New Oral Anticoagulants After Total Knee Arthroplasty
New Oral Anticoagulants After Total Knee Arthroplasty
Traditional agents (LMWHs [such as enoxaparin], fondaparinux, vitamin K antagonists [such as warfarin], and aspirin) are among those recommended by the ACCP for the prevention of VTE after TKA. These antithrombotics have proven effective at reducing the incidence of VTE in patients, after TKA. However, these agents have drawbacks in terms of their modes of administration, efficacy, adverse-event profiles, and pharmacokinetic and pharmacodynamic properties.
Heparins (unfractionated heparin [UFH] and LMWHs) are administered parenterally. They mediate their anticoagulant effects by binding to antithrombin (AT), with high affinity. AT inactivates thrombin (Factor IIa) and Factor Xa, and when AT is bound to heparins this activity is significantly augmented (Figure 1). However, UFH and, to a lesser extent, LMWHs lack specificity and bind to other plasma proteins and cellular components. These nonspecific interactions mediate nonhemorrhagic adverse events, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. The incidence of nonhemorrhagic adverse events is higher in patients treated with UHF than with LMWHs. The poor specificity of UFH also means that it has an unpredictable pharmacokinetic and pharmacodynamic profile and, unlike LMWH treatment, UFH treatment necessitates routine coagulation monitoring and dose adjustment in patients.
(Enlarge Image)
Figure 1.
The coagulation cascade and targets for anticoagulant agents. LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.
For patients who receive UFH after neuraxial blockade, the risk of spinal hematoma is estimated to be 1 in 22,000 with continuous epidural anesthesia and 1 in 32,500 with spinal anesthesia. For patients receiving LMWH prophylaxis, the risk of spinal hematoma is estimated (based on sales, prevalence of neuraxial techniques, and reported cases) to be approximately 1 in 3000 with continuous epidural anesthesia and 1 in 41,000 with spinal anesthesia. Detailed guidance on the use of neuraxial blockade in patients receiving heparin-based thromboprophylaxis has been published by both the ASRA and the ESA (Table 1).
Fondaparinux is a synthetic indirect inhibitor of Factor Xa, with potent anticoagulant activity (Figure 1). Fondaparinux may be administered as a fixed dose, once daily without the need for anticoagulant monitoring, as it has a longer half-life than LMWHs. However, like UFH and LMWHs, fondaparinux is administered parenterally and lacks the convenience of an oral agent.
A meta-analysis of four randomized double-blind studies revealed that in patients receiving fondaparinux prophylaxis after major orthopaedic surgery, major bleeding events were slightly more common than in patients receiving enoxaparin, occurring in 2.7% of fondaparinux-treated patients compared with 1.7% of enoxaparin-treated patients (P=0.008); however, the clinical significance of these data is unclear.
The risk of spinal hematoma associated with fondaparinux prophylaxis in patients receiving neuraxial blockade is unknown. Guidelines recommend caution when using fondaparinux in these patients (Table 1).
Warfarin is a vitamin K antagonist that exerts its anticoagulant effect indirectly by interfering with the synthesis of the vitamin K–dependent clotting factors–Factor II (thrombin), Factor VII, Factor IX, and Factor X.
Unlike heparins and fondaparinux, warfarin is orally administered. However, like UFH, warfarin has highly complex pharmacokinetic and pharmacodynamic properties, with dose response susceptible to genetic factors, drug–drug interactions, and drug–food interactions. Warfarin also has a narrow therapeutic window, putting patients at risk of blood clots or bleeding events if international normalized ratios (INRs) are not maintained in a relatively narrow range (generally 2.0–3.0). Routine coagulation monitoring and dose adjustments are therefore essential, particularly in an ambulatory setting.
Warfarin also has a slow onset and offset of action, which makes it difficult to use in the perioperative setting. In patients who are receiving anticoagulation therapy before surgery, warfarin must be stopped several days in advance of the procedure. Once warfarin therapy is reinitiated, it takes several days for patients to reach therapeutic INRs. This means that for a period of 4–5 days before and after surgery patients are at increased risk of blood clots; therefore, bridging therapy with UFH or LMWHs often is done. However, the efficacy of bridging therapy has not been established in randomized trials.
Several studies have investigated the use of regional anesthesia and analgesia in patients who received warfarin for thromboembolic prophylaxis. No spinal hematomas were reported, but the power of these studies to detect rare complications was low. The ASRA guidelines recommend that if thromboprophylaxis with a vitamin K antagonist is used with epidural analgesia, catheters should be removed while the INR is <1.5 (Table 1).
The antithrombotic action of aspirin is mediated via inhibition of platelet function by acetylation of the platelet cyclooxygenase (COX). This blocks production of platelet-dependent thromboxane, limiting activation and aggregation of platelets.
The effectiveness of aspirin in the prevention of VTE after TKA is subject to debate. Available data are of variable quality; there have been few high-quality randomized controlled trials comparing aspirin with other antithrombotic agents. However, aspirin would not appear to be as effective as other antithrombotic agents for preventing VTE after TKA.
The ASRA and ESA note that, on the basis of the available data, nonsteroidal antiinflammatory drugs (NSAIDs) including aspirin, when given in isolation, do not increase the risk of spinal hematoma in patients receiving epidural or spinal anesthesia (Table 1).
Traditional Antithrombotics for the Prevention of VTE After TKA
Traditional agents (LMWHs [such as enoxaparin], fondaparinux, vitamin K antagonists [such as warfarin], and aspirin) are among those recommended by the ACCP for the prevention of VTE after TKA. These antithrombotics have proven effective at reducing the incidence of VTE in patients, after TKA. However, these agents have drawbacks in terms of their modes of administration, efficacy, adverse-event profiles, and pharmacokinetic and pharmacodynamic properties.
Heparins
Heparins (unfractionated heparin [UFH] and LMWHs) are administered parenterally. They mediate their anticoagulant effects by binding to antithrombin (AT), with high affinity. AT inactivates thrombin (Factor IIa) and Factor Xa, and when AT is bound to heparins this activity is significantly augmented (Figure 1). However, UFH and, to a lesser extent, LMWHs lack specificity and bind to other plasma proteins and cellular components. These nonspecific interactions mediate nonhemorrhagic adverse events, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. The incidence of nonhemorrhagic adverse events is higher in patients treated with UHF than with LMWHs. The poor specificity of UFH also means that it has an unpredictable pharmacokinetic and pharmacodynamic profile and, unlike LMWH treatment, UFH treatment necessitates routine coagulation monitoring and dose adjustment in patients.
(Enlarge Image)
Figure 1.
The coagulation cascade and targets for anticoagulant agents. LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.
For patients who receive UFH after neuraxial blockade, the risk of spinal hematoma is estimated to be 1 in 22,000 with continuous epidural anesthesia and 1 in 32,500 with spinal anesthesia. For patients receiving LMWH prophylaxis, the risk of spinal hematoma is estimated (based on sales, prevalence of neuraxial techniques, and reported cases) to be approximately 1 in 3000 with continuous epidural anesthesia and 1 in 41,000 with spinal anesthesia. Detailed guidance on the use of neuraxial blockade in patients receiving heparin-based thromboprophylaxis has been published by both the ASRA and the ESA (Table 1).
Fondaparinux
Fondaparinux is a synthetic indirect inhibitor of Factor Xa, with potent anticoagulant activity (Figure 1). Fondaparinux may be administered as a fixed dose, once daily without the need for anticoagulant monitoring, as it has a longer half-life than LMWHs. However, like UFH and LMWHs, fondaparinux is administered parenterally and lacks the convenience of an oral agent.
A meta-analysis of four randomized double-blind studies revealed that in patients receiving fondaparinux prophylaxis after major orthopaedic surgery, major bleeding events were slightly more common than in patients receiving enoxaparin, occurring in 2.7% of fondaparinux-treated patients compared with 1.7% of enoxaparin-treated patients (P=0.008); however, the clinical significance of these data is unclear.
The risk of spinal hematoma associated with fondaparinux prophylaxis in patients receiving neuraxial blockade is unknown. Guidelines recommend caution when using fondaparinux in these patients (Table 1).
Warfarin
Warfarin is a vitamin K antagonist that exerts its anticoagulant effect indirectly by interfering with the synthesis of the vitamin K–dependent clotting factors–Factor II (thrombin), Factor VII, Factor IX, and Factor X.
Unlike heparins and fondaparinux, warfarin is orally administered. However, like UFH, warfarin has highly complex pharmacokinetic and pharmacodynamic properties, with dose response susceptible to genetic factors, drug–drug interactions, and drug–food interactions. Warfarin also has a narrow therapeutic window, putting patients at risk of blood clots or bleeding events if international normalized ratios (INRs) are not maintained in a relatively narrow range (generally 2.0–3.0). Routine coagulation monitoring and dose adjustments are therefore essential, particularly in an ambulatory setting.
Warfarin also has a slow onset and offset of action, which makes it difficult to use in the perioperative setting. In patients who are receiving anticoagulation therapy before surgery, warfarin must be stopped several days in advance of the procedure. Once warfarin therapy is reinitiated, it takes several days for patients to reach therapeutic INRs. This means that for a period of 4–5 days before and after surgery patients are at increased risk of blood clots; therefore, bridging therapy with UFH or LMWHs often is done. However, the efficacy of bridging therapy has not been established in randomized trials.
Several studies have investigated the use of regional anesthesia and analgesia in patients who received warfarin for thromboembolic prophylaxis. No spinal hematomas were reported, but the power of these studies to detect rare complications was low. The ASRA guidelines recommend that if thromboprophylaxis with a vitamin K antagonist is used with epidural analgesia, catheters should be removed while the INR is <1.5 (Table 1).
Aspirin
The antithrombotic action of aspirin is mediated via inhibition of platelet function by acetylation of the platelet cyclooxygenase (COX). This blocks production of platelet-dependent thromboxane, limiting activation and aggregation of platelets.
The effectiveness of aspirin in the prevention of VTE after TKA is subject to debate. Available data are of variable quality; there have been few high-quality randomized controlled trials comparing aspirin with other antithrombotic agents. However, aspirin would not appear to be as effective as other antithrombotic agents for preventing VTE after TKA.
The ASRA and ESA note that, on the basis of the available data, nonsteroidal antiinflammatory drugs (NSAIDs) including aspirin, when given in isolation, do not increase the risk of spinal hematoma in patients receiving epidural or spinal anesthesia (Table 1).
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