Blutungsrisiko und Blutungsnotfälle unter Rivaroxaban

J. Koscielny; J. Beyer-Westendorf; C. von Heymann; J. Braun; R. Klamroth; E. Lindhoff-Last; A. Tiede; M. Spannagl

doi:10.5482/ha-2012030001

Hämostaseologie, Table of Contents

Hamostaseologie 2012; 32(04): 287-293
DOI: 10.5482/ha-2012030001

Konsens

Schattauer GmbH

Blutungsrisiko und Blutungsnotfälle unter Rivaroxaban

Periinterventionelles Hämostase managementRisk of bleeding and haemorrhagic complication with rivaroxabanPeriprocedural management of haemostasis

Authors

J. Koscielny

¹Institut für Transfusionsmedizin, Charité – Universitätsklinikum Berlin
J. Beyer-Westendorf

²Bereich Thromboseforschung und Gerinnungs störungen am Universitäts-GefäßCentrum, Universitätsklinikum Carl Gustav Carus der TU Dresden
C. von Heymann

³Klinik für Anästhesiologie mit Schwerpunkt operative Intensivmedizin Charité-Universitätsmedizin Berlin Campus Virchow- Klinikum
J. Braun

⁴Innere Medizin I, Asklepios Klinik
R. Klamroth

⁵Innere Medizin – Angiologie, Hämostaseologie und Pneumologie, Vivantes Klinikum Berlin
E. Lindhoff-Last

⁶Gefäßzentrum, Schwerpunkt Angiologie/Hämostaseologie, Johann-Wolfgang-Goethe- Universitätsklinik Frankfurt am Main
A. Tiede

⁷Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltrans - plantation, Medizinische Hochschule Hannover
M. Spannagl

⁸Haemo staseologie – Campus Innenstadt, Klinikum der Universität München

Abstract

Summary

Rivaroxaban, the first direct factor-Xa inhibitor anticoagulant, has been approved for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery, for stroke prophylaxis in patients with non-valvular atrial fibrillation and for the treatment of deep vein thrombosis. There is no requirement for coagulation monitoring with rivaroxaban in routine clinical practice. However, in certain clinical circumstances such as life-threatening bleeding or an emergency operation the measurement of the thromboplastin time with a sensitive reagent will deliver first information. A quantitative determination of rivaroxaban plasma concentration is possible using an anti-factor Xa assay.

In the case of a patient under long-term anticoagulation with rivaroxaban requiring an elective surgery, a discontinuation of rivaroxaban 20 to 30 hours before the operation is sufficient to normalize the associated bleeding risk, as long as the renal and liver function is normal. A longer interval should be taken into consideration, when the patient presents a renal and liver impairment or is of a higher age. In the event of an emergency operation effective rivaroxaban concentrations might be present. Nevertheless, we advise against using a prophylactic dose of factor concentrates. Recommendations: From a clinical perspective, in the event of a minor bleeding we recommend a temporary discontinuation of rivaroxaban, whereas for clinically relevant major or severe bleeding events a mechanical compression or a limited surgical i. e. interventional treatment is required. Supportive measures such as the administration of blood products or tranexamic acid might be beneficial. In addition to haemodynamic supportive measures life threatening bleeding events demand a comprehensive haemostasis management, as well as the application of PCC.

Zusammenfassung

Rivaroxaban ist zugelassen zur Thromboseprophylaxe nach elektivem Hüft- und Knie - gelenkersatz, zur Schlaganfallprophylaxe bei Vorhofflimmern und zur Therapie der tiefen Venenthrombose. Ein Monitoring der gerinnungshemmenden Wirkung ist in der klinischen Routine nicht nötig, bei lebensbedrohlichen Blutungen oder Notoperationen kann jedoch die mit einem empfindlichen Reagenz gemessene Thromboplastinzeit erste Informationen liefern. Quantitative Aussagen zu Plasmakonzentration sind über Anti- FXa-Assays möglich.

Bei Elektiveingriffen unter Langzeitantikoagulation mit Rivaroxaban ist zur Normalisierung des Blutungsrisikos bei normaler Nieren-und Leberfunktion ein Absetzen von Rivaroxaban 20 bis 30 Stunden vor der Operation ausreichend, ein längerer Abstand sollte bei eingeschränkter Nieren- und Leberfunktion sowie bei hohem Lebensalter erwogen werden. Empfehlungen: Bei aus klinischer Sicht leichten Blutungen ist ein passageres Absetzen von Rivaroxaban anzuraten, bei mittelschweren bis schweren Blutungen eine begrenzte chirurgische bzw. Interventionelle Versorgung. Weitere Maßnahmen wie die Gabe von Blutprodukten oder Tranexamsäure können indiziert sein. Vital bedrohliche Blutungen erfordern neben Maßnahmen zur hämo dynamischen Stabilisierung ein umfassendes Hämostasemanagement sowie die Anwendung von PPSB.

Keywords

Rivaroxaban - anticoagulants - bleedings - bleeding risk - management of haemostasis - perinterventional management

Schlüsselwörter

Rivaroxaban - Antikoagulanzien - Blutungen - Blutungsrisiko - Hämostasemanagement - periinterventionelles Management

Full Text

References

Literatur
1 Bayer AGPharma. Xarelto^® (rivaroxaban) Summary of Product Characteristics. 2011 http://www.xarelto.com/html/downloads/Xarelto_Summary_of_Product_Characteristics_Dec2011.pdf (accessed on 9 January 2012).
2 Perzborn E, Roehrig S, Straub A. et al. The discovery and development of rivaroxaban, an oral, direct Factor Xa inhibitor. Nat. Rev. Drug Discov 2011; 10: 61-75.
3 Lang D, Freudenberger C, Weinz C. In vitro metabolism of rivaroxaban – an oral, direct Factor Xa inhibitor – in liver microsomes and hepatocytes of rat, dog and man. Drug Metab Dispos 2009; 37: 1046-1055.
4 Weinz C, Schwarz T, Kubitza D. et al. Metabolism and excretion of rivaroxaban, an oral, direct Factor Xa inhibitor, in rats, dogs and humans. Drug Metab Dispos 2009; 37: 1056-1064.
5 Harbrecht U. Old and new anticoagulants. Hämostaseologie 2011; 31: 21-27.
6 Turpie AGG, 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.
7 The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
8 Mega JL, Braunwald E, Mohanavelu S. et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009; 374: 29-38.
9 Patel MR, Mahaffey KW, Garg J. et al. Prevention of stroke and systemic embolism using the oral direct Factor Xa inhibitor rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: the ROCKET AF trial. N Engl J Med 2011; 365: 883-891.
10 Mega JL, Braunwald E, Wiviott SD. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2011; 366: 9-19.
11 The EINSTEIN-PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 2012; 366: 1287-1297.
12 Lindhoff-Last E, Samama MM, Ortel TL. et al. Assays for measuring rivaroxaban:their suitability and limitations. Ther Drug Monit 2010; 32: 673-679.
13 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.
14 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.
15 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.
16 Lindhoff-Last E, Samama MM, Ortel TL. et al. Assays for measuring rivaroxaban:their suitability and limitations. Ther Drug Monit 2010; 32: 673-679.
17 Mani H, Hesse C, Stratmann G, Lindhoff-Last E. Rivaroxaban differentially influences ex vivo global coagulation assays based on the administration time. Thromb Haemost 2011; 106: 1-9.
18 Haas S, Turpie A, Lassen M. et al. Prothrombin time and bleeding events in patients undergoing total hip or knee replacement surgery receiving 10 mg rivaroxaban. ASH 2009, Poster Session: Antithrombotic Therapy Poster II. 2099.
19 Samama MM, Contant G, Spiro T. et al. Evaluationof the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost 2012; 107: 379-387.
20 Mani H, Rohde G, Stratmann G. et al. Accurate determination of rivaroxaban levels requires different calibrator sets but not addition of antithrombin. Thromb Haemost 2012; 108: 191-198.
21 Mueck W, Lensing A, Agnelli G. et al. Rivaroxaban:Population pharmacokinetic analyses in patients treated for acute deepvein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 10: 675-686.
22 Fachinformation Xarelto. Rote Liste. 2012
23 Van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
24 McCormack PL. Tranexamic acid: A review of its use in the treatment of hyperfibrinolysis. Drugs 2012; 72: 585-617.
25 Fachinformation Cyklokapron® . Rote Liste (Dezember 2010).
26 Spannagl M, Koscielny J, Kiesewetter H. Prokoagulatoren. In: Aktuelle Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten der Bundesärztekammer. 2009: 153-154.
27 Guyatt GH, Akl EA, Crowther M, Gutterman DD. forthe American College of Chest Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis,9^th ed. American College of Chest Physicians. Chest 2012; 141: 7S-47S.
28 Marlu R, Hodaj E, Paris A. et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. Thromb Haemost 2012; 108: 217-224.