Thromb Haemost 2013; 109(04): 596-605
DOI: 10.1160/TH12-08-0573
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Effective elimination of dabigatran by haemodialysis

A phase I single-centre study in patients with end-stage renal disease
Dmytro Khadzhynov*,#
1   Department of Nephrology, Charité Universitätsmedizin Berlin, Charité Campus Mitte, Humboldt University, Berlin, Germany
,
Frank Wagner*,#
2   Charité Research Organisation GmbH, Berlin, Germany
,
Stephan Formella
3   Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
,
Erol Wiegert
2   Charité Research Organisation GmbH, Berlin, Germany
,
Viktoria Moschetti
3   Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
,
Torsten Slowinski
1   Department of Nephrology, Charité Universitätsmedizin Berlin, Charité Campus Mitte, Humboldt University, Berlin, Germany
,
Hans-H. Neumayer
1   Department of Nephrology, Charité Universitätsmedizin Berlin, Charité Campus Mitte, Humboldt University, Berlin, Germany
,
Karl-Heinz Liesenfeld
3   Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
,
Thorsten Lehr
3   Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
,
Sebastian Härtter
3   Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
,
Jeffrey Friedman
4   Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Conneticut, USA
,
Harm Peters*,#
1   Department of Nephrology, Charité Universitätsmedizin Berlin, Charité Campus Mitte, Humboldt University, Berlin, Germany
,
Andreas Clemens*,#
3   Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
› Author Affiliations
Further Information

Publication History

Received: 21 August 2012

Accepted after major revision: 29 February 2012

Publication Date:
22 November 2017 (online)

Summary

Dabigatran, a specific, reversible direct thrombin inhibitor, is used to prevent ischaemic and haemorrhagic strokes in patients with atrial fibrillation. As with every anticoagulant, there is a need to rapidly reverse its effects in emergency situations. In an open-label, single-centre phase I study with two fixed multiple dosing periods, we investigated the pharmacokinetics, pharmacodynamics and safety of dabigatran before, during and after 4 hour haemodialysis sessions with either 200 or 400 ml/min targeted blood flow in seven end-stage renal disease patients without atrial fibrillation. Dabigatran was administered over three days in a regimen designed to achieve peak plasma concentrations comparable to those observed in atrial fibrillation patients receiving 150 mg b.i.d. and to attain adequate distribution of dabigatran in the central and peripheral compartments. Plasma concentration-time profiles were similar in both periods on Day 3 (Cmax: 176 and 159 ng/ml). Four hours of haemodialysis removed 48.8% and 59.3% of total dabigatran from the central compartment with 200 and 400 ml/minute targeted blood flow, respectively. The anticoagulant activity of dabigatran was linearly related to its plasma levels. There was a minor redistribution of dabigatran (<16%) after the end of the haemodialysis session. In conclusion, a 4 hour haemodialysis session can rapidly eliminate a substantial amount of dabigatran from the central compartment with a concomitant marked reduction in its anticoagulant activity. There was a clinically negligible redistribution of dabigatran after haemodialysis. These results demonstrate that haemodialysis can be a suitable approach to eliminate dabigatran in emergency situations.

*,# Both authors equally contributed to the present study.


 
  • References

  • 1 Ansell J, Hirsh J, Hylek E. et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (06) Suppl 160S-198S.
  • 2 Connolly SJ, Pogue J, Eikelboom J. et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008; 118: 2029-2037.
  • 3 Baetz BE, Spinler SA. Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases. Pharmacotherapy 2008; 28: 1354-1373.
  • 4 Stangier J, Stahle H, Rathgen K. et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47: 47-59.
  • 5 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.
  • 6 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.
  • 7 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.
  • 8 Ginsberg JS, Davidson BL, Comp PC. et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009; 24: 1-9.
  • 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.
  • 10 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
  • 11 Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Haemost 2009; 15 (Suppl. 01) 9S-16S.
  • 12 Dansirikul C, Lehr T, Liesenfeld KH. et al. A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery. Thromb Haemost 2012; 107: 775-785.
  • 13 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.
  • 14 Stangier J, Rathgen K, Stahle H. et al. 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.
  • 15 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-295.
  • 16 Stangier J, Stahle H, Rathgen K. et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol 2008; 48: 1411-1419.
  • 17 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 2011; 52: 1373-1378.
  • 18 Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med 2005; 353: 1028-1040.
  • 19 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.
  • 20 Boehringer Ingelheim. Pradaxa. Summary of product characteristics. 2011
  • 21 Stangier J, Feuring M. Using the HAEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinol 2012; 23: 138-143.
  • 22 Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. N Engl J Med 2011; 365: 2039-2040.
  • 23 Michaels AS. Operating parameters and performance criteria for haemodialysers and other membrane-separation devices. Trans Am Soc Artific Int Organ 1966; 12: 387-392.
  • 24 Warkentin TE, Margetts P, Connolly SJ. et al. Recombinant factor VIIa (rFVIIa) and haemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 2012; 119: 2172-2174.
  • 25 Wanek MR, Horn ET, Elapavaluru S. et al. Safe use of haemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 2012; 46: e21.