Rivaroxaban differentially influences ex vivo global coagulation assays based on the administration time

Summary

It was the objective of this study to quantify the effects of rivaroxaban administration on global coagulation parameters associated with routine clinical procedures, we collected plasma samples from patients undergoing major orthopaedic surgery receiving rivaroxaban at various time points after drug administration. Forty-seven patients received rivaroxaban (10 mg daily) for venous thromboembolism prophylaxis. Blood samples were collected at four different time points: A) before surgery; B) before drug administration at day 4–5 after surgery (steady state of rivaroxaban); C) 2 hours (h) after drug administration and D) 12 h after drug administration. The prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), antithrombin (AT) level, fibrinogen level by Clauss method (FibC), and derived fibrinogen (dFIB) level were assessed with various reagents. At 2 h after rivaroxaban administration, the PT and aPTT clotting times were significantly prolonged to different extents up to 1.4 fold, whereas 12 h after drug administration, no significant effect was observed. Rivaroxaban administration had no influence on the TT or the FibC concentration. The dFIB assay was differentially affected by rivaroxaban when different reagents were tested. The AT assay dependent on thrombin activity was not influenced by rivaroxaban, whereas the AT levels dependent on factor Xa activity were significantly increased by rivaroxaban. Clinicians should be aware of the time-dependent influence of rivaroxaban on factor Xa-dependent routine coagulation assays. Therefore, routine coagulation parameters should be assessed directly before drug administration to keep the interaction of rivaroxaban low.

keyword

Rivaroxaban - prothrombin time - activated partial thromboplastin time - thrombin time - antithrombin - fibrinogen

• References

• 1 Geerts WH, Bergqvist D, Pineo GF. et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest (8th Edition). 2008; 133 (Suppl. 06) 381S-453S.
• 2 Phillips KW, Ansell J. The clinical implications of new oral anticoagulants: will the potential advantages be achieved?. Thromb Haemost 2010; 103: 34-39.
• 3 Perzborn E, Roehrig S, Straub A, Kubitza D, Mueck W, Laux V. Rivaroxaban: a new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol 2010; 30: 376-381.
• 4 Laux V, Perzborn E, Heitmeier S. et al. Direct inhibitors of coagulation proteins - the end of the heparin and low-molecular-weight heparin era for anticoagulant therapy?. Thromb Haemost 2009; 102: 892-899.
• 5 Eriksson BI, Borris L, Dahl OE. et al. ODIXa-HIP Study Investigators. Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4: 121-128.
• 6 Merli G, Spyropoulos AC, Caprini JA. Use of emerging oral anticoagulants in clinical practice: translating results from clinical trials to orthopedic and general surgical patient populations. Ann Surg 2009; 250: 219-228.
• 7 Ageno W. Rivaroxaban for the prevention of venous thromboembolism following major orthopedic surgery: the RECORD trials. Expert Rev Cardiovasc Ther 2009; 7: 569-576.
• 8 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: 444-453.
• 9 Xarelto® Summary of Product Characteristics. 2009. http://emc.medicines.org.uk/medicine/21265/SPC/Xarelto10mgfilm-coatedtablets.
• 10 Kubitza D, Becka M, Voith B. et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-421.
• 11 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: 203-216.
• 12 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939–an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 3: 514-521.
• 13 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: 453-461.
• 14 Kubitza D, Becka M, Wensing G. et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939–an oral, direct Factor Xa inhibitor-after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61: 873-880.
• 15 Samama MM, Martinoli JL, LeFlem L. et al. Assessment of laboratory assays to measure rivaroxaban-an oral, direct factor Xa inhibitor. Thromb Haemost 2010; 103: 815-825.
• 16 Jiang J, Hu Y, Zhang J. et al. Safety, pharmacokinetics and pharmacodynamics of single doses of rivaroxaban - an oral, direct factor Xa inhibitor - in elderly Chinese subjects. Thromb Haemost 2010; 103: 234-241.
• 17 Graff J, von Hentig N, Misselwitz F. et al. Effects of the oral, direct factor xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombi- nase activity. J Clin Pharmacol 2007; 47: 1398-1407.
• 18 Merriman E, Kaplan Z, Butler J. et al. Rivaroxaban and false positive lupus anticoagulant testing. Thromb Haemost 2011; 105: 385-386.
• 19 Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabig- atran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010; 103: 572-585.
• 20 Lindhoff-Last E, Samama MM, Ortel TL. et al. Assays for Measuring Rivaroxaban: Their Suitability and Limitations. Ther Drug Monit 2010; 32: 673-679.
• 21 Hillarp A, Baghaei F, Blixter IF. et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 9: 133-139.
• 22 Hawkey CJ, Stirling Y, Chakrabarti R. et al. Haemostatic changes following surgery. Thromb Res 1983; 32: 223-227.
• 23 Lowe GD, Rumley A, Mackie IJ. Plasma fibrinogen. Ann Clin Biochem 2004; 41: 430-440.
• 24 Mismetti P, Laporte S. New oral antithrombotics: a need for laboratory monitoring. J Thromb Haemost 2010; 8: 621-626.
• 25 Samama MM, Amiral J, Guinet C. et al. An optimised, rapid chromogenic assay, specific for measuring direct factor Xa inhibitors (rivaroxaban) in plasma. Thromb Haemost 2010; 104: 1078-1079.
• 26 EINSTEIN Investigators. Bauersachs R, Berkowitz SD, Brenner B. et al. Oral rivar- oxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
• 27 Bereznicki LR, Peterson GM. New Antithrombotics for Atrial Fibrillation. Car- diovasc Ther 2010; 28: 278-286.
• 28 Ahrens I, Lip GY, Peter K. New oral anticoagulant drugs in cardiovascular disease. Thromb Haemost 2010; 104: 49-60.