The Effect of BMI and Gender on Bleeding Events when Rivaroxaban Is Administered for Thromboprophylaxis Following Total Hip and Total Knee Arthroplasty

Eugene S. Krauss; MaryAnne Cronin; Nancy Dengler; Barry G. Simonson; Kathleen Altner; Madison Daly; Ayal Segal

doi:10.1055/s-0038-1676319

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2019; 45(02): 180-186
DOI: 10.1055/s-0038-1676319

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Effect of BMI and Gender on Bleeding Events when Rivaroxaban Is Administered for Thromboprophylaxis Following Total Hip and Total Knee Arthroplasty

Eugene S. Krauss

¹Department of Orthopaedics, Syosset Hospital, Syosset, New York

²New York Orthopaedic and Spine Center, Great Neck, New York

³Krasnoff Quality Management Institute, Northwell Health System, Great Neck, New York

⁴Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, East Garden City, New York

⁵Krauss Musculoskeletal Institute, Peconic Bay Medical Center, Riverhead, New York

,

MaryAnne Cronin

¹Department of Orthopaedics, Syosset Hospital, Syosset, New York

,

Nancy Dengler

¹Department of Orthopaedics, Syosset Hospital, Syosset, New York

,

Barry G. Simonson

¹Department of Orthopaedics, Syosset Hospital, Syosset, New York

⁶Orthopedic Associates of Great Neck, Great Neck, New York

,

Kathleen Altner

²New York Orthopaedic and Spine Center, Great Neck, New York

,

Madison Daly

⁴Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, East Garden City, New York

,

Ayal Segal

¹Department of Orthopaedics, Syosset Hospital, Syosset, New York

²New York Orthopaedic and Spine Center, Great Neck, New York

› Author Affiliations

Abstract

Rivaroxaban is approved in Europe and the United States for thromboprophylaxis following total joint arthroplasty. As the rate of obesity increases, confirming safety and efficacy in this patient population is paramount. This retrospective chart review assessed the efficacy and safety of rivaroxaban between two body mass index (BMI) groups: normal or overweight (< 30 kg/m²) and obese or morbidly obese (≥30 kg/m²). Safety outcome was a major bleeding event, defined as a decrease in hemoglobin of at least 2 g/dL from postoperative day 1(POD 1) to discharge or a blood transfusion of at least two units. Efficacy outcome was venous thromboembolism within 35 days postoperatively. There were 68 (68/1,241; 5.48%) major bleeding events. There was no significant association between major bleeding events and BMI in the univariable analysis (p < 0.36). However, after adjusting for other factors in the multivariable model, there was a significant interaction between BMI and gender (p < 0.001). Among males, the incidence of major bleeding events was three times greater in obese/morbidly obese subjects as compared with normal/overweight male subjects (odds ratio [OR]: 3.09, 95% confidence interval [CI]: 1.25, 7.62). Among females, incidence of having a major bleeding event was almost two times greater in normal/overweight subjects as compared with obese/morbidly obese female subjects (OR: 2.17, 95% CI: 1.10, 4.35). Incidence of venous thromboembolism was 0.4% in each group. The authors' study results highlight a previously unexplored association between BMI and gender-dependent differences in bleeding outcomes when rivaroxaban is used for thromboprophylaxis following total joint arthroplasty.

Keywords

thromboprophylaxis - rivaroxaban - bleeding - total joint arthroplasty

Full Text

References

References
1 Fender D, Harper WM, Thompson JR, Gregg PJ. Mortality and fatal pulmonary embolism after primary total hip replacement. Results from a regional hip register. J Bone Joint Surg Br 1997; 79 (06) 896-899
2 Warwick D, Williams MH, Bannister GC. Death and thromboembolic disease after total hip replacement. A series of 1162 cases with no routine chemical prophylaxis. J Bone Joint Surg Br 1995; 77 (01) 6-10
3 Warwick DJ, Whitehouse S. Symptomatic venous thromboembolism after total knee replacement. J Bone Joint Surg Br 1997; 79 (05) 780-786
4 Ansari S, Warwick D, Ackroyd CE, Newman JH. Incidence of fatal pulmonary embolism after 1,390 knee arthroplasties without routine prophylactic anticoagulation, except in high-risk cases. J Arthroplasty 1997; 12 (06) 599-602
5 Falck-Ytter Y, Francis CW, Johanson NA. , et al. Prevention of VTE in orthopedic surgery patients. Antithrombotic Therapy and Prevention of Thrombosis, 9th edition: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 2012; ;141(2, Suppl): e278s-e325s
6 Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med 2003; 163 (14) 1711-1717
7 Nutescu EA, Shorr AF, Farrelly E, Horblyuk R, Happe LE, Franklin M. Burden of deep vein thrombosis in the outpatient setting following major orthopedic surgery. Ann Pharmacother 2008; 42 (09) 1216-1221
8 Geerts WH, Bergqvist D, Pineo GF. , et al. Prevention of venous thromboembolism: American College of Chest Physicians 8th edition evidence-based clinical practice guidelines. Chest 2008. ;133(6, Suppl):381S–453S
9 Clinical guideline on prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty. American Academy of Orthopaedic Surgeons (AAOS). Agency for Healthcare Research and Quality. 2011 :847. Available at: http://www.guideline.gov/content.aspx?id=10850 . Accessed August 30, 2018
10 Riva N, Dentali F, Permunian ET, Ageno W. Major bleeding and case fatality rate with the direct oral anticoagulants in orthopedic surgery: a systematic review and meta-analysis. Semin Thromb Hemost 2016; 42 (01) 42-54
11 Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 2014; 53 (01) 1-16
12 Xarelto (rivaroxaban) [package insert]. Titusville, NJ. Janssen Pharmaceuticals. 2011
13 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) 2765-2775
14 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): 31-39
15 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) 2776-2786
16 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): 1673-1680
17 Levitan B, Yuan Z, Turpie AG. , et al. Benefit-risk assessment of rivaroxaban versus enoxaparin for the prevention of venous thromboembolism after total hip or knee arthroplasty. Vasc Health Risk Manag 2014; 10: 157-167
18 Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol 2007; 47 (02) 218-226
19 Turpie AG, Lassen MR, Eriksson BI. , et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011; 105 (03) 444-453
20 Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14 (06) 1308-1313
21 Stürmer T, Günther KP, Brenner H. Obesity, overweight and patterns of osteoarthritis: the Ulm Osteoarthritis Study. J Clin Epidemiol 2000; 53 (03) 307-313
22 de Guia N, Zhu N, Keresteci M, Shi JE. Obesity and joint replacement surgery in Canada: findings from the Canadian Joint Replacement Registry (CJRR). Healthc Policy 2006; 1 (03) 36-43
23 Finucane MM, Stevens GA, Cowan MJ. , et al; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index). National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. Lancet 2011; 377 (9765): 557-567
24 Fehring TK, Odum SM, Griffin WL, Mason JB, McCoy TH. The obesity epidemic: its effect on total joint arthroplasty. J Arthroplasty 2007; 22 (06) , Suppl (Suppl. 02) 71-76
25 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. ; Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126
26 Turpie AG, Eriksson BI, Mueck W. , et al. Pharmacokinetic and pharmacodynamic analyses of rivaroxaban in patients undergoing orthopaedic surgery. . [abstract] Pathophysiol Haemost Thromb 2006; 35: A2 Abstract 1182
27 Mueck W, Eriksson BI, Bauer KA. , et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor Xa inhibitor--in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008; 47 (03) 203-216
28 Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J 2013; 11 (01) 10
29 Jensen CD, Steval A, Partington PF, Reed MR, Muller SD. Return to theatre following total hip and knee replacement, before and after the introduction of rivaroxaban: a retrospective cohort study. J Bone Joint Surg Br 2011; 93 (01) 91-95
30 Jameson SS, Rymaszewska M, Hui AC, James P, Serrano-Pedraza I, Muller SD. Wound complications following rivaroxaban administration: a multicenter comparison with low-molecular-weight heparins for thromboprophylaxis in lower limb arthroplasty. J Bone Joint Surg Am 2012; 94 (17) 1554-1558
31 Ricket AL, Stewart DW, Wood RC. , et al. Comparison of postoperative bleeding in total hip and knee arthroplasty patients receiving rivaroxaban or enoxaparin. Ann Pharmacother 2016; 50 (04) 270-275
32 Turpie AG, Haas S, Kreutz R. , et al. A non-interventional comparison of rivaroxaban with standard of care for thromboprophylaxis after major orthopaedic surgery in 17,701 patients with propensity score adjustment. Thromb Haemost 2014; 111 (01) 94-102
33 Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009; 48 (01) 1-22
34 Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013; 76 (03) 455-466
35 Gong IY, Mansell SE, Kim RB. Absence of both MDR1 (ABCB1) and breast cancer resistance protein (ABCG2) transporters significantly alters rivaroxaban disposition and central nervous system entry. Basic Clin Pharmacol Toxicol 2013; 112 (03) 164-170
36 Tucker TG, Milne AM, Fournel-Gigleux S, Fenner KS, Coughtrie MW. Absolute immunoquantification of the expression of ABC transporters P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein 2 in human liver and duodenum. Biochem Pharmacol 2012; 83 (02) 279-285
37 Merino G, van Herwaarden AE, Wagenaar E, Jonker JW, Schinkel AH. Sex-dependent expression and activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP/ABCG2) in liver. Mol Pharmacol 2005; 67 (05) 1765-1771
38 Imai Y, Ishikawa E, Asada S, Sugimoto Y. Estrogen-mediated post transcriptional down-regulation of breast cancer resistance protein/ABCG2. Cancer Res 2005; 65 (02) 596-604
39 Pasquali R. Obesity and androgens: facts and perspectives. Fertil Steril 2006; 85 (05) 1319-1340
40 Smith SR. The endocrinology of obesity. Endocrinol Metab Clin North Am 1996; 25 (04) 921-942
41 Lip GY, Pan X, Kamble S. , et al. Major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin: a “real-world” observational study in the United States. Int J Clin Pract 2016; 70 (09) 752-763
42 Noseworthy PA, Yao X, Abraham NS, Sangaralingham LR, McBane RD, Shah ND. Direct comparison of dabigatran, rivaroxaban and apixaban for effectiveness and safety in nonvalvular atrial fibrillation. Chest 2016; 150 (06) 1302-1312