Rivaroxaban, an Oral, Direct Factor Xa Inhibitor: A New Option for Thromboprophylaxis

Transcription

1 n Feature Article, an Oral, Direct Factor Xa Inhibitor: A New Option for Thromboprophylaxis Louis M. Kwong, MD, FACS abstract Full article available online at Healio.com/Orthopedics. Search: 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. 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. Dr Kwong is from the Department of Orthopaedic Surgery, Harbor UCLA Medical Center, Torrance, California. Dr Kwong has received research funding from Bayer HealthCare, Sanofi Aventis, and Astellas. Dr Kwong thanks Elizabeth Ng for editorial support in the preparation of this manuscript, with funding from Bayer HealthCare. Correspondence should be addressed to: Louis M. Kwong, MD, FACS, Department of Orthopaedic Surgery, Harbor UCLA Medical Center, 1000 W Carson St, Box 422, Torrance, CA (lkwong@ dhs.lacounty.gov). doi: / Figure: Pharmacokinetic model of rivaroxaban plasma concentration profile after a fixed dose of 10 mg once daily in extreme case scenarios compared with the observed profile in an average patient (65 years, 75 kg, creatinine clearance [CrCl] 90 ml/min). Editor s Comment The Editor would like to issue a word of caution on rivaroxaban use, especially in surgical settings where bleeding issues exist and in situations that may require the need for sudden reversal. Bleeding issues were experienced with dextran in the 1960s. Reversal techniques currently exist with heparin and coumadin, and not having the ability to reverse treatment, especially in the trauma and surgical settings, is a limitation of rivaroxaban. I have not changed my prophylaxis regimen since the approval of rivaroxaban. Robert D. D Ambrosia, MD Editor-in-Chief, Orthopedics e932 Healio.com The new online home of ORTHOPEDICS Healio.com/Orthopedics

2 for Thromboprophylaxis Kwong Patients undergoing major orthopedic surgery, including total hip arthroplasty (THA) and total knee arthroplasty (TKA), are at high risk for developing venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism. Prophylaxis with anticoagulants after THA or TKA is recommended for 2 weeks to reduce the risk of VTE and subsequent morbidity and mortality, which often occur after patients have been discharged. Guidelines recommend extending thromboprophylaxis to 35 days after THA. 1 Thromboprophylactic options include vitamin K antagonists (eg, warfarin), heparin, low-molecular-weight heparins (LMWHs) such as enoxaparin, the synthetic pentasaccharide fondaparinux (an indirect Factor Xa inhibitor), and acetylsalicylic acid. However, acetylsalicylic acid is an antiplatelet agent rather than an anticoagulant, and the American College of Chest Physicians (ACCP) guidelines specifically recommend against the use of acetylsalicylic acid alone as a thromboprophylactic strategy for the prevention of VTE. 2 Recent studies have highlighted the poor uptake of guideline-recommended thromboprophylaxis after major orthopedic surgery, with approximately half of patients receiving care as recommended in the seventh ACCP guidelines in the United States and across other global health care systems. 3,4 Low compliance with guideline recommendations may be a result of the limitations of current thromboprophylactic agents. These limitations include unpredictable pharmacokinetics and pharmacodynamics (vitamin K antagonists), parenteral/subcutaneous administration (heparin, fondaparinux, and LMWHs), complicated dosing, and the poor balance between efficacy and bleeding. As such, an ongoing need exists for additional prophylactic options that will ideally offer an oral route of intake, once-daily administration, and fixed dosing over a wide range of patients. Such features could potentially improve patient compliance. is an oral, direct Factor Xa inhibitor that was approved by the Food and Drug Administration in July 2011 for the prophylaxis of DVT, which may lead to pulmonary embolism, in patients undergoing hip or knee replacement. The pharmacologic and clinical properties of this agent may address the limitations of older thromboprophylactic options. This article provides an overview of the rationale for once-daily dosing with rivaroxaban in this indication and reviews the phase III results of rivaroxaban for the prevention of VTE after THA or TKA. Clinical Pharmacology of The clinical pharmacology of rivaroxaban in healthy men has been assessed in 2 phase I studies. demonstrated a good safety profile when administered to healthy volunteers over the dose range of 5 to 60 mg/day, with no clinically relevant changes in bleeding time or other safety variables across all doses and regimens evaluated. 5 dose-dependently inhibits Factor Xa, with the maximum inhibitory effect occurring 1 to 4 hours after administration, with detectable thrombin inhibition persisting at 24 hours for doses.5 mg. 5,6 This latter observation suggested that once-daily dosing might be feasible. A multiple-dose study also showed that maximum inhibition did not differ significantly between initial drug administration and steady state, indicating no substantial accumulation of rivaroxaban after multiple doses. 5 also dose-dependently prolonged the prothrombin time, again with no apparent accumulation of effect. 5-7 These studies also provided important information on the pharmacokinetic profile of rivaroxaban (Table 1). displayed dose-proportional pharmacokinetics (over the range of 5 to 60 mg/day) that correlated closely with the pharmacodynamic profile described previously. 5 To determine whether dose adjustment might be necessary for defined patient populations, the Table 1 Key Pharmacokinetic Properties of 5,20,29,37 Parameter Half-life, h Healthy young participants Profile 5-9 Elderly participants Variability Intra-individual Inter-individual Excretion Hepatic Renal Circulating metabolites Low Moderate One-third of oral dose Two-thirds of oral dose (one-third as unchanged drug) None pharmacokinetic profile of rivaroxaban was also determined by age group, sex, and body weight. 8,9 Age had no significant effect on the maximum plasma concentration (C max ) achieved with rivaroxaban, although bioavailability was higher in elderly participants compared with younger participants. 10 Similarly, regarding the inhibition of Factor Xa activity and the prolongation of prothrombin time, the area under the concentration time curve was higher in elderly participants than in younger participants. 10 However, the maximum effect for these parameters was not affected significantly by age. 10 Neither sex nor body weight were found to appreciably affect the pharmacokinetic or pharmacodynamic profile of rivaroxaban. 9,10 Thus, dose adjustment of rivaroxaban was considered to be unnecessary in these patient populations. 9,10 The effects of renal or hepatic impairment on the pharmacology of rivaroxaban have also been evaluated. 11,12 Increasing renal impairment resulted in decreased renal clearance, and hence decreased total body clearance of rivaroxaban, resulting JUNE 2012 Volume 35 Number 6 e933

3 n Feature Article in increased overall exposure to rivaroxaban. 11 This was reflected in the higher area under the concentration time curve values in participants with mild, moderate, and severe renal impairment (44%, 52%, and 64% higher, respectively) compared with healthy participants (P,.05). 11 However, the C max of rivaroxaban was relatively unaffected, confirming that the increased exposure to rivaroxaban was a result of decreased clearance rather than increased absorption. Patients with mild or moderate renal impairment were included in phase II clinical studies and received the same fixed dose as those without renal impairment, with no apparent effects on efficacy or safety. In a separate study, in participants with mild hepatic impairment, rivaroxaban showed no clinically relevant pharmacologic differences compared with healthy participants. However, in participants with moderate hepatic impairment, a decrease in rivaroxaban clearance was observed, which led to increased plasma levels, an increase in Factor Xa inhibition activity, and prolongation of prothrombin time. 12 has not been studied in patients with significant hepatic disease associated with coagulopathy leading to a clinically relevant bleeding risk. has a low risk of drug drug interactions with frequently used concomitant medications. Randomized studies in healthy participants have investigated the effect of concomitant medications on the safety, tolerability, pharmacokinetics, and pharmacodynamics of rivaroxaban. When coadministered with acetylsalicylic acid, naproxen (a nonsteroidal antiinflammatory drug [NSAID]), enoxaparin, digoxin, atorvastatin, H 2 antagonists, or antacids, no clinically relevant effect on the pharmacodynamic profile of rivaroxaban was observed is not recommended in patients concomitantly receiving strong inhibitors of cytochrome P450 3A4 (CYP3A4) or the transport protein P-glycoprotein (P-gp) both of which are involved in the elimination of rivaroxaban because these may increase rivaroxaban plasma concentrations to a clinically relevant degree, which may increase the risk of bleeding. These agents include azole-antimycotics (such as ketoconazole, itraconazole, voriconazole, and posaconazole) and human immunodeficiency virus protease inhibitors (such as ritonavir). 20 No specific antidote exists to reverse the effects of rivaroxaban; however, preclinical studies suggest that the administration of recombinant activated Factor VII or activated prothrombin complex concentrate may reverse the effects of high-dose rivaroxaban A study in healthy participants also showed that prothrombin complex concentrate reversed the anticoagulant effect of rivaroxaban. 24 If standard strategies such as delaying the next dose of rivaroxaban or discontinuation, mechanical compression, surgical intervention, and blood product transfusion fail to control bleeding, these agents may be considered as antidotes in bleeding emergencies. However, there is currently little experience with the use of either of these agents in patients receiving rivaroxaban. Clinical Studies: Prevention of Venous Thromboembolism Phase II: ODIXa Studies was assessed relative to the LMWH comparator enoxaparin for the prevention of VTE after THA or TKA in 4 phase II studies A large and extensive phase II program assessed once-daily and twice-daily dosing regimens, over a twelvefold dose range of rivaroxaban (total daily doses, 5-60 mg) Details of the study designs and of the efficacy and safety endpoints are summarized in Table 2. These dose-finding studies indicated that all tested rivaroxaban dose regimens had similar efficacy to enoxaparin. The open-label ODIXa (Oral, DIrect Factor Xa inhibition with BAY for the prevention of venous thromboembolism after total hip replacement)-hip study 25 demonstrated the proof of principle of rivaroxaban for the prevention of VTE after THA. Results with the rivaroxaban 30 mg once-daily dose for efficacy and safety were similar to the twice-daily results, indicating that once-daily dosing of rivaroxaban was feasible. The ODIXa-HIP2 and ODIXa- KNEE studies demonstrated that rivaroxaban regimens of 5 to 20 mg total daily dose offered a flat dose response relationship after THA and TKA for the composite primary efficacy endpoint of DVT, pulmonary embolism, and all-cause mortality 26,27 and were considered to provide the most favorable balance between efficacy and safety. The data from these studies highlighted the wide therapeutic window for rivaroxaban. These studies also confirmed that the incidence of major bleeding over this dose range was similar to that of enoxaparin. Finally, a once-daily dosing study, ODIXa- HIP-OD, 28 in association with the results of other studies, indicated that the optimum dose of rivaroxaban when efficacy and safety outcomes were considered together was 10 mg once daily. The pharmacodynamic relationship between rivaroxaban plasma concentration and prothrombin time is similar in healthy participants and in patients undergoing THA or TKA. 29 A pooled analysis of 2 phase II studies of rivaroxaban given either once or twice daily in patients undergoing THA 26,28 suggested that differences in plasma concentrations between the 2 regimens were not clinically relevant. 30 The analysis also confirmed the predictable pharmacokinetic/pharmacodynamic profile of rivaroxaban in patients, which was consistent with that observed in healthy participants. 30 These data support fixed dosing of rivaroxaban regardless of age, sex, or body weight, and in patients with mild-to-moderate renal impairment. 30 In addition, evaluation of rivaroxaban plasma concentrations in extreme case scenarios patients with extremes of the demographic factors suggested these factors should not lead to significant changes in rivaroxaban exposure after a 10 mg once-daily dose (Figure 1). 30 These data further supported a fixed dose of rivaroxaban 10 mg once daily for a wide range of patients. e934 Healio.com The new online home of ORTHOPEDICS Healio.com/Orthopedics

4 for Thromboprophylaxis Kwong Table 2 Study Design and Safety and Efficacy Endpoints in the Phase II ODIXa Studies of for the Prevention of Venous Thromboembolism After THA or TKA Study Design Population N Regimen Duration, d Endpoints ODIXa-HIP 25 ODIXa-HIP2 26 ODIXa-KNEE 27 ODIXa-HIP-OD 28 Open label, dose escalation dose finding dose finding dose finding THA , 5, 10, 20, or 30 mg twice daily or 30 mg once daily vs enoxaparin 40 mg once daily THA , 5, 10, 20, or 30 mg twice daily vs enoxaparin 40 mg once daily TKA , 5, 10, 20, or 30 mg twice daily vs enoxaparin 30 mg twice daily THA mg once daily vs enoxaparin 40 mg once daily 5-9 Efficacy endpoints Evaluated 5-9 days postoperatively in the open-label and twice-daily studies and 6-10 days postoperatively in the once-daily study 5-9 Primary: total VTE (composite of any DVT, nonfatal PE, and all-cause mortality) Secondary: major VTE (composite of proximal DVT, nonfatal PE, and VTE-related death) 5-9 Safety endpoints Bleeding occurring after the first postoperative dose of study drug and no later than days after the last dose Primary: major bleeding Other: clinically relevant nonmajor bleeding; minor bleeding; laboratory parameters Abbreviations: DVT, deep vein thrombosis; ODIXa, Oral, Direct Factor Xa inhibition with BAY for the prevention of venous thromboembolism after total hip replacement; PE, pulmonary embolism; THA, total hip arthroplasty; TKA, total knee arthroplasty; VTE, venous thromboembolism. Figure 1: Pharmacokinetic model of rivaroxaban plasma concentration profile after a fixed dose of 10 mg once daily in extreme case scenarios compared with the observed profile in an average patient (65 years, 75 kg, creatinine clearance [CrCl] 90 ml/min). 30 Phase III Studies: The RECORD Program The RECORD (REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism) program comprised 4 studies investigating the efficacy and safety of rivaroxaban 10 mg once daily compared with standard doses of enoxaparin in.12,500 patients undergoing THA or TKA (Table 3) All patients in the RECORD 1 studies received once-daily rivaroxaban. There was no upper age or weight limit for participation. The primary efficacy endpoint of these studies was the composite of DVT, nonfatal pulmonary embolism, and all-cause mortality (total VTE) up to day 42 in the hip studies and up to day 17 in the knee studies. Major and symptomatic VTE were also evaluated. The primary safety endpoint was major bleeding. The RECORD1 study, in patients undergoing THA, showed that rivaroxaban was significantly more effective than enoxaparin 40 mg once daily for extended prophylaxis in patients undergoing THA. 31 Total VTE and major VTE occurred at a significantly lower frequency than with enoxaparin, whereas symptomatic VTE occurred in fewer patients, but the difference did not reach statistical significance (Table 4). The results of the RECORD2 study in patients undergoing THA demonstrated that extended-duration rivaroxaban prophylaxis was significantly more effective than short-duration prophylaxis with enoxaparin followed by placebo in patients undergoing THA. 32 Total VTE, major VTE, and symptomatic VTE occurred at a significantly lower frequency with rivaroxaban than with JUNE 2012 Volume 35 Number 6 e935

5 n Feature Article Table 3 Study Design and Safety and Efficacy Endpoints in the Phase III RECORD Studies of for the Prevention of Venous Thromboembolism After THA or TKA Study Design Population N a Regimen Duration Endpoints b RECORD1 31 RECORD2 32 RECORD3 33 RECORD4 34 double dummy double dummy double dummy double dummy THA mg once daily vs enoxaparin 40 mg once daily THA mg once daily vs enoxaparin 40 mg once daily TKA mg once daily vs enoxaparin 40 mg once daily TKA mg once daily vs enoxaparin 30 mg twice daily days; enoxaparin days days; enoxaparin days followed by placebo days; enoxaparin days days; enoxaparin days Efficacy endpoints Primary: total VTE (composite of any DVT, nonfatal PE, and all-cause mortality up to day 42 [RECORD1 and 2] or day 17 [RECORD3 and 4]) Secondary: major VTE (composite of proximal DVT, nonfatal PE, and VTE-related death) Other: incidence of any DVT, the incidence of symptomatic VTE during the active therapy and follow-up periods, and death during the follow-up period Safety endpoints Bleeding occurring after the first blinded dose of study drug and no later than 2 days after the last dose Primary: major bleeding (bleeding that was fatal, into a critical organ, or required reoperation; extra-surgical-site bleeding associated with a drop in hemoglobin >2 g/dl or requiring transfusion of >2 units of blood) Other: any on-treatment bleeding; nonmajor bleeding; clinically relevant nonmajor bleeding; hemorrhagic wound complications; cardiovascular adverse events; liver enzyme levels Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; RECORD, REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism; THA, total hip arthroplasty; TKA, total knee arthroplasty; VTE, venous thromboembolism. a Randomized. b As assessed by central independent adjudication committees. enoxaparin (Table 4). This supports the benefits of the recommended duration of therapy after THA (35 days). In RECORD3, in patients undergoing TKA, rivaroxaban was significantly more effective than enoxaparin 40 mg once daily for short-term prophylaxis in patients undergoing TKA, with a similar safety profile. 33 Total VTE, major VTE, and symptomatic VTE were significantly less frequent with rivaroxaban than with enoxaparin (Table 4). The RECORD4 study, in patients undergoing TKA, showed rivaroxaban to be significantly more effective than the standard US regimen of enoxaparin 30 mg twice daily every 12 hours. 34 This is the only study to date of a new oral anticoagulant that has shown superiority to this regimen after TKA. Apixaban and dabigatran (direct inhibitors of Factor Xa and thrombin, respectively) failed to show noninferiority to enoxaparin 30 mg twice daily after TKA. 35,36 The safety profile for rivaroxaban was consistent with that previously reported across the phase II studies. The incidence of major bleeding across the RECORD studies was similar to that for enoxaparin (Table 4). The incidence of cardiovascular events during treatment was low and similar between rivaroxaban and enoxaparin, and no consistent treatment differences were observed after completion of drug administration. No additional safety concerns were raised for rivaroxaban therapy across the 4 phase III clinical trials conducted for this agent. No evidence was found of any liver safety issues attributable to rivaroxaban. Conclusion has been shown to be an effective oral anticoagulant. In healthy participants, it has a rapid onset of action and predictable regulation of coagulation after a single dose and multiple dosing. A low risk of drug drug interactions exists with frequently used medications such as acetylsalicylic acid and NSAIDs. has shown effective anticoagulation and a favorable safety profile in clinical studies for the prevention of VTE after THA or TKA. The clinical pharmacology of oral rivaroxaban, in combination with results from phase II studies, suggested that once-daily, fixed dosing was feasible for the prevention of VTE after THA or TKA, without compromising efficacy and safety. These findings have been confirmed in large phase III VTE prevention studies where rivaroxaban 10 mg once daily after THA or TKA was shown to have superior efficacy in the prevention of VTE with a similar incidence of major bleeding compared with enoxaparin e936 Healio.com The new online home of ORTHOPEDICS Healio.com/Orthopedics

6 for Thromboprophylaxis Kwong Table 4 Incidence of Venous Thromboembolism and Bleeding Events Across the RECORD Studies Endpoint, %, n/n Efficacy endpoints RECORD1 (THA) RECORD2 (THA) RECORD3 (TKA) RECORD4 (TKA) Enoxaparin 40 mg od d d d d d 10 mg od Enoxaparin 40 mg od followed by placebo 10 mg od Enoxaparin 40 mg od 10 mg od Enoxaparin 30 mg bid 10 mg od Total VTE a 3.7, 58/ , 18/ , 81/ , 17/ , 166/ , 79/ , 97/ , 67/965 RRR: 70% RRR: 79% RRR: 49% RRR: 31% P,.001 b P,.0001 b P,.001 b P b Major VTE a 2.0, 33/ , 4/ , 49/ , 6/ , 24/ , 9/ , 22/ , 13/1122 RRR: 88% RRR: 88% RRR: 62% RRR: 41% P,.001 b P,.0001 b P5.01 b P b Symptomatic VTE c 0.5, 11/ , 6/ , 15/ , 3/ , 24/ , 8/ , 18/ , 11/1526 Bleeding endpoints RRR: 45% RRR: 80% RRR: 66% RRR: 40% P5.22 b P b P5.005 b P b Major bleeding d 0.1, 2/ , 6/2209,0.1, 1/1229,0.1, 1/ , 6/ , 7/ , 4/ , 10/1526 Clinically relevant 2.4, 54/ , 65/ , 33/ , 40/ , 28/ , 33/ , 138/ , 155/1526 nonmajor bleeding d Abbreviations: bid, twice daily; od, once daily; RECORD, REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism; RRR, relative risk reduction; THA, total hip arthroplasty; TKA, total knee arthroplasty; VTE, venous thromboembolism. a Modified intention-to-treat population. b All P values for efficacy calculated from absolute risk reduction. c Safety population who underwent surgery. d Safety population. the other anticoagulants licensed for VTE prevention after major orthopedic surgery. Because it is administered orally, once daily, and at a fixed dose without the need for routine coagulation monitoring, rivaroxaban is a convenient and effective option for patients and physicians after THA or TKA. Figure 2: Summary of the incidence of total venous thromboembolism from the RECORD trials RECORD2 compared extended prophylaxis with rivaroxaban (3564 days) with short-term prophylaxis with enoxaparin (1262 days). regimens. Across the RECORD studies, no evidence was found of a requirement for routine coagulation monitoring or dose adjustment. In all 4 studies, rivaroxaban demonstrated superior efficacy without compromising safety. was significantly more effective than enoxaparin regimens in the prevention of total VTE (Figure 2). represents an effective, well-tolerated, and convenient alternative to 2 References 1. 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(6 suppl):381s-453s. 2. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004; 126(3 suppl):338s-400s. 3. Friedman RJ, Gallus AS, Cushner FD, Fitzgerald G, Anderson FA Jr; Global Orthopedic Registry Investigators. Physician compliance with guidelines for deep-vein thrombosis prevention in total hip and knee arthroplasty. Curr Med Res Opin. 2008; 24(1): Cohen AT, Tapson VF, Bergmann JF, et al; ENDORSE Investigators. Venous thromboembolism risk and prophylaxis in the acute hos- JUNE 2012 Volume 35 Number 6 e937

7 n Feature Article pital care setting (ENDORSE study): a multinational cross-sectional study. Lancet. 2008; 371(9610): Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY an oral, direct Factor Xa inhibitor after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005; 61(12): Graff J, von Hentig N, Misselwitz F, et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity [published online ahead of print September 14, 2007]. J Clin Pharmacol. 2007; 47(11): Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY , an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005; 78(4): Kubitza D, Becka M, Mueck W, Zuehlsdorf M. The effect of extreme age and gender on the pharmacology and tolerability of rivaroxaban an oral, direct Factor Xa inhibitor. Blood (ASH Annual Meeting Abstracts). 2006; 108(11):abstract Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY ) in healthy subjects. J Clin Pharmacol. 2007; 47(2): Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Pharmacology of the oral, direct Factor Xa inhibitor rivaroxaban effect of extreme age and gender. Hämostaseologie. 2007; 27:A40:abstract P Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. 2010; 70(5): Halabi A, Kubitza D, Zuehlsdorf M, Becka M, Mueck W, Maatouk H. Effect of hepatic impairment on the pharmacokinetics, pharmacodynamics and tolerability of rivaroxaban an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2007; 5(suppl 2):abstract P-M Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Aspirin has no effect on the safety, tolerability, pharmacodynamics and pharmacokinetics of BAY an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005; 3(suppl 1):abstract P Kubitza D, Becka M, Zuehlsdorf M, Mueck W. No interaction between the novel, oral direct Factor Xa inhibitor BAY and digoxin. J Clin Pharmacol. 2006; 46(6):702:abstract Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an antacid, and the H 2 antagonist ranitidine on the absorption of BAY (rivaroxaban), an oral, direct Factor Xa inhibitor, in healthy subjects. J Clin Pharmacol. 2006; 46(5): Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban an oral, direct Factor Xa inhibitor are not affected by aspirin. J Clin Pharmacol. 2006; 46(9): Kubitza D, Becka M, Mueck W, Zuehlsdorf M., a novel, oral, direct Factor Xa inhibitor, has no clinically relevant interaction with acetylsalicylic acid or naproxen. J Thromb Haemost. 2007; 5(suppl 2):abstract P-T Kubitza D, Becka M, Voith B, Zuehlsdorf M. Effect of enoxaparin on the safety, tolerability, pharmacodynamics and pharmacokinetics of BAY an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005; 3(suppl 1):abstract P Kubitza D, Mueck W, Becka M. No interaction between rivaroxaban a novel, oral, direct Factor Xa inhibitor and atorvastatin. Pathophysiol Haemost Thromb. 2008; 36(suppl 1):A40:abstract P Xarelto (rivaroxaban) Summary of Product Characteristics. Bayer Pharma AG Web site. Characteristics_Dec2011.pdf. Accessed March 22, Gruber A, Marzec UM, Buetehorn U, Hanson S, Perzborn E. Potential of activated prothrombin complex concentrate and activated Factor VII to reverse the anticoagulant effects of rivaroxaban in primates. Blood (ASH Annual Meeting Abstracts). 2008; 112(11):1307:abstract Perzborn E, Trabandt A, Selbach K, Tinel H. Prothrombin complex concentrate reverses the effects of high-dose rivaroxaban in rats. J Thromb Haemost. 2009; 7(suppl 2):379:abstract PP-MO Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor [published online ahead of print December 17, 2010]. Nat Rev Drug Discov. 2011; 10(1): Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebocontrolled, crossover study in healthy subjects. Circulation. 2011; 124(14): Eriksson BI, Borris LC, Dahl OE, et al. Dose-escalation study of rivaroxaban (BAY ) an oral, direct Factor Xa inhibitor for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Res. 2007; 120(5): Eriksson BI, Borris L, Dahl OE, et al. Oral, direct Factor Xa inhibition with BAY for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost. 2006; 4(1): Turpie AG, Fisher WD, Bauer KA, et al. BAY : an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost. 2005; 3(11): Eriksson BI, Borris LC, Dahl OE, et al. A oncedaily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY ), for thromboprophylaxis after total hip replacement. Circulation. 2006; 114(22): Mueck W, Eriksson BI, Bauer KA, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban an oral, direct factor Xa inhibitor in patients undergoing major orthopedic surgery. Clin Pharmacokinet. 2008; 47(3): Mueck W, Borris LC, Dahl OE, et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost. 2008; 100(3): Eriksson BI, Borris LC, Friedman RJ, et al. versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008; 358(26): Kakkar AK, Brenner B, Dahl OE, et al; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial [published online ahead of print June 24, 2008]. Lancet. 2008; 372(9632): Lassen MR, Ageno W, Borris LC, et al. versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008; 358(26): Turpie AG, Lassen MR, Davidson BL, et al. versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial [published online ahead of print May 4, 2009]. Lancet. 2009; 373(9676): 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(6): 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): Kubitza D, Becka M, Roth A, Mueck W. Doseescalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin. 2008; 24(10): e938 Healio.com The new online home of ORTHOPEDICS Healio.com/Orthopedics

8 for Thromboprophylaxis Kwong Editor s Comment The Editor would like to issue a word of caution on rivaroxaban use, especially in surgical settings where bleeding issues exist and in situations that may require the need for sudden reversal. Bleeding issues were experienced with dextran in the 1960s. Reversal techniques currently exist with heparin and coumadin, and not having the ability to reverse treatment, especially in the trauma and surgical settings, is a limitation of rivaroxaban. I have not changed my prophylaxis regimen since the approval of rivaroxaban. Robert D. D Ambrosia, MD Editor-in-Chief, Orthopedics JUNE 2012 Volume 35 Number 6 e939