery;7 because VKAs take several days of dosing to reach their full therapeutic effect, a parenteral anticoagulant may need to be given initially in parallel
- The NOACs combine the rapid onset of action of parenteral agents with oral dosing and do not require routine coagulation monitoring; apixaban, dabigatran and rivaroxaban were compared with enoxaparin for VTE prevention after elective hip or knee replacement surgery and are licenced for this indication:
- Apixaban: ADVANCE-18 (knee replacement surgery), ADVANCE-29 (knee replacement surgery), ADVANCE-310 (hip replacement surgery) and a pooled analysis of ADVANCE-2 and ADVANCE-311
- Dabigatran: RE-MODEL12 (knee replacement surgery), RE-MOBILIZE13 (knee replacement surgery), RE-NOVATE14 (hip replacement surgery), RE-NOVATE II15 (hip replacement surgery) and a pooled analysis of RE-MODEL, RE-MOBILIZE and RE-NOVATE16
- Rivaroxaban: RECORD117 (hip replacement surgery), RECORD218 (hip replacement surgery), RECORD319 (knee replacement surgery), RECORD420 (knee replacement surgery) and a pooled analysis of all four studies21
Guideline recommendations
The 2012 American College of Chest Physicians (ACCP) guidelines for the prevention of VTE in patients undergoing surgery or hospitalized for other medical conditions are summarized below.22,23
| ACCP recommendation for anticoagulant prophylaxis [grade of recommendation] | Duration of anticoagulation [grade of recommendation] | |
|---|---|---|
| Major orthopaedic surgery – high VTE risk24 | ||
| Elective hip or knee replacement | Low-dose UFH, LMWH, fondaparinux (parenteral); adjusted-dose VKA, aspirin, apixaban, dabigatran or rivaroxaban (oral) [1B]; IPCD [1C] | 10–14 days [1B] and up to 35 days [2B] |
| Hip fracture surgery | Low-dose UFH, LMWH, fondaparinux (parenteral); adjusted-dose VKA, aspirin (oral) [1B]; IPCD [1C] | 10–14 days [1B] and up to 35 days [2B] |
| Non-orthopaedic surgery | ||
| Surgery associated with high VTE risk | Low-dose UFH or LMWH [1B] | No specific recommendations |
| Abdominal or pelvic surgery for cancer and high VTE risk | LMWH [1B] | 4 weeks [1B] |
| Other surgery associated with moderate VTE risk | Low-dose UFH or LMWH [2B] | No specific recommendations |
| Surgery associated with low VTE risk | No pharmacological prophylaxis [2C] | – |
| Hospitalized medical patients22 | ||
| High VTE risk | Low-dose UFH, LMWH or fondaparinux [1B] | Duration of immobilization or acute hospital stay [2B] |
| Low VTE risk | No pharmacological or mechanical prophylaxis [1B] | – |
N/A, not applicable
Risks and benefits of anticoagulant prophylaxis
The benefits of thromboprophylaxis after major orthopaedic surgery have been shown to outweigh the risks of bleeding, regardless of the therapy used, resulting in clear guideline recommendations for thromboprophylaxis.24
Although data regarding thromboprophylaxis after hip fracture surgery are limited, LMWHs, low-dose UFH, adjusted-dose VKA, fondaparinux, aspirin and intermittent pneumatic compression devices (IPCD) appear to have positive efficacy and safety profiles and are recommended.24 In the real-world XAMOS study, rivaroxaban was shown to be similarly efficacious and as safe as enoxaparin as thromboprophylaxis after hip/femur or below-knee fracture surgery.25
Patient characteristics that are associated with an increased risk of bleeding with anticoagulant use include:26
- Advanced age (>65 years)
- Cancer
- Renal failure
- Liver failure
- Co-morbidity and reduced functional capacity
Validated risk scores have been developed to help identify which hospitalized acutely medically ill patients at increased risk of VTE may benefit from anticoagulant prophylaxis.27,28
Scoring algorithms to assess the risk of bleeding may also help physicians to decide whether a patient should receive thromboprophylaxis.
| Bleeding risk factor | Points |
|---|---|
| Active gastroduodenal ulcer | 4.5 |
| Bleeding during the 3 months before admission | 4 |
| Platelet count <50 × 109 cells/l | 4 |
| Advanced age, ≥85 years vs <40 years | 3.5 |
| Severe renal failure, eGFR <30 ml/min/m2 vs ≥60 ml/min/m2 | 2.5 |
| Hepatic failure (INR >1.5) | 2.5 |
| Intensive care unit/coronary care unit | 2.5 |
| Central venous catheter | 2.5 |
| Rheumatic disease | 2 |
| Cancer at the time of hospital admission | 2 |
| Age, 40–84 years vs <40 years | 2 |
| Male sex | 1.5 |
| Moderate renal impairment, eGFR 30–59 ml/min/m2 vs ≥60 ml/min/m2 | 1 |
eGFR, estimated glomerular filtration rate
The risk of bleeding increased exponentially in patients with a risk score of ≥7.0 points. In the cases where bleeding contributed to death, the mean score was 8.6. Both major bleeding and any bleeding were uncommon in patients with a bleeding risk score of <7.0.26
Among other potential adverse events, HIT can be associated with the use of heparins in up to 5% of patients after cardiac or orthopaedic surgery.29 HIT usually occurs in the first weeks of therapy; therefore, platelet counts should be monitored in patients receiving heparins for more than a few days.
The optimal duration of thromboprophylaxis is an important consideration when balancing the benefits and risks of therapy:
- In surgical patients, the risk of VTE remains high and persists after hospital discharge, particularly after total hip replacement surgery30
- The 2012 ACCP guidelines recommend thromboprophylaxis for a minimum of 10–14 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 surgery24
- In hospitalized acutely medically ill patients at increased risk of thrombosis the 2012 ACCP guidelines recommend anticoagulant thromboprophylaxis with LMWH, low-dose UFH or fondaparinux for 6 to 21 days or until full mobility is restored or discharge from hospital (whichever comes first)22
References
- 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;340:152–156. Return to content
- 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;102:295–309. Return to content
- Lassen MR, Bauer KA, Eriksson BI et al. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002;359:1715–1720. Return to content
- 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;359:1721–1726. Return to content
- Bauer KA, Eriksson BI, Lassen MR et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345:1305–1310. Return to content
- 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;345:1298–1304 Return to content
- 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:929–938. Return to content
- Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009;361:594–604 Return to content
- 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;375:807–815. Return to content
- Lassen MR, Gallus A, Raskob GE et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487–2498. Return to content
- 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;94:257–264. Return to content
- 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;5:2178–2185. Return to content
- 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;24:1–9. Return to content
- 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;370:949–956. Return to content
- 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;105:721–729. Return to content
- 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;126:175–182. Return to content
- Eriksson BI, et al. N Engl J Med. 2008;358:2765-2775. Eriksson BI, et al. N Engl J Med. 2008;358:2765-2775. Return to content
- Kakkar AK, et al. Lancet; 2008:372(9632):31-9. Kakkar AK, et al. Lancet; 2008:372(9632):31-9. Return to content
- Eriksson BI, et al. N Engl J Med. 2008;358:2765-2775. Eriksson BI, et al. N Engl J Med. 2008;358:2765-2775. Return to content
- Turpie AGG, et al. Lancet. 2009;373:1673-1680. Return to content
- 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;105:444–453. Return to content
- 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. Return to content
- Gould MK, Garcia DA, Wren SM et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e227S–e277S. Return to content
- 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. Return to content
- Lassen MR, Haas S, Kreutz R et al. Rivaroxaban for thromboprophylaxis after fracture-related orthopedic surgery in routine clinical practice. Clin Appl Thromb Hemost 2016;22:138–146. Return to content
- Decousus H, Tapson VF, Bergmann JF et al. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 2011;139:69–79. Return to content
- Spyropoulos AC, Anderson FA, Jr., Fitzgerald G et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011;140:706–714. Return to content
- Gibson CM, Spyropolous AC, Cohen A et al. The IMPROVEDD VTE risk score: incorporation of D-dimer into the IMPROVE score to improve venous thromboembolism risk stratification. TH Open 2017;01:e56–e65. Return to content
- Linkins LA, Dans AL, Moores LK et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e495S–e530S. Return to content
- 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. 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. Return to content
See Also
Peripheral Artery Disease: causes and consequences
See Also
Coronary Artery Disease: causes and consequences
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Updated date 10/10/2022
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