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Thromb Haemost 2016; 116(04): 739-746
DOI: 10.1160/TH16-02-0087
Stroke, Systemic or Venous Thromboembolism
Schattauer GmbH

Treatment of venous thromboembolism with rivaroxaban in relation to body weight

A sub-analysis of the EINSTEIN DVT/PE studies
Marcello Di Nisio
1   Department of Medical, Oral and Biotechnological Sciences, University „G. D’Annunzio” of Chieti-Pescara, Chieti, Italy
,
Maria C. Vedovati
2   Internal and Cardiovascular Medicine and Stroke Unit, University of Perugia, Italy
,
Antoni Riera-Mestre
3   Department of Internal Medicine, Hospital Universitari de Bellvitge, IDIBELL, L’Hospitalet de Llobregat, and Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain
,
Martin H. Prins
4   University Medical Center, Maastricht, The Netherlands
,
Katharina Mueller
5   Bayer HealthCare AG, Germany
,
Alexander T. Cohen
6   Department of Haematological Medicine, Guys and St Thomas’ Hospitals, King’s College Hospital, London, UK
,
Philip S. Wells
7   Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ontario, Canada
,
Jan Beyer-Westendorf
8   University Hospital “Carl-Gustav Carus”, Department of Vascular Medicine, Technische Universität Dresden, Germany
,
Paolo Prandoni
9   Department of Cardiovascular Sciences, Vascular Medicine Unit, University of Padua, Padua, Italy
,
Henri Bounameaux
10   Division of Angiology and Hemostasis, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
,
Dagmar Kubitza
5   Bayer HealthCare AG, Germany
,
Jonas Schneider
5   Bayer HealthCare AG, Germany
,
Ron Pisters
11   Department of Cardiology, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Jan Fedacko
12   First Department Of Internal Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Košice, Slovakia
,
Ricardo Fontes-Carvalho
13   Department of Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
14   Cardiology Department, Gaia Hospital Center, Gaia, Portugal
,
Anthonie W. A. Lensing
5   Bayer HealthCare AG, Germany
› Author Affiliations
Further Information

Publication History

Received: 03 February 2016

Accepted after major revision: 07 June 2016

Publication Date:
02 December 2017 (online)

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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 (ptrend=0.87 and 0.62, respectively), major bleeding (ptrend=0.24 and 0.36, respectively) or clinically relevant bleeding (ptrend=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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    PubMedSearch in Google Scholar
  • 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)
    PubMedSearch in Google Scholar
  • 11 ten Cate H. New oral anticoagulants: discussion on monitoring and adherence should start now!. Thromb J 2013; 11: 8.
    CrossrefPubMedSearch in Google Scholar
  • 12 The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous throm-boembolism. N Engl J Med 2010; 363: 2499-2510.
    CrossrefPubMedSearch in Google Scholar
  • 13 The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 16 Ageno W, Becattini C, Brighton T. et al. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117: 93-102.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 18 Stein PD, Beemath A, Olson RE.. Obesity as a risk factor in venous thromboembolism. Am J Med 2005; 118: 978-980.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 23 Holst AG, Jensen G, Prescott E.. Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study. Circulation 2010; 121: 1896-1903.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 33 Heit JA, Silverstein MD, Mohr DN. et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001; 86: 452-463.
    Thieme ConnectPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    PubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 41 Badimon L, Hernandez VR, Padro T. et al. Antithrombotic therapy in obesity. Thromb Haemost 2013; 110: 681-688.
    Thieme ConnectPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 45 Freeman AL, Pendleton RC, Rondina MT.. Prevention of venous thromboembolism in obesity. Expert Rev Cardiovasc Ther 2010; 08: 1711-1721.
    CrossrefPubMedSearch in Google Scholar
  • 46 Samad F, Ruf W.. Inflammation, obesity, and thrombosis. Blood 2013; 122: 3415-3422.
    CrossrefPubMedSearch in Google Scholar
  • 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.
    Thieme ConnectPubMedSearch in Google Scholar