Treatment of venous thromboembolism with rivaroxaban in relation to body weight

Summary

The pharmacokinetics of oral rivaroxaban are highly predictable and only affected to a limited extent by bodyweight; therefore, dose adjustments for bodyweight are not required. However, this raises concerns among physicians for potential under- or overdosing. This substudy of the randomised EINSTEIN DVT and EINSTEIN PE trials, which compared rivaroxaban with enoxaparin/vitamin K antagonist (VKA) therapy, aimed to determine the incidence of major bleeding in patients with a low bodyweight and recurrent venous thromboembolism (VTE) in patients with a high bodyweight during rivaroxaban or enoxaparin/VKA therapy. More than 8,000 patients with objectively diagnosed deepvein thrombosis or pulmonary embolism were included. Adjusted hazard ratios for recurrent VTE and bleeding were calculated using the Cox proportional hazards model. Analyses were performed for both the first 21 days of treatment and the whole treatment period. For rivaroxaban recipients, there was no association between bodyweight or body mass index (BMI) and risk of recurrent VTE (p_trend=0.87 and 0.62, respectively), major bleeding (p_trend=0.24 and 0.36, respectively) or clinically relevant bleeding (p_trend=0.17 and 0.63, respectively). Major bleeding events were numerically lower in rivaroxaban patients across all bodyweight and BMI categories. Hazard ratios for rivaroxaban vs enoxaparin/VKA were similar in all bodyweight and BMI categories, both during the first 21 days and the whole treatment period. The fixed-dose rivaroxaban regimen is not associated with an increased risk of major bleeding or recurrent VTE in patients with either a low or high bodyweight. A high BMI was not associated with an increased risk of recurrent VTE during anticoagulation.

Note: This study was presented at the 25th Congress of the International Society on Thrombosis and Haemostasis; June, 2015, Toronto, Canada. Trial registration: EINSTEIN DVT (NCT00440193), EINSTEIN PE (NCT00439777).

Keywords

Body mass index - bodyweight - rivaroxaban - venous thromboembolism

• References

• 1 Yeh CH, Hogg K, Weitz JI.. Overview of the new oral anticoagulants: opportunities and challenges. Arterioscler Thromb Vasc Biol 2015; 35: 1056-1065.
• 2 Sarich TC, Peters G, Berkowitz SD. et al. Rivaroxaban: a novel oral anticoagulant for the prevention and treatment of several thrombosis-mediated conditions. Ann NY Acad Sci 2013; 1291: 42-55.
• 3 Mueck W, Lensing AWA, Agnelli G. et al. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50: 675-686.
• 4 Buller HR, Lensing AWA, Prins MH. et al. A dose-ranging study evaluating once-daily oral administration of the Factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study. Blood 2008; 112: 2242-2247.
• 5 Kubitza D, Becka M, Zuehlsdorf M. et al. 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: 218-226.
• 6 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: 703-712.
• 7 Kubitza D, Becka M, Roth A. et al. The influence of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct Factor Xa inhibitor. J Clin Pharmacol 2013; 53: 249-255.
• 8 Weinz C, Buetehorn U, Daehler HP. et al. Pharmacokinetics of BAY 59–7939 – an oral, direct Factor Xa inhibitor - in rats and dogs. Xenobiotica 2005; 35: 891-910.
• 9 Bayer Pharma AG. Xarelto^© (rivaroxaban) Summary of Product Characteristics. 2015 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf Accessed January 20, 2016.
• 10 Turpie AGG, Eriksson BI, Mueck W. et al. Pharmacokinetic and pharmacodynamic analyses of rivaroxaban in patients undergoing orthopaedic surgery. Pa-thophysiol Haemost Thromb. 2006 35. (Abstract 1182)
• 11 ten Cate H. New oral anticoagulants: discussion on monitoring and adherence should start now!. Thromb J 2013; 11: 8.
• 12 The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous throm-boembolism. N Engl J Med 2010; 363: 2499-2510.
• 13 The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
• 14 Prins MH, Lensing AWA, Bauersachs R. et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11: 21.
• 15 Glynn RJ, Rosner B.. Comparison of risk factors for the competing risks of coronary heart disease, stroke, and venous thromboembolism. Am J Epidemiol 2005; 162: 975-982.
• 16 Ageno W, Becattini C, Brighton T. et al. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117: 93-102.
• 17 Tsai AW, Cushman M, Rosamond WD. et al. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002; 162: 1182-1189.
• 18 Stein PD, Beemath A, Olson RE.. Obesity as a risk factor in venous thromboembolism. Am J Med 2005; 118: 978-980.
• 19 Hansson PO, Eriksson H, Welin L. et al. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: „the study of men born in 1913”. Arch Intern Med 1999; 159: 1886-1890.
• 20 Borch KH, Braekkan SK, Mathiesen EB. et al. Anthropometric measures of obesity and risk of venous thromboembolism: the Tromsø study. Arterioscler Thromb Vasc Biol 2010; 30: 121-127.
• 21 Severinsen MT, Kristensen SR, Johnsen SP. et al. Anthropometry, body fat, and venous thromboembolism: a Danish follow-up study. Circulation 2009; 120: 1850-1857.
• 22 Goldhaber SZ, Grodstein F, Stampfer MJ. et al. A prospective study of risk factors for pulmonary embolism in women. J Am Med Assoc 1997; 277: 642-645.
• 23 Holst AG, Jensen G, Prescott E.. Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study. Circulation 2010; 121: 1896-1903.
• 24 Lutsey PL, Virnig BA, Durham SB. et al. Correlates and consequences of venous thromboembolism: The Iowa Women's Health Study. Am J Public Health 2010; 100: 1506-1513.
• 25 Lindqvist PG, Epstein E, Olsson H.. The relationship between lifestyle factors and venous thromboembolism among women: a report from the MISS study. Br J Haematol 2009; 144: 234-240.
• 26 Parkin L, Sweetland S, Balkwill A. et al. Body mass index, surgery, and risk of venous thromboembolism in middle-aged women: a cohort study. Circulation 2012; 125: 1897-1904.
• 27 Kucher N, Tapson VF, Goldhaber SZ.. Risk factors associated with symptomatic pulmonary embolism in a large cohort of deep vein thrombosis patients. Thromb Haemost 2005; 93: 494-498.
• 28 Samama MM.. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160: 3415-3420.
• 29 Cushman M, Kuller LH, Prentice R. et al. Estrogen plus progestin and risk of venous thrombosis. J Am Med Assoc 2004; 292: 1573-1580.
• 30 Pomp ER, le Cessie S, Rosendaal FR. et al. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 2007; 139: 289-296.
• 31 Abdollahi M, Cushman M, Rosendaal FR.. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb Haemost 2003; 89: 493-498.
• 32 Eichinger S, Hron G, Bialonczyk C. et al. Overweight, obesity, and the risk of recurrent venous thromboembolism. Arch Intern Med 2008; 168: 1678-1683.
• 33 Heit JA, Silverstein MD, Mohr DN. et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001; 86: 452-463.
• 34 Laczkovics C, Grafenhofer H, Kaider A. et al. Risk of recurrence after a first venous thromboembolic event in young women. Haematologica 2007; 92: 1201-1207.
• 35 Garcia-Fuster MJ, Forner MJ, Fernandez C. et al Long-term prospective study of recurrent venous thromboembolism in patients younger than 50 years. Pathophysiol Haemost Thromb 2005; 34: 6-12.
• 36 Bauersachs RM, Lensing AWA, Prins MH. et al. Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment. Thromb J 2014; 12: 25.
• 37 Prins MH, Lensing AWA, Brighton TA. et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol 2014; 01: e37-e46.
• 38 Ikesaka R, Delluc A, Le Gal G. et al. Efficacy and safety of weight-adjusted heparin prophylaxis for the prevention of acute venous thromboembolism among obese patients undergoing bariatric surgery: a systematic review and meta-analysis. Thromb Res 2014; 133: 682-687.
• 39 Eriksson BI, Dahl OE, Feuring M. et al. Dabigatran is effective with a favourable safety profile in normal and overweight patients undergoing major orthopaedic surgery: a pooled analysis. Thromb Res 2012; 130: 818-820.
• 40 Sarich TC, Teng R, Peters GR. et al. No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. Clin Pharmacokinet 2003; 42: 485-492.
• 41 Badimon L, Hernandez VR, Padro T. et al. Antithrombotic therapy in obesity. Thromb Haemost 2013; 110: 681-688.
• 42 Davidson BL, Verheijen S, Lensing AWA. et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med 2014; 174: 947-953.
• 43 Cuker A, Siegal DM, Crowther MA. et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014; 64: 1128-1139.
• 44 Sennesael AL, Dogne JM, Spinewine A.. Optimizing the safe use of direct oral anticoagulants in older patients: a teachable moment. JAMA Intern Med 2015; 175: 1608-1609.
• 45 Freeman AL, Pendleton RC, Rondina MT.. Prevention of venous thromboembolism in obesity. Expert Rev Cardiovasc Ther 2010; 08: 1711-1721.
• 46 Samad F, Ruf W.. Inflammation, obesity, and thrombosis. Blood 2013; 122: 3415-3422.
• 47 Rega-Kaun G, Kaun C, Wojta J. More than a simple storage organ: adipose tissue as a source of adipokines involved in cardiovascular disease. Thromb Haemost 2013; 110: 641-650.