Bayer Pharma AG

Essence of this Article

For 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 thromboembolism

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

Pharmacological prophylaxis for venous thromboembolism survey

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 surgery54
  • The 2012 American College of Chest Physicians (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 surgery65
  • 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.66-68 There has been a renewed focus on identifying at-risk groups of medically ill patients who would benefit from extended-duration thromboprophylaxis – for more information, click here
Anticoagulants and their targets

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) E.g. enoxaparin: subcutaneous injection, 40 mg od given for 7–10 days70 Meta-analysis71
Meta-analysis72
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 EPHESUS74 (hip replacement surgery)
PENTATHLON75 (hip replacement surgery)
PENTAMAKS76 (knee replacement surgery)
PENTHIFRA77 (hip fracture surgery)
Meta-analysis of the four studies78
VKA Vitamin K (inhibits synthesis of Factors II, VII, IX and X) Oral, od dosing to maintain a target international normalized ratio of 2.0–3.0 Meta-analysis following elective hip replacement surgery79
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 RECORD181 (hip replacement surgery)
RECORD282 (hip replacement surgery)
RECORD383 (knee replacement surgery)
RECORD484 (knee replacement surgery)
Pooled analysis of all four studies85
Apixaban Factor Xa (direct) Oral, 2.5 mg bid started 12–24 hours after hip or knee replacement surgery and continued for 10–14 days (knee replacement surgery) or 32–38 days (hip replacement surgery)86 ADVANCE-187 (knee replacement surgery)
ADVANCE-288 (knee replacement surgery)
ADVANCE-389 (hip replacement surgery)
Pooled analysis of ADVANCE-2 and ADVANCE-390
Edoxabana Factor Xa (direct) Oral, 30 mg od for 11–14 days after hip replacement surgery STARS J-V97
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 28–35 days (hip replacement surgery)91 RE-MODEL92 (knee replacement surgery)
RE­MOBILIZE93 (knee replacement surgery)
RE-NOVATE94 (hip replacement surgery)
RE­NOVATE II95 (hip replacement surgery)
Pooled analysis of RE-MODEL, RE­MOBILIZE and RE-NOVATE96
Immobilized medical patients
UFH Factor Xa and thrombin (indirect via AT) bid or tid dosing63  
LMWH Factor Xa (indirect via AT) Enoxaparin 20 mg or 40 mg od given for 6–14 days MEDENOX trial98
Fondaparinux Factor Xa (indirect via AT) 2.5 mg fondaparinux or placebo subcutaneously

od for 6-14 days
ARTEMIS trial99
aApproved 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.

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