Venous thromboembolism (VTE) comprises deepvein

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1 At a Glance Original Research Practical Implications p 107 Author Information p 110 Full text and PDF Economic Model Comparing Rivaroxaban and Enoxaparin for Post-Orthopedic VTE Prophylaxis Louis M. Kwong, MD; Brahim K. Bookhart, MBA, MPH; and Samir H. Mody, PharmD, MBA ABSTRACT Objectives: Venous thromboembolism (VTE) is a common complication following orthopedic surgery with a signifi cant impact on healthcare resources. This analysis evaluates the health outcomes and costs associated with rivaroxaban compared with enoxaparin for prevention of VTE following elective total hip replacement (THR) or total knee replacement (TKR) surgery from a US payer perspective. Study Design: Events data from 3 RECORD trials presented in the US package insert were used to develop an economic model comparing once-daily oral rivaroxaban with subcutaneous generic enoxaparin for prevention of VTE after THR and TKR surgery. Methods: Projected drug and event-related costs in the United States associated with symptomatic VTE events over a 90-day period were estimated for a simulated cohort of 1000 patients undergoing either THR or TKR. Sensitivity analyses were performed to determine the impact of varying costs of generic enoxaparin and VTE events. Results: The RECORD trials demonstrated a signifi cant reduction in risk of symptomatic VTE and a decrease in all-cause mortality in patients receiving rivaroxaban following THR or TKR surgery, with a similar rate of bleeding events, compared with enoxaparin. Total projected savings per cohort with rivaroxaban, including drug acquisition costs and symptomatic event-related costs, were $523,841 and $304,031 for the THR and TKR populations, respectively. The cost savings with rivaroxaban remained after performing multiple sensitivity analyses. Conclusions: Clinical trials have demonstrated that rivaroxaban is a safe and effective alternative to enoxaparin for prevention of VTE after THR and TKR. Compared with enoxaparin, it also results in signifi cant cost savings. (Am J Pharm Benefi ts. 2013;5(3): ) Venous thromboembolism (VTE) comprises deepvein thrombosis (DVT) and pulmonary embolism (PE) and represents a significant health burden in the United States. Venous thromboembolism occurs frequently after major orthopedic surgery, and patients undergoing total hip replacement (THR) or total knee replacement (TKR) are among those with the highest risk for VTE. 1 The economic impact of this complication is substantial because patients who develop VTE after major orthopedic surgery are more likely to be rehospitalized and/or remain hospitalized for a longer period. 2 Furthermore, the number of total joint replacement surgeries in the United States is expected to rise as the population ages, making appropriate thromboprophylaxis strategies important for reducing the incidence and recurrence of VTE. 3 Pharmacologic thromboprophylaxis in patients undergoing THR and TKR significantly reduces the risk of postoperative VTE. The 9th American College of Chest Physicians evidence-based guidelines suggest at least 10 and up to 35 days of thromboprophylaxis with an anticoagulant after THR/TKR. 1 However, continuing anticoagulant therapy after patients have been discharged is complicated. Information from the Multinational Global Orthopaedic Registry indicates that in real-world practice, the standards for prophylaxis recommended by the American College of Chest Physicians are largely not followed. 4 This may reflect the myriad inconveniences associated with the current standard of care (eg, frequent monitoring and dose adjustments, daily selfadministered subcutaneous injections, narrow therapeutic window, numerous food and drug interactions) and bolsters the rationale for use of an oral, fixed-dose anticoagulant that can be administered without the practical management challenges associated with traditional anticoagulants. Rivaroxaban is an oral, once-daily anticoagulant that directly inhibits Factor Xa activity, resulting in the inhibition of thrombin generation by both intrinsic and tissue factor 106 The American Journal of Pharmacy Benefi ts May/June

2 Economic Model Comparing Rivaroxaban and Enoxaparin pathways. 5 The pivotal phase 3 RECORD trials evaluated thromboprophylaxis with rivaroxaban in more than 12,500 patients undergoing THR (RECORD trials 1 and 2) and TKR (RECORD trials 3 and 4) and provided the foundation for its approval in Canada and the United States The goal of this analysis was to evaluate, from a payer s perspective, the economic impact of using rivaroxaban versus enoxaparin, a low-molecular-weight heparin, for thromboprophylaxis after THR or TKR surgery. METHODS Clinical Data Sources for Model The RECORD trials were randomized, multinational, double-blind, phase 3 trials conducted to assess the efficacy and safety of rivaroxaban compared with enoxaparin in patients undergoing THR or TKR. Data cited in the Xarelto (rivaroxaban) US package insert from the first, second, and third RECORD clinical trials were analyzed using an Excel-based model (Microsoft Corp, Redmond, Washington). 6 The duration of thromboprophylaxis, dosing regimens, and rationale for data inclusion in the current study are summarized in Table 1. 6,12-15 Identical efficacy and safety end points were assessed in all the clinical trials. All patients were evaluated for asymptomatic DVT using ascending bilateral venography the day after the last dose of the study drug, or earlier if symptoms arose Presence of PE was assessed by spiral computed tomography, perfusion-ventilation lung scintigraphy, or pulmonary angiography. 8,10 All end points were analyzed by a central blinded adjudication committee up to day 42 for the RECORD 1 and 2 studies, 8,9 and up to day 17 in the RECORD 3 study. 10 For the THR analysis, the rivaroxaban arms from RECORD trials 1 and 2 were combined because the dosages of rivaroxaban and the durations of rivaroxaban administration in these 2 trials were similar (10 mg once daily for 35 days in RECORD trial 1 and 31 to 39 days in RECORD trial 2). The THR data for enoxaparin from only RECORD trial 1 were used for comparison because the duration of prophylaxis was the same as that for rivaroxaban (ie, 35 days). For TKR, data from RECORD trial 3 were used for both the rivaroxaban (10 mg once daily) and enoxaparin (40 mg once daily) arms (both for 12 days). The model incorporated 4 clinical end points: total VTE, major VTE, symptomatic VTE, and major bleeding. The primary end point evaluated in the clinical trials was total VTE, which was defined as a composite of any DVT, nonfatal PE, or death from any cause up to 36 days PRACTICAL IMPLICATIONS Outcomes with the use of rivaroxaban versus enoxaparin for thromboprophylaxis after total hip replacement or total knee replacement surgery were projected. With rivaroxaban, there was a decreased number of symptomatic thrombotic events based on data from the RECORD clinical trial program. With rivaroxaban, there also were signifi cant savings to the healthcare system in both drug acquisition costs and event-related costs. postoperatively. Other end points assessed included major VTE comprising proximal DVT, nonfatal PE, and VTErelated death and symptomatic VTE that occurred during the prophylaxis period or within 30 to 35 days after the last dose of either drug. 8,11 The primary safety outcome for all trials was the incidence of major bleeding events, which was defined as bleeding that was fatal, occurred in a critical organ, or required surgical intervention, or any clinically overt bleeding that occurred at an extra-surgical site that resulted in a drop in hemoglobin of 2 or more g/ dl (20 g/l) or that required a transfusion of 2 or more units of blood products. 8,11 Cost Data Drug costs were based on wholesale acquisition costs for rivaroxaban and generic enoxaparin (lowest wholesale acquisition cost for generic enoxaparin as of July 2012), 16 and calculations were made based on the dosing schedule and duration used in the RECORD trials. Only the costs of symptomatic events were considered for the event cost analysis (symptomatic VTEs and major bleeding events). Differences in total and major VTEs are presented, but they were not used in the cost analysis. Symptomatic VTE costs were derived from the study by Encinosa and Hellinger, 17 who found that the cost of care for patients being treated in a hospital setting for postoperative VTE within 90 days of surgery was approximately $50,911, whereas patients who did not have any complicating factors in the same postoperative time period incurred costs of approximately $18,284. Once adjustments for age, sex, concurrent medical conditions, and other factors were made between the 2 groups, the cost difference was approximately $7838 (2002 dollars), which was adjusted to a value of $10,546 in 2010 dollars. 17 In addition, costs associated with postoperative major bleeding events were derived from a model presented at the 2008 American Society of Hematology Meeting by Kwong and colleagues. 12 The analysis used major bleeding event Vol. 5, No. 3 The American Journal of Pharmacy Benefi ts 107

3 Kwong Bookhart Mody Table 1. Data Source Descriptions and Rationale for Use in the Economic Model Surgery Type and Intervention Data Source(s) Rationale THR Rivaroxaban a RECORD 1 b RECORD 2 c Data were combined because the same dose and duration were used in both arms Enoxaparin d RECORD 1 b Only data from RECORD 1 were included because this was the only study with a 35-day duration of prophylaxis (the same as that for rivaroxaban) TKR Rivaroxaban RECORD 3 e Duration of prophylaxis was 2 weeks; dosage was 10 mg Enoxaparin RECORD 3 e Duration of prophylaxis was 2 weeks; dosage was 40 mg DVT indicates deep vein thrombosis; PE, pulmonary embolism; THR, total hip replacement; TKR, total knee replacement. a Rivaroxaban10 mg once daily for 35 days. b Incidence of DVT/PE/death with rivaroxaban versus enoxaparin: 1.1% versus 3.9% (N = 4541). c Incidence of DVT/PE/death with rivaroxaban versus enoxaparin: 2.0% versus 9.3% (N = 2509). d Enoxaparin 40 mg once daily for 35 days. e Incidence of DVT/PE/death with rivaroxaban versus enoxaparin: 9.6% versus 18.9% (N = 2531). costs of $3828 in 2007, which were converted to $4195 in 2010 dollars. 12 Applying the RECORD event data described previously, an economic model was created using Excel to compare the projected difference in clinical events and projected cost of thromboprophylaxis for a sample population of 1000 patients undergoing THR or TKR surgery. Results of the analysis were reported in terms of differences in event rates and associated costs of VTE, major VTE, symptomatic VTE, and major bleeding events or the separate THR and TKR cohorts of patients receiving rivaroxaban versus enoxaparin. Sensitivity analyses were undertaken to explore the impact of varying generic enoxaparin and event costs by ±30%. RESULTS Clinical Event and Cost Comparison Model After Total Hip Replacement In the RECORD 1 and 2 trials, rivaroxaban 10 mg once daily was administered for 35 days. At a cost of $7.72 per day (for a 35-day study duration), drug acquisition costs were $ per patient (total for 1000 patients was $270,200). The enoxaparin drug acquisition costs per patient for the same 35-day study duration were $ based on a per day cost of $22.00 for a 40-mg generic (total for 1000 patients was $770,000). This resulted in cost savings of approximately $499,800, or $ per patient over the course of thromboprophylaxis therapy with rivaroxaban. Based on the events data from RECORD trials 1 and 2 for rivaroxaban and from the RECORD trial 1 data for enoxaparin, 1000 THR patients treated with rivaroxaban instead of enoxaparin would have 24.2 fewer total VTEs, 17.2 fewer major VTEs, 2.8 fewer symptomatic VTEs, and 1.2 additional major bleeding events. Monetizing the symptomatic events, $29,032 was saved because of the symptomatic VTEs avoided. After including the additional cost of prophylaxis-related bleeding events of $4991, there was an overall projected cost savings from clinical events avoided of $24,041. Once drug acquisition cost savings were included, the model projected potential cost savings of $523,841 associated with the use of rivaroxaban compared with prophylaxis with enoxaparin in this patient population (or a savings of ~$ per patient). These projections are summarized in Table 2. Clinical Event and Cost Comparison Model After Total Knee Replacement In this 1000-patient example, the duration of thromboprophylaxis for both anticoagulants was 12 days on average, based on RECORD trial 3 data. Drug costs for rivaroxaban 10 mg at $7.72 per day were $92,640 over the course of the study period for 1000 patients. The prophylactic dose for enoxaparin was based on the RECORD trial 3 dosing regimen of 40 mg once daily. Daily drug costs were $22.00 per patient, or $264,000 for all patients receiving enoxaparin. Switching the 1000-patient cohort from generic enoxaparin to rivaroxaban would result in potential drug cost savings of $171,360 over the course of thromboprophylaxis. Based on the event data from the RECORD 3 trial for rivaroxaban and enoxaparin, the 1000-patient TKR cohort would experience 91.1 fewer total VTEs, 15.0 fewer major VTEs, and 12.9 fewer symptomatic VTEs, with The American Journal of Pharmacy Benefi ts May/June

4 Economic Model Comparing Rivaroxaban and Enoxaparin Table 2. Projected Cost Savings With Rivaroxaban in THR/TKR Cost Element THR TKR Rivaroxaban 10 mg once daily cost $7.72 $7.72 Enoxaparin 40 mg once daily cost $22.00 $22.00 Total prophylaxis duration, days Drug acquisition savings when using rivaroxaban per 1000 patients $499,800 $171,360 Savings from symptomatic VTEs avoided when using rivaroxaban per 1000 patients $29,032 $136,490 Costs for major bleeding events per 1000 patients ($4991) ($3819) Net event savings when using rivaroxaban per 1000 patients $24,041 $132,671 Projected total cost savings with rivaroxaban $523,841 $304,031 THR indicates total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism. additional major bleeding events using rivaroxaban instead of enoxaparin. Thus, the use of rivaroxaban in this patient population would result in potential event savings of $136,490 in symptomatic VTE events avoided. When the cost of possible major bleeding events of approximately $3819 was accounted for, there was a projected cost benefit in adverse events avoided of $132,671. Overall total cost savings, including drug acquisition costs, were $304,031 (or $ per patient) if rivaroxaban was used for thromboprophylaxis in the TKR population. These projections are summarized in Table 2. The overall findings of rivaroxaban cost savings remained after performing sensitivity analyses. Decreasing generic enoxaparin prices by 30% reduced the magnitude of rivaroxaban cost savings in THR ($292,840) and TKR ($224,831), while increasing enoxaparin prices by 30% increased the cost savings associated with rivaroxaban (THR $754,841; TKR $383,231). Increasing and decreasing costs of symptomatic events (symptomatic VTEs and major bleeding) did not alter the results significantly (data not shown). DISCUSSION Using data from 3 large published clinical trials from the rivaroxaban US package insert, 6 this economic model demonstrated significant cost savings and improvement in patient outcomes when rivaroxaban was used for thromboprophylaxis after total joint replacement surgery. For a cohort of 1000 patients over a 35-day prophylaxis regimen following THR, savings of nearly $500 per patient were projected when using rivaroxaban for VTE prophylaxis. In the TKR population, there were projected savings of approximately $304 per patient over the course of therapy when rivaroxaban was used. This analysis was based on data within a 90-day postoperative period; however, it is possible that the concurrent minimization of the risk of subsequent VTE and complications arising from post-thrombotic syndrome and/or chronic pulmonary hypertension might translate into even greater cost savings. 1,2,13-15,18 It is important to note that these event-related costs only included symptomatic events. Asymptomatic events could also lead to increased costs and negative clinical consequences, but these costs were not included in this economic model because only shortterm costs were assessed. It must be noted, however, that a number of these initially asymptomatic events may become symptomatic or, as a worse consequence, only present as PE at death. 2,14,15 In a retrospective study ( ) done in the United Kingdom, it was found that DVT was particularly common after THR surgery, with approximately 50% of individuals undergoing hip replacement found to have a DVT by venography. 13 These investigators found that, based on case records of 195 autopsies in which the cause of death was attributed to PE, no symptoms of DVT were reported in 77% (124/162) of the cases that reported finding DVT at autopsy. In addition, the percentage of patients with PE postmortem was shown to be 52% in individuals undergoing THR surgery. 13 While these findings are intriguing, it is important to consider some of the limitations of this assessment. The definition of major bleeding may differ from the definition typically used in other studies. 19 In the RECORD trials, the definition of major bleeding did not include bleeding at the surgical site unless the event required surgical intervention or was fatal. It is possible that this may have resulted in fewer major bleeding events being reported. However, the definition was discussed with regulatory authorities and agreed upon in advance of the analyses to allow for the assessment of clinically relevant bleeding events. 9,11 In addition, the costs associated with training patients on how to use enoxaparin were not included. Furthermore, this model was not intended to be used for comparison with other agents, and any changes made in dosing or duration will likely alter the results. Finally, the prescribed dose of generic enoxaparin for TKR in the United States is often 30 mg twice daily Vol. 5, No. 3 The American Journal of Pharmacy Benefi ts 109

5 Kwong Bookhart Mody ($33.00/day vs $22.00/day for 40 mg once daily), serving to increase the cost difference between generic enoxaparin and rivaroxaban and increasing the cost savings realized by rivaroxaban administration. CONCLUSION Rivaroxaban, a direct Factor Xa inhibitor, provided a safe and effective alternative to enoxaparin for prevention of VTE in patients undergoing THR or TKR. When analyzing these data from a payer s perspective, there was a clear and significant economic impact associated with VTE, which makes the choice of appropriate thromboprophylaxis an important one. Based on data from the rivaroxaban US package insert and 3 large head-to-head clinical trials, the use of rivaroxaban over enoxaparin not only decreased the number of thrombotic events, but also generated significant potential cost savings in both drug acquisition costs and event-related costs. Acknowledgments The authors would like to acknowledge Richard Dobson, PhD, who provided editorial support with funding from Janssen Scientific Affairs, LLC. This contribution represents original work and has not been previously published or simultaneously submitted for publication elsewhere. The manuscript was read and approved by all the authors, and all conditions stated by the International Committee of Medical Journal Editors have been met. Author Affiliations: From Department of Orthopedic Surgery (LMK), Harbor-UCLA Medical Center, Torrance, CA; Health Economics and Outcomes Research (BKB, SHM), Janssen Scientific Affairs LLC, Raritan, NJ. Funding Source: This research was funded by Janssen Scientific Affairs, LLC, Raritan, New Jersey. Author Disclosures: Dr Kwong has served as a consultant for Zimmer Orthopaedics and has received grants from Astellas, Bayer, Takeda, GlaxoSmithKline, and Pfizer. He has served as a paid speaker for Zimmer Orthopaedics, Bayer, Janssen, and ConvaTec. He has received royalties from Zimmer Orthopaedics for product development and has received payment for the development of an educational presentation by Joint Commission Resources. Mr Bookhart is an employee of Janssen Scientific Affairs, LLC, a subsidiary of Johnson & Johnson (J&J), and is a stockholder of J&J. Dr Mody is an employee of Janssen Scientific Affairs, LLC, a subsidiary of J&J, and is a stockholder of J&J. Authorship Information: Concept and design (BKB, SHM); acquisition of data (BKB); analysis and interpretation of data (LMK, BKB, SHM); drafting of the manuscript (LMK, SHM); critical revision of the manuscript for important intellectual content (LMK, BKB, SHM); statistical analysis (SHM); provision of study materials or patients (BKB); obtaining funding (BKB); administrative, technical, or logistic support (BKB, SHM); and supervision (BKB). Address correspondence to: Samir H. Mody, PharmD, MBA, Director, Translational Science Team/Health Economics and Outcomes Research, Janssen Scientific Affairs, LLC, 1000 Rt 202 S, Raritan, NJ smody2@its.jnj.com. REFERENCES 1. Falck-Ytter Y, Francis CW, Johanson NA, et al; American College of Chest Physicians. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl): e278s-e325s. 2. Baser O, Supina D, Sengupta N, Wang L, Kwong L. Impact of postoperative venous thromboembolism on Medicare recipients undergoing total hip replacement or total knee replacement surgery. Am J Health Syst Pharm. 2010;67(17): Deitelzweig SB, Johnson BH, Lin J, Schulman KL. Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. Am J Hematol. 2011;86(2): Friedman RJ, Gallus A, Gil-Garay E, FitzGerald G, Cushner F. Practice patterns in the use of venous thromboembolism prophylaxis after total joint arthroplasty insights from the Multinational Global Orthopaedic Registry (GLORY). Am J Orthop (Belle Mead NJ). 2010;39(9)(suppl): Xarelto [summary of product characteristics]. Titusville, NJ: Janssen Pharmaceuticals; Inc; Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; Lovenox [package insert]. Bridgewater, NJ: sanofi -aventis; Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban 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. Lancet. 2008;372(9632): Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26): Turpie AG, Lassen MR, Davidson BL, et al; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373(9676): Kwong L, Diamantopoulos A, Forster F, et al. Will rivaroxaban be cost-effective for prevention of venous thromboembolism after total hip replacement in US patients? Paper presented at: 50th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2008; San Francisco, CA. 13. Bullingham A, Strunin L. Prevention of postoperative venous thromboembolism. Br J Anaesth. 1995;75(5): Goldhaber SZ, Tapson VF; DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasound-confi rmed deep vein thrombosis. Am J Cardiol. 2004;93(2): Agency for Healthcare Research and Quality. Preventing Hospital-Acquired Venous Thromboembolism: A Guide for Effective Quality Improvement. Published August Accessed September 15, Analy$ource Online. Wholesale acquisition costs of rivaroxaban and generic enoxaparin [member access only]. Accessed July 31, Encinosa WE, Hellinger FJ. The impact of medical errors on ninety-day costs and outcomes: an examination of surgical patients. Health Serv Res. 2008;43(6): US Department of Health and Human Services. The Surgeon General s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. Published Accessed September 15, Melillo SN, Scanlon JV, Exter BP, Steinberg M, Jarvis CI. Rivaroxaban for thromboprophylaxis in patients undergoing major orthopedic surgery. Ann Pharmacother. 2010;44(6): The American Journal of Pharmacy Benefi ts May/June