Therapie mit Dabigatran

 

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Summary Dabigatran, an oral, reversible direct factor IIa inhibitor, is approved in Europe for stroke prevention in atrial fibrillation and for the prevention of venous thromboembolism after elective hip and knee replacement. In contrast to vitamin K antagonists, a routine coagulation monitoring during the treatment with dabigatran etexilate is not necessary. However, in specific clinical situations such as invasive emergency procedures or serious haemorrhage, the actual anticoagulant status of dabigatran may be of importance for the treating clinician and can be assessed by clotting tests (aPTT, TT, ECT). The diluted thrombin time test (Hemoclot^®), which is specifically calibrated for dabigatran, is useful for quantitative determination of the dabigatran serum concentration. In general, discontinuation of dabigatran etexilate 24 hours before standard elective surgery is sufficient to normalise the bleeding risk in patients with normal renal function. In patients with renal impairment and/or in the case of a high bleeding risk procedure the recommended duration of discontinuation is prolonged. If a bleeding episode occurs in a patient on dabigatran, further treatment should be based on the severity and localisation of the bleeding. A distinct feature of dabigatran is the possibility of effectively removing dabigatran from the circulation by haemodialysis. Recommendation: In the case of clinically minor bleedings, a delay in the administration of the next dabigatran etexilate dose is recommended. The length of the delay is based on the patient’s individual thromboembolic risk. In minor bleedings the use of prothrombin complex concentrates is not indicated. In the case of moderate or major bleedings the main focus should be on stabilising the circulation by using fluids and blood products and, if a lesion can be identified, the local treatment thereof. If time and infrastructure is available, dialysis offers an effective and fast option to remove dabigatran out of the circulation. In the incidence of severe and life threatening bleedings, an additional, more complex haemostasis management is required. Besides haemodynamic stabilisation of the circulation, administration of prothrombin complex concentrates should not be delayed. It has to be kept in mind that standard laboratory coagulation parameters may not accurately reflect the effect of prothrombin complex concentrates in patients on dabigatran. Hence the effect of the prothrombin complex concentrate should be monitored clinically and adjusted by means of onset of coagulation in vivo.

Zusammenfassung

Dabigatran, ein direkter und reversibel bindender Faktor-IIa-Hemmer, ist in Europa zur Schlaganfallprophylaxe bei Vorhofflimmern und zur primären Thromboseprophylaxe nach elektivem Hüft- und Kniegelenkersatz zugelassen. Im Gegensatz zu Vitamin-K-Antagonisten ist eine routinemäßige Kontrolle der gerinnungshemmenden Wirkung von Dabigatran nicht notwendig. Eine Abschätzung der antikoagulatorischen Wirkung von Dabigatran könnte für den klinisch tätigen Arzt in spezifischen Situationen wie vor Notfalloperationen oder schweren Blutungen wichtig sein und kann durch die aktivierte partielle Thromboplastinzeit, Ecarin Clotting Time oder Thrombinzeit durchgeführt werden. Der spezifisch für Dabigatran kalibrierte verdünnte Thrombinzeit Test (Hemoclot^®) kann für quantitative Aussagen zu Plasmakonzentrationen eingesetzt werden. Zur Normalisierung des Blutungsrisikos vor elektiven Eingriffen bei Patienten mit normaler Nierenfunktion reicht in der Regel ein Absetzen von Dabigatranetexilat 24 Stunden vor dem Eingriff aus. Bei eingeschränkter Nierenfunktion oder bei einem Eingriff mit erhöhtem Blutungsrisiko verlängern sich die empfohlenen Absetzfristen dementsprechend. Beim Auftreten von Blutungen während einer Therapie mit Dabigatran richtet sich die weiterführende Behandlung nach dem Schweregrad und Lokalisation der Blutung. Eine Besonderheit besteht darin, dass Dabigatran mittels Dialyse aus dem Kreislaufsystem relativ rasch entfernt werden kann. Empfehlungen: Bei aus klinischer Sicht leichten Blutungen ist eine kurzfristige Verschiebung der Substanzeinnahme anzuraten. Der Zeitraum basiert hier auf dem individuellen Thromboserisiko des Patienten. Die Gabe von Faktorenkonzentraten ist bei leichten Blutungen nicht indiziert. Bei mittelschweren bis schweren Blutungen sollte nach Absetzen von Dabigatran insbesondere auf die Stabilisierung der Herz- und Kreislauffunktion durch Volumenersatz und Blutprodukte sowie auf die (lokale) Behandlung des Blutungsherdes geachtet werden. Falls die Option besteht, kann Dabigatran mittels Haemo filtration oder Dialyse schnell und effektiv aus dem Kreislaufsystem entfernt werden. Bei schweren oder lebensbedrohlichen Blutungen wird ein spezielles Hämostasemanagement erforderlich. Je nach Lokalisation der Blutung sollte nebst der hämodynamischen Stabilisierung des Kreislaufes der Einsatz von Faktorenkonzentraten in dieser Situation zeitnah erfolgen. Wichtig ist hierbei, dass die Standard- Laborparameter den Effekt der Faktorenkonzentrate nicht akkurat wiedergeben. Daher sollte der Effekt klinisch anhand der einsetzenden Blutgerinnung beurteilt werden.

• Literatur

• 1 Fachinformation Pradaxa 75 mg und 110 mg Hartkapseln. Juni 2012 Boehringer Ingelheim.
  PubMedGoogle Scholar
• 2 Fachinformation Pradaxa 110 mg und 150 mg Hartkapseln. Juni 2012 Boehringer Ingelheim.
  PubMedGoogle Scholar
• 3 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.
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
  CrossrefPubMedGoogle Scholar
• 5 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: 1875-1876.
  CrossrefPubMedGoogle Scholar
• 6 Eriksson BI, Dahl OE, Rosencher N. et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370: 949-956.
  CrossrefPubMedGoogle Scholar
• 7 Eriksson BI, Dahl OE, Rosencher N. et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 05: 2178-2185.
  PubMedGoogle Scholar
• 8 Eriksson BI, Dahl OE, Huo MH. et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105: 721-729.
  PubMedGoogle Scholar
• 9 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
  CrossrefPubMedGoogle Scholar
• 10 Schulman S, Baanstra D, Eriksson H. et al. Dabigatran versus placebo for extended maintenance therapy of venous thromboembolism. J Thromb Haemost. 2011 09. O-Mo-037.
  PubMedGoogle Scholar
• 11 Schulman S, Eriksson H, Goldhaber SZ. et al. Dabigatran or warfarin for extended maintenance therapy of venous thromboembolism. J Thromb Haemost. 2011 09. O-Thu-033..
  PubMedGoogle Scholar
• 12 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.
  CrossrefPubMedGoogle Scholar
• 13 Huisman MV, Lip GY, Diener HC. et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: Resolving uncertainties in routine practice. Thromb Haemost 2012; 107: 838-847.
  Article in Thieme ConnectPubMedGoogle Scholar
• 14 Steiner T, Dichgans M, Diener HC. et al. Handlungsempfehlungen zum Notfallmanagement bei Dabigatran assoziierten Akut-Komplikationen. DIVI 2012; 03: 10-16.
  PubMedGoogle Scholar
• 15 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.
  CrossrefPubMedGoogle Scholar
• 16 Van Ryn J, Ruehl D, Priepke H. et al. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor, dabigatran, by recombinant factor VIIa or activated prothrombin complex concentrate. 13th Congress of the European Hematology Association, Copenhagen, Denmark. June 12-15 2008: 148.
  PubMedGoogle Scholar
• 17 Van Ryn J, Dörr B, Kaspereit F. Beriplex P/N reverses bleeding in an acute renal injury model after dabigatran overdose in rabbits. 21^st International Congress on Thrombosis, Milan, Italy, July. July 6–9 2010; A94.
  PubMedGoogle Scholar
• 18 Van Ryn J, Schurer J, Kink-Eiband M, Clemens A. The successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. ASH Annual Meeting Abstracts 2011; Nov 18; 118: 2316.
  PubMedGoogle Scholar
• 19 Zhou W, Schwarting S, Illanes S. et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011; 42: 3594-3599.
  CrossrefPubMedGoogle Scholar
• 20 Liesenfeld KH, Lehr T, Dansirikul C. et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011; 09: 2168-2175.
  CrossrefPubMedGoogle Scholar
• 21 Mueck W, Lensing AW, 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.
  CrossrefPubMedGoogle Scholar
• 22 Stangier J, Rathgen K, Stahle H. et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64: 292-303.
  CrossrefPubMedGoogle Scholar
• 23 Liesenfeld KH, Schafer HG, Troconiz IF. et al. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol 2006; 62: 527-537.
  CrossrefPubMedGoogle Scholar
• 24 Ezekowitz MD, Reilly PA, Nehmiz G. et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100: 1419-1426.
  CrossrefPubMedGoogle Scholar
• 25 Weltermann A, Brodmann M, Domanovits H. et al. Dabigatran in patients with atrial fibrillation: perioperative and periinterventional management. Wien Klin Wochenschr 2012; 124: 340-347.
  CrossrefPubMedGoogle Scholar
• 26 Van Ryn J, Baruch L, Clemens A. Interpretation of Point-of-care INR results in patients treated with dabigatran. Am J Med 2012; 125: 417-420.
  CrossrefPubMedGoogle Scholar
• 27 Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49: 259-268.
  CrossrefPubMedGoogle Scholar
• 28 Wagner F, Peters H, Formella Wiegert E. et al. Effective elimination of dabigatran with haemodialysis: A phase I single-centre study in patients with end stage renal disease. Amercian Heart Association Scientific Session 2011, Orlando Florida 13–15 November: 4–11–2011.
  PubMedGoogle Scholar
• 29 Wanek MR, Horn ET, Elapavaluru S. et al. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother. 2012 46. e21.
  PubMedGoogle Scholar
• 30 PHARMAC New Zealand Government. Guidelines for management of bleeding with dabigatran – for possible inclusion into local management protocols. 2011
  PubMedGoogle Scholar
• 31 Shakur H, Roberts I, Bautista R. et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010; 376: 23-32.
  CrossrefPubMedGoogle Scholar
• 32 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.
  CrossrefPubMedGoogle Scholar
• 33 Lehr T, Haertter S, Liesenfeld KH. et al. Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: Dose identification using pharmacokinetic modeling and simulation. J Clin Pharmacol 2012; 52: 1373-1378.
  CrossrefPubMedGoogle Scholar
• 34 Hohnloser SH, Diener HC. Dabigatran for stroke prevention in atrial fibrillation. Hämostaseologie 2012; 32: 216-220.
  Article in Thieme ConnectPubMedGoogle Scholar