Novel oral anticoagulants for venous thromboembolism prophylaxis after total hip or knee replacement: an update on rivaroxaban (xarelto).

In 2005, approximately 285,000 individuals underwent total hip replacement (THR) procedures, and approximately 523,000 individuals had total knee replacement (TKR) procedures in the U.S.1 As the population ages, it is estimated that by 2030 the demand for these surgeries will increase, and the numbers are expected to grow to 572,000 THR procedures and 3,480,000 TKR procedures annually.1 Venous thromboembolism (VTE), which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant source of morbidity and mortality following THR and TKR.2 In the absence of thromboprophylaxis, the prevalence of proximal DVT after THR and TKR procedures is 18% to 36% and 5% to 22%, respectively.2 PE occurs in approximately 0.9% to 28% of patients after THR surgery and in 1.5% to 10% of patients after TKR surgery. Rates of fatal PE are estimated to be as high as 2% following these procedures.2 The American College of Chest Physicians (ACCP) and the American Academy of Orthopaedic Surgeons have produced evidence-based clinical practice guidelines for the prevention of VTE following THR or TKR procedures.3,4 The guidelines recommend the use of pharmacological agents, mechanical compressive devices, or both, for thromboprophylaxis.3,4 Recently updated ACCP guidelines recommend the routine use of traditional anticoagulants, such as low-molecular-weight heparins (LMWHs), fondaparinux (Arixtra, GlaxoSmithKline), vitamin K antagonists such as warfarin (Coumadin, Bristol-Myers Squibb), aspirin, or one of the newer oral anticoagulants—rivaroxaban (Xarelto, Janssen), dabigatran (Pradaxa, Boehringer Ingelheim), or apixaban (Eliquis, Pfizer/Bristol-Myers Squibb)—for pharmacological thromboprophylaxis after THR or TKR surgery.3 Despite the availability of clinical practice guidelines for thromboprophylaxis after hip or knee replacement surgery, data from the Global Orthopaedic Registry suggest that compliance with the guideline recommendations is poor in real-world clinical practice, particularly in the U.S.5 Failure to provide optimal thromboprophylaxis after orthopedic surgery clearly puts patients at risk of VTE and has significant cost implications for health care institutions. Since June 2011, the Centers for Medicare & Medicaid Services has required states to implement non-payment policies for provider preventable conditions, namely VTE following THR and TKR.6 The quality of patient care after replacement surgery would be improved by closer adherence to clinical practice guidelines, and ongoing quality monitoring programs may help to address this. The Surgical Care Improvement Project (SCIP) has released a series of National Hospital Quality Measures designed to improve care after surgery by significantly reducing complications.7 Two core measures apply to VTE: SCIP-VTE-1 records the number of patients who have been prescribed VTE prophylaxis, and SCIP-VTE-2 looks at the number of patients who actually receive VTE prophylaxis.7 Even with optimal prophylaxis, some patients remain at risk for VTE, because symptomatic VTE continues to occur in 1.3% to 10% of patients within the 3-month period following THR or TKR surgery.2 There is, therefore, an urgent need for improved prophylactic agents. The goal of this article is to educate clinicians, including pharmacists, nurses, and physicians, on new developments in VTE prophylaxis following THR or TKR surgery and to present study data, clinical highlights, and pharmacoeconomic analyses of the oral anticoagulant rivaroxaban. Clinical Trials ADVANCE: Apixaban Dose Orally vs. Anti-coagulation with Enoxaparin DURAC: Duration of Anticoagulation RECORD: Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism RE-MODEL: Dabigatran Etexilate 150 or 220 mg Once Daily vs. Enoxaparin 40 mg Once Daily in Prevention of Venous Thromboembolism Post Total Knee Replacement RE-MOBILIZE: Dabigatran Etexilate 220 mg vs. Enoxaparin 30 mg Twice Daily in Prevention of Venous Thromboembolism Post Total Knee Replacement RE-NOVATE: Dabigatran Etexilate Compared With Enoxaparin in Prevention of Venous Thromboembolism Following Total Hip Arthroplasty NOVEL ANTICOAGULANTS Several oral anticoagulants have completed phase 3 trials for VTE prophylaxis following THR or TKR surgery and have now been included in the ACCP guidelines. These anticoagulants include the direct thrombin inhibitor dabigatran and the selective, direct factor Xa inhibitors apixaban and rivaroxaban.3,8–19 These agents have been developed to address some of the limitations associated with current thromboprophylactic options. The vitamin K antagonist warfarin has been used as an oral anticoagulant for more than 60 years. Results from the DURAC studies have shown that extended vitamin K antagonist therapy is associated with a lower rate of VTE recurrence.20,21 Indeed, chronic administration of warfarin is commonly used when anticoagulation is required to prevent recurrent VTE. Although warfarin is highly effective, it has complex pharmacokinetic and pharmacodynamic properties, with a dose response that is highly susceptible to genetic factors, and numerous drug–drug and food–drug interactions.22,23 Warfarin’s narrow therapeutic window makes routine coagulation monitoring and dose adjustments essential,22 and its delayed onset and offset of action complicate its use in practice.22,24 By contrast, the newer oral anticoagulants have predictable pharmacokinetic and pharmacodynamic properties, display minimal interactions with food and other drugs, and do not require routine coagulation monitoring.25 Unlike warfarin, LMWHs such as enoxaparin (Lovenox, Sanofi) do not need to be routinely monitored and they have minimal drug interactions.26 However, subcutaneous (SQ) administration is required for LMWHs, thereby making routine treatment difficult and costly, particularly in the outpatient setting, and creating a potential barrier to patient adherence. Oral administration and a predictable response of the novel anticoagulants illustrate their advantages over both warfarin and LMWHs. The new oral anticoagulants are selective, reversible inhibitors of different components of the coagulation cascade. The direct thrombin inhibitor dabigatran is administered as a prodrug (dabigatran etexilate), which is rapidly converted to the active entity dabigatran by unspecified plasma esterases. This entity blocks the activity of free and clot-bound thrombin, preventing the transformation of fibrinogen to fibrin.25 By contrast, the direct factor Xa inhibitors rivaroxaban and apixaban directly block the activity of free and clot-bound factor Xa, preventing the transformation of prothrombin to thrombin.25 Neither rivaroxaban nor apixaban relies on the presence of antithrombin for its activity. With activity higher up the coagulation cascade, at the junction of the extrinsic and intrinsic pathways, factor Xa inhibitors have a theoretical advantage in terms of anticoagulant activity over thrombin inhibitors (Figure 1). Figure 1 The clotting cascade, highlighting the targets of new oral anticoagulants. The RE-NOVATE, RE-MODEL, and RE-MOBILIZE Trials The utility of dabigatran for VTE prophylaxis after hip or knee replacement has been investigated in four phase 3 studies. Dabigatran (150 mg or 220 mg once daily) demonstrated non-inferior efficacy and a similar safety profile to enoxaparin (40 mg once daily) for 28 to 35 days after THR surgery in RE-NOVATE and RE-NOVATE II and for 6 to 10 days after TKR surgery in RE-MODEL.8–10 There was no significant difference in the rates of major bleeding between the treatment groups in either study for dabigatran 150 mg once daily, dabigatran 220 mg once daily, and enoxaparin 40 mg once daily, respectively:8,9 RE-MODEL: 1.3%, 1.5%, and 1.3% RE-NOVATE: 1.3%, 2.0%, and 1.6% In RE-MOBILIZE, dabigatran failed to meet the non-inferiority criteria for efficacy after TKR surgery, compared with enoxaparin (30 mg twice daily) for 12 to 15 days.11 Enoxaparin 30 mg twice daily is the regimen most commonly used in North America.11