Blutungen unter NOAK^[1]

Summary

The doses of these drugs are barely tested and the potential clinical thromboembolic risk must be taken into account. Despite the widespread use of NOAC (non vitamin-K dependent oral anticoagulants) and recommendations of regulatory agencies and first consensus meeting on handling the bleeding situation under NOAC, especially in hospitals without a large hemostatic focus, uncertainty still exists. In case of mild bleeding from a clinical perspective, the medical care of these patients and the delay of the next dose or discontinuation is advised. A special laboratory analysis is indicated i.e. in case of known higher grade liver and kidney failure, which can cause a prolonged elimination of NOAC. The administration of factor concentrates is not indicated in this situation. In case of moderate to severe bleeding, the primary measures focus on the stabilization of the heart and circulatory function and parallel on the treatment depending on the localization of the bleeding source. According to experience, mostly gastrointestinal bleeding occurs under the NOAC, which should be supplied endoscopically. In life-threatening bleeding in addition to the measures of hemodynamic stabilization usually a special haemostasis management is required, which should be mainly clinically oriented. After the assessment of bleeding predictor, the time of the last dose and the dose of NOAC should be learned, but other causes of bleeding, including Fibrinolysis, should be excluded or treated. Subsequently, routinely promptly rivaroxaban and/ or apixaban sensitive thromboplastin time (Quick’s value) and a thrombin time (thrombin- poor calibrator) for qualitative assessment can be carried out because only very few hospitals have specific tests (anti-Xa measurements, bovine thrombin), which could be promptly done. If there is a significant deviation from the normal range or to present preliminary value of particular patient, an effect of NOAC most likely exists. In life-threatening bleeding the use of factor concentrates (procoagulants) is indicated. The first-line therapy should be PPSB. Only in exceptional cases, especially when dabigatran is taken, the use of aPPSB (FEIBA®) for prompt haemostasis can be considered. The haemostasis should be always clinically estimated and not according to coagulation tests. The use of rFVIIa (Novo Seven®) shows different results in the bleeding therapy (reversal) under Dabigatran. The doses of these drugs are barely tested and the potential clinical thromboembolic risk must be taken into account.

Conclusion

The current concepts of the newly developed antidotes are not clinically validated. First prospective, clinical registries have been started.

Zusammenfassung

Trotz des breiten Einsatzes von NOAK (nicht Vitamin-K-abhängige Antikoagulanzien) und Empfehlungen der Zulassungsbehörden und erster Konsensusmeetings zum Umgang in der Blutungssituation mit NOAK besteht insbesondere in Krankenhäusern ohne hämo - staseologischen Schwerpunkt eine große Handlungsunsicherheit. Bei aus klinischer Sicht leichten Blutungen ist die medizinische Überwachung dieser Patienten und die Verzögerung der nächsten Einnahme oder das passagere Absetzen anzuraten. Eine spezielle Laboranalytik ist u.a. besonders bei bekannter hochgradiger Leber- und Niereninsuffizienz, die eine verlängerte Elimination der NOAK verursachen können, angezeigt. Die Gabe von Faktorenkonzentraten ist in dieser Situation kontraindiziert. Bei mittelschweren bis schweren Blutungen richten sich die primären Maßnahmen auf die Stabilisierung der Herz- und Kreislauffunktion sowie parallel auf die Behandlung je nach Lokalisation des Blutungsherdes. Bei den NOAK können dies erfahrungsgemäß meist gastrointestinale Blutungen sein, welche endoskopisch versorgt werden sollten. Bei vital bedrohlichen Blutungen ist neben den Maßnahmen der hämodynamischen Stabilisierung in aller Regel ein spezielles Hämostasemanagement erforderlich, welches vorwiegend klinisch orientiert sein sollte. Nach der Beurteilung von Blutungsprädiktoren sollte der Zeitpunkt der letzten Einnahme und die NOAK-Dosis in Erfahrung gebracht werden, aber auch andere Blutungsursachen, z. B. Hyperfibrinolyse, sind auszuschließen bzw. zu behandeln. Anschließend kann zeitnah routinemäßig eine Rivaro- xaban bzw. Apixaban empfindliche Thromboplastinzeit (Quick-Wert) sowie eine Thrombinzeit (thrombinverdünnter Kalibrator) zur qualitativen Beurteilung durchgeführt werden, da den wenigsten Krankenhäusern spezifische Tests (Anti-Xa-Messung, bovine Thrombinzeit) zeitnah zur Verfügung stehen. Ist eine deutliche Abweichung zum Normbereich oder zum vorliegenden Vorwert des jeweiligen Patienten erkennbar, ist eine Wirkung von NOAK mit großer Wahrscheinlichkeit gegeben. Bei vital bedrohlichen Blutungen ist dann der Einsatz von Faktorenkonzentraten (Prokoagulatoren) indiziert. Die Therapie der ersten Wahl sollte PPSB sein. Nur in absoluten Ausnahmefällen, insbesondere bei Dabigatran, kann der Einsatz von aPPSB (FEIBA®) für eine zeitnahe Blutstillung, die stets klinisch und nicht durch einen Gerinnungstest zu beurteilen ist, erwogen werden. Der Einsatz von rFVIIa (Novo Seven®) zeigt bei Blutungen unter Dabigatran unterschiedliche Ergebnisse. Die Dosierungen dieser Präparate sind klinisch kaum erprobt und das potentielle thromboembolische Risiko ist zu berücksichtigen.

Schlussfolgerung

Die aktuellen Konzepte der neu entwickelten Antidots sind klinisch nicht erprobt. Erste prospektive Register sind gestartet.

Keywords

Rivaroxaban - apixaban - dabigatran - anticoagulants - bleedings - bleeding risk - management of haemostasis - management of bleedings - PCC - FEIBA - antidots

Schlüsselwörter

Rivaroxaban - Apixaban - Dabigatran - Antikoagulanzien - Blutungen - Blutungsrisiko - Hämostasemanagement - Blutungsmanagement - PPSB - FEIBA - Antidots

¹ nicht Vitamin- K-abhängige Antikoagulanzien

• Literatur

• 1 Healey JS, Eikelboom J, Douketis J. et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: Results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial. Circulation 2012; 126: 343-348.
• 2 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.
• 3 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
• 4 The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
• 5 The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
• 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 Lindhoff-Last E, Samama MM, Ortel TL. et al. Assays for measuring rivaroxaban: their suitability and limitations. Ther Drug Monit 2010; 32: 673-679.
• 10 Van Ryn J, Strangier 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.
• 11 Pradaxa. Summary of Product Characteristics 2013. www.ema.europa.eu/docs/en GB/document library/EPAR-Product Information/ human/000829/WC500041059.pdf.
• 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 Cuker A, Siegal D, Crowther M, Garcia D. Laboratory Measurement of the Anticoagulant Activity of the Non–Vitamin K Oral Anticoagulants. J Am Coll Cardiol 2014; 64: 1128-1139.
• 16 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.
• 17 Lindhoff-Last E, Samama MM, Ortel TL. et al. Assays for measuring rivaroxaban: their suitability and limitations. Ther Drug Monit 2010; 32: 673-679.
• 18 Koscielny J, Beyer-Westendorf J, von Heymann C. et al. Risk of bleeding and haemorrhagic complication with rivaroxaban – periprocedural management of haemostasis. Hämostaseologie 2012; 32: 287-293.
• 19 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.
• 20 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, Abstract 2099
• 21 Samama MM, Contant G, Spiro T. et al. Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost 2012; 107: 379-387.
• 22 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; 191-198.
• 23 Xarelto. Summary of Product Characteristics. 2013 www.ema.europa.eu/docs/en GB/document library/EPAR-Product Information/ human/000944/WC500057108.pdf.
• 24 Samama MM, Amiral J, Guinet C. et al. Monitoring plasma levels of factor Xa inhibitors: how, why and when?. Expert Rev Hematol 2013; 06: 155-164.
• 25 Eliquis. Summary of Product Characteristics 2013. www.ema.europa.eu/docs/en GB/document library/EPAR-Product Information/ human/002148/WC500107728.pdf.
• 26 Heneghan C. et al. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet 2006; 367: 404-411.
• 27 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
• 28 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: 1875-1876.
• 29 FDA Drug Safety Communication from 05–13–2014: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin. Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran) that was issued on November 2. 2012 www.fda.gov/Drugs/DrugSafety/ ucm326580.htm.
• 30 Graham DJ, Reichman ME, Wernecke M. et al. Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation. Circulation. 2014 pii: CIRCULATIONAHA.114.012061.
• 31 Steinberg B, Hellkamp A, Lokhnygina Y. et al. on behalf of the ROCKET-AF Steering Committee and Investigators. Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. Eur Heart J 2014; 359: 1-9.
• 32 Beyer-Westendorf J, Förster K, Pannach S. et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014; 124: 955-962.
• 33 Wang Y, Bajorek B. New oral anticoagulants in practice: Pharmacological and practical considerations. Am J Cardiovasc Drugs. 2014 …((AUTOR BITTE ERGÄNZEN))
• 34 Spannagl M, Bauersachs R, Debus ES. et al. Dabigatran therapy--perioperative management and interpretation of coagulation tests. Hämostaseologie 2012; 32: 294-305.
• 35 Giebl A K, Gürtler K. Neue orale Antikoagulanzien in der perioperativen Medizin. Anaesthesist 2014; 63: 347-364.
• 36 Eisele R, Melzer N, Bramlage P. Perioperatives Gerinnungsmanagement bei oraler Antikoagulation. Chirurg 2014; 85: 513-519.
• 37 Pernod G, Albaladejo P, Godier A. et al. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: Proposals of the Working Group on Perioperative Haemostasis (GIHP) — March 2013. Arch Cardiovasc Dis 2013; 106: 382-393.
• 38 Aktuelle Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten der Bundesärztekammer (4. Auflage) 2009: Kapitel 7: Prokoagulatoren. Spannagl M, Koscielny J, Kiesewetter H. 153-154.
• 39 Heidbuchel H, Verhamme P, Alings M. et al. EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013; 27: 1-13.
• 40 Koscielny J, Rutkauskaite E. Rivaroxaban and Hemostasis in Emergency Care. Emergency Medicine International 2014; 9-18.
• 41 Gordon H, Guyatt E A, Akl M. et al. for the American College of Chest Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9^th ed. Chest 2012; 141: 7S-47S.
• 42 Chang D, Dager W, Chin A. Removal of dabigatran by hemodialysis. Am J Kidney Dis 2013; 61: 487-489.
• 43 Gruber A, Marzec U, Buetehorn U. et al. Potential of activated prothrombin complex concentrate and activated factor VII to reverse the anticoagulant effects of rivaroxaban in primates. Blood. 2008 Poster Session: Antithrombotic Therapy, Abstract 3825.
• 44 Eerenberg ES, Kamphuisen PW, Sijpkens MK. et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: 1573-1579.
• 45 Godier A, Miclot A, Le Bonniec B. et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012; 116: 94-102.
• 46 Marlu R, Hodaj E, Paris A. et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108: 8-12.
• 47 Kaatz S, Crowther M. Reversal of target-specific oral anticoagulants. J Thromb Thrombolysis 2013; 36: 195-202.
• 48 Dager W, Roberts A. Reversing dabigatran in a life-threatening bleed occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med 2013; 41: 42-46.
• 49 Dager W, Roberts A. Reversing dabigatran with Feiba in a patient with a transseptal perforation during cardiac ablation. Crit Care Med 2011; 39 (Suppl. 12) 243-244.
• 50 Steiner T, Dichgans M, Diener HC. et al. Handlungsempfehlungen zum Notfallmanagement bei Dabigatran assoziierten Akut-Komplikationen. DIVI 2012; 03: 10-16.
• 51 Elg M, Carlsson S, Gustafsson S. Effect of activated prothrombin complex concentrate or recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor. Thromb Res 2001; 101: 145-157.
• 52 Warkentin TE, Margetts P, Connolly SJ. et al. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 2012; 119: 2172-2174.
• 53 Hsia C, Chin-Yee I, McAlister V. Use of recombinant activated Factor VII in patients without hemophilia: a meta-analysis of randomized control trials. Ann Surg 2008; 248: 61-68.
• 54 Baxter Healthcare Corporation. Thrombotic and thromboembolic events following infusion of FEIBA VH or FEIBA NF. 2010 www.fda.gov/down loads/ biologicsbloodvaccines/ safetyavailability/ ucm221755.pdf.
• 55 Lu G, DeGuzman F, Hollenbach S. et al. A specific antidote for reversal on anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nature Med 2013; 19: 446-451.
• 56 Crowther M. et al. Phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by Andexanet Alfa (PRT064445), an antidote for FXa inhibitors. Poster Session: Antithrombotic Therapy Poster II. Blood. 2013 Abstract 3636.
• 57 FDA. Adexanet-alfa. www.clinicaltrials.gov, NCT01758432.
• 58 Schiele F, van Ryn J, Canada K. et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 11: 3554-3562.
• 59 FDA. Idarucizumab. www.clinicaltrials.gov, NCT01688830.
• 60 FDA. Idarucizumab. www.clinicaltrials.gov, NCT02104947.
• 61 Glund S, Stangier J, Schmohl M. et al. Idarucizumab, a specific antidote for dabigatran: Immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. Session: 332. Antithrombotic Therapy: Anticoagulant Therapy. Blood. 2014 Abstract 344.
• 62 Laulicht B, Bakhru S, Jiang X. et al. Antidote for new oral anticoagulants: mechanism of action and binding specificity of PER977. J Thromb Haemost. 2013 11. (Suppl 2): Abstract AS 47.1.
• 63 Lu G, Kotha J, Cárdenas J. et al. In vitro characterization of Adexanet Alfa (PRT064445), a specific FXa inihibitor antidote versus Aripazine (PER977), a non-specific reversal agent. AHA (American Heart Association) 2014, Poster 3184.