Rivaroxaban: A direct factor Xa inhibitor for VTE prophylaxis in patients undergoing total knee or hip replacement surgery
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Rivaroxaban is a highly potent direct factor Xa inhibitor that is pending FDA approval for the indication of venous thromboembolism (VTE) prophylaxis in patients undergoing total knee replacement or total hip replacement surgery.Keywords:
Total Knee Replacement
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Comparative safety and efficacy of antithrombotics in the management of venous thromboembolism after knee or hip replacement surgery: focus on rivaroxaban Louis M KwongDepartment of Orthopedic Surgery, Harbor-UCLA Medical Center, Torrance, CA, USAAbstract: Routine thromboprophylaxis represents the current standard of care in the management of patients following total hip or knee replacement. Legacy agents used to address the issue of risk of venous thromboembolism present barriers to use, either by the need for monitoring and dose adjustment (warfarin) or the need for injection (low molecular weight heparins and fondaparinux), or pose a risk of upper gastrointestinal bleeding (acetylsalicylic acid and all antithrombotic agents). The introduction of new pharmacologic agents in recent years has sought to address the issues of not only efficacy, but also safety, ease of use, and patient compliance. New orally administered agents, ie, apixaban, dabigatran, and rivaroxaban, have demonstrated various degrees of efficacy over enoxaparin while preserving safety. Indirect comparisons of the relative efficacies of apixaban, dabigatran, and rivaroxaban have shown rivaroxaban to be more efficacious than dabigatran and apixaban in reducing symptomatic and total venous thromboembolism following total hip or knee replacement surgery. A pooled analysis of the four RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent deep vein thrombosis and pulmonary embolism) trials (two in total hip replacement and two in total knee replacement) demonstrated rivaroxaban to be the first and only antithrombotic agent ever to demonstrate superiority in reducing symptomatic venous thromboembolism and all-cause mortality compared with another antithrombotic agent (enoxaparin). New oral antithrombotic agents have demonstrated efficacy in prophylaxis against venous thromboembolism following total hip or knee replacement surgery while preserving safety, with increased ease of administration of thromboprophylaxis for both the patient and the physician, which may contribute to improved compliance.Keywords: thromboprophylaxis, venous thromboembolism, rivaroxaban, total hip replacement, total knee replacement
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Patients undergoing orthopedic surgery, particularly total hip or knee replacement, also referred as total hip arthroplasty (THA) or total knee arthroplasty (TKA), are at high risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). Approximately 59,000 THA and 70,000 TKA were performed in Canada in 2017 and 2018. Without pharmacologic prophylaxis, the rate of VTE, both asymptomatic and symptomatic, could be as high as 84% for patients undergoing TKA and THA. The rate of symptomatic VTE following THA or TKA in patients receiving pharmacologic prophylaxis has been reported to be at 0.5 to 1% during in-hospital stay, and potentially increased up to 2% during 90 days after surgery.Current available chemoprophylactic agents include low molecular weight heparin (LMWH; enoxaparin, dalteparin), vitamin K antagonists (warfarin), direct Factor Xa inhibitors (rivaroxaban, apixaban), direct thrombin inhibitor (dabigatran) and aspirin (also known as acetylsalicylic acid, ASA). These agents differ among each other in terms of mechanism of action, potency, efficacy and safety.Unlike the other anticoagulants, ASA does not affect any step in the coagulation cascade, rather it irreversibly inhibits cyclooxygenase-1, an enzyme involved in platelet aggregation. ASA has been recently found to be involved in several mechanisms of venous thrombosis in addition to its anti-platelet aggregation property, suggesting its involvement in VTE prophylaxis. Interest in ASA as a means of VTE prophylaxis has recently grown, and recent literature suggests that ASA could be a viable option for VTE prophylaxis following THA or TKA, due to its potentially favorable efficacy and safety profile. A recent 2017 CADTH report found mixed evidence on the clinical effectiveness of ASA compared with LMWH and Factor Xa inhibitors.The aim of this report is to review the evidence regarding the clinical effectiveness and evidence-based guidelines regarding the use of ASA for VTE prophylaxis in patients undergoing THA or TKA. The term aspirin is used interchangeably with ASA throughout this review, particularly in the Summary of Evidence section, to be consistent with the terminology used in all included studies.
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Patients undergoing major orthopedic surgery, including total hip arthroplasty (THA) and total knee arthroplasty (TKA), are at high risk for developing venous thromboembolism (VTE). Although largely a preventable complication, VTE develops in a significant proportion of patients, highlighting the need for improved methods of VTE prevention. Current thromboprophylactic options are limited by unpredictable pharmacokinetics and pharmacodynamics (vitamin K antagonists), parenteral/subcutaneous administration (heparin and low-molecular-weight heparins), complicated dosing, and increased risk of bleeding.Rivaroxaban is an oral, direct Factor Xa inhibitor that has recently received marketing authorization in the United States for prophylaxis of deep vein thrombosis in patients undergoing hip or knee replacement surgery. The clinical pharmacology of rivaroxaban supports a convenient, oral, once-daily dosing regimen without the need for routine coagulation monitoring after THA or TKA. A comprehensive phase II and III study program supports its safety and efficacy for VTE prevention after THA or TKA. Phase III results have demonstrated the superior efficacy of rivaroxaban regimens compared with enoxaparin regimens, with similar rates of major bleeding. This article provides an overview of the phase II and III results that support the use of this agent for the prevention of VTE after elective total hip or knee replacement.
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Venous thromboembolic (VTE) events are important causes of morbidity in elective total hip replacement (THR) and total knee replacement (TKR) procedures. Current guidelines recommend thromboprophylaxis in patients undergoing THR or TKR, although the American Academy of Orthopaedic Surgeons (AAOS) guidelines suggest individual assessment of patients when choosing the specific thromboprophylaxis strategy. Low molecular weight heparin (LMWH) and adjusted-dose warfarin are the most commonly used anticoagulants for thromboprophylaxis in the United States, but a number of other treatment options are available, including unfractionated heparin, aspirin, mechanical devices, and newer oral anticoagulants.Prior to 1980, rates of symptomatic VTE were 15 to 30 percent. However, improved surgical care and techniques have decreased the rate of symptomatic VTE. A recent analysis that incorporated data from trials and observational studies estimated the contemporary 35-day rate of symptomatic VTE without thromboprophylaxis at 4.3 percent.Pharmacological thromboprophylaxis for THR or TKR surgery decreases VTE by approximately 50 percent but with the tradeoff of increased bleeding. The risk of bleeding is a concern because bleeding can lead to infections, reoperation, delayed wound healing, and extended hospital stay. The choice of which antithrombotic thus becomes pivotal for balancing the prevention of thromboembolism with the risk of bleeding. Newer oral anticoagulants have been developed with the goal of overcoming the limitations of warfarin and the available parenteral agents. These newer anticoagulants belong to two drug classes, based on their target coagulation protein: factor Xa (FXa) inhibitors and direct thrombin inhibitors (DTIs). These drugs are given as fixed oral doses and have the advantage of a more predictable anticoagulant effect, eliminating the need for monitoring when used for short-term thromboprophylaxis. Disadvantages of newer oral anticoagulants include the lack of specific antidotes to reverse their anticoagulant effect in a timely fashion in case of bleeding, and drug costs.Given the emerging data on new oral anticoagulants, this report was commissioned by the VA to examine the following key questions (KQs): KQ 1. For patients undergoing total hip or total knee replacement, what is the comparative effectiveness of newer oral anticoagulants and standard drug classes (low molecular weight heparin, injectable factor Xa inhibitors, unfractionated heparin, warfarin, aspirin) on the incidence of symptomatic, objectively confirmed venous thromboembolism (VTE), other VTE events, total mortality, and bleeding outcomes? KQ2. For patients undergoing total hip or total knee replacement, what are the effects of combined pharmacological and mechanical modalities versus pharmacological treatment alone on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, and bleeding outcomes? KQ3. For patients undergoing total hip or total knee replacement, what is the comparative efficacy of individual newer oral anticoagulants on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, and bleeding outcomes?
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Summary A number of novel oral anticoagulants that directly target factor Xa or thrombin have been developed in recent years. Rivaroxaban and apixaban (direct factor Xa inhibitors) and dabigatran etexilate (a direct thrombin inhibitor) have shown considerable promise in large-scale, randomised clinical studies for the management of thromboembolic disorders, and have been approved for clinical use in specific indications. Rivaroxaban is licensed for the prevention of venous thromboembolism in patients undergoing elective hip or knee replacement surgery, the treatment of deep-vein thrombosis and prevention of recurrent venous thromboembolism, and for stroke prevention in patients with non-valvular atrial fibrillation. Based on the clinical trial data for rivaroxaban, feedback on its use in clinical practice and the authors’ experience with the use of rivaroxaban, practical guidance for the use of rivaroxaban in special patient populations and specific clinical situations is provided. Although most recommendations are in line with the European summary of product characteristics for the approved indications, additional and, in several areas, different recommendations are given based on review of the literature and the authors’ clinical experience.
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To review the pharmacology, pharmacokinetics, and clinical efficacy/safety profile of rivaroxaban to inform health-care professionals of this new agent for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopedic surgery.A literature search was performed in PubMed/MEDLINE (1966-March 2010), International Pharmaceutical Abstracts (1970-March 2010), and EMBASE (1990-March 2010), limited to publications in English, using the search terms BAY 59-7939, rivaroxaban, factor Xa inhibitor, hip replacement, and/or knee replacement to identify literature sources. References from retrieved articles were evaluated to identify relevant literature. Unpublished Phase 3 clinical trials in progress (using www.clinicaltrials.gov) were also reviewed. The Food and Drug Administration, European Medicines Agency, and Health Canada Web sites were used to retrieve product monographs, regulatory guidance, and advisory committee briefing packets.All available studies relevant to the pharmacology, pharmacokinetics, and clinical safety/efficacy of rivaroxaban for the prevention of VTE in patients undergoing major orthopedic surgery were included, with preference for clinical data.Rivaroxaban use was significantly more effective for thromboprophylaxis in patients undergoing total knee replacement (TKR) or total hip replacement (THR), compared to enoxaparin for the composite incidence of deep vein thrombosis, nonfatal pulmonary embolism, all-cause mortality, and the rate of major VTE; bleeding events occurred at statistically similar rates. In Phase 3 studies, rivaroxaban 10 mg was administered orally 6-8 hours post-surgery and post-hemostasis. Thereafter, administration was once daily for 35 days in THR and 10-14 days in TKR.Rivaroxaban has demonstrated comparable safety and superior efficacy to the commonly used low-molecular-weight heparin, enoxaparin. Ongoing and future clinical trials will allow clinicians to further assess the efficacy, safety, and pharmacoeconomics of rivaroxaban.
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Venous thromboembolism (VTE) is a common complication after total hip and total knee arthroplasty. Currently used methods of VTE prophylaxis after these procedures have important limitations, including parenteral administration, and unpredictable plasma levels requiring frequent monitoring and dose adjustment leading to decreased patient compliance with recommended guidelines. New oral anticoagulants have been demonstrated in clinical trials to be equally efficacious to enoxaparin and allow for fixed dosing without the need for monitoring. Rivaroxaban is one of the new oral anticoagulants and is a direct factor Xa inhibitor that has demonstrated superior efficacy to that of enoxaparin. However, the data also suggest that rivaroxaban has an increased risk of bleeding compared to enoxaparin. This paper reviews the available data on the efficacy and safety of rivaroxaban for VTE prophylaxis after total hip and total knee arthroplasty.
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Thromboprophylactic regimens based on rivaroxaban – a novel, oral, once-daily, direct Factor Xa inhibitor approved in the EU and Canada for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective total hip and total knee replacement (THR/TKR) surgery – were compared with subcutaneous enoxaparin (40 mg once daily) regimens in phase III randomized clinical trials in patients undergoing THR (RECORD1 and RECORD2) 1,2 or TKR (RECORD3) 3 In addition to the clinical benefits associated with reducing symptomatic VTE, significant economic benefits may be achievable because fewer healthcare resources may be required with rivaroxaban
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