Journal of Thrombosis and Thrombolysis

, Volume 41, Issue 2, pp 293–300 | Cite as

Standardized use of novel oral anticoagulants plasma level thresholds in a new thrombolysis decision making protocol

  • Jessica Kepplinger
  • Alexandra Prakapenia
  • Kristian Barlinn
  • Gabriele Siegert
  • Siegmund Gehrisch
  • Charlotte Zerna
  • Jan Beyer-Westendorf
  • Volker Puetz
  • Heinz Reichmann
  • Timo Siepmann
  • Ulf Bodechtel
Article

Abstract

Acute ischemic stroke (AIS) patients receiving non-vitamin-K antagonist oral anticoagulants (NOAC) are commonly excluded from thrombolytic therapy, as interpretation of coagulation tests remains unclear. We aimed to investigate the applicability of a novel institutional protocol for thrombolysis based on current expert recommendations and NOAC specific coagulation assessment. We included hospitalized AIS patients receiving NOAC for at least 24 h and consecutive AIS patients not receiving NOAC into a prospective study. We performed standard coagulation tests and specific tests for dabigatran, rivaroxaban and apixaban plasma levels. We studied 65 patients: mean age 72 ± 13 years, 30 (46 %) male, median NIHSS score 3 (IQR 6). Fifteen (23 %) were on NOAC treatment (5 dabigatran, 5 rivaroxaban, and 5 apixaban, respectively) and 50 (77 %) were not. In patients without NOAC, dabigatran was not detectable (0 ng/ml), and plasma levels of rivaroxaban (median: 10.0 ng/ml, IQR 7.0) and apixaban (7.2 ng/ml, IQR 6.7) were below our lower thresholds that allow thrombolysis. In patients with dabigatran pre-treatment, trough levels (58.0 ng/ml, IQR 143.0) were below our upper threshold that would allow thrombolysis in 3/5 patients. In patients receiving rivaroxaban, trough level (68.0 ng/ml, IQR 64.0) was below our predefined upper thresholds that would allow thrombolysis in 4/5 patients. In all patients on apixaban, trough level was above our predefined threshold of 40 ng/ml that precludes thrombolysis (98.2 ng/ml, IQR 84.3). Predefined thresholds of NOAC plasma levels in the decision of thrombolysis in NOAC treated AIS patients might supplement routine coagulation tests and should be validated in a larger study population.

Keywords

Acute ischemic stroke Thrombolysis Novel oral anticoagulants 

References

  1. 1.
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al (2009) RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151CrossRefPubMedGoogle Scholar
  2. 2.
    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:883–891CrossRefPubMedGoogle Scholar
  3. 3.
    Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M et al (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992CrossRefPubMedGoogle Scholar
  4. 4.
    Weitz JI (2015) Anticoagulation therapy in 2015: where we are and where we are going. J Thromb ThrombolysisGoogle Scholar
  5. 5.
    Steiner T, Böhm M, Dichgans M, Diener HC, Ell C, Endres M et al (2013) Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban. Clin Res Cardiol 102:399–412CrossRefPubMedGoogle Scholar
  6. 6.
    Mazya MV, Lees KR, Markus R, Roine RO, Seet RC, Wahlgren N, Ahmed N, Safe Implementationof Thrombolysis in Stroke Investigators (2013) Safety of intravenous thrombolysis for ischemic stroke in patients treated with warfarin. Ann Neurol. 74:266–274CrossRefPubMedGoogle Scholar
  7. 7.
    McGrath ER, Eikelboom JW, Kapral MK, O’Donnell MJ (2014) Novel oral anticoagulants: a focused review for stroke physicians. Int J Stroke 9:71–78CrossRefPubMedGoogle Scholar
  8. 8.
    Hankey GJ, Norrving B, Hacke W, Steiner T (2014) Management of acute stroke in patients taking novel oral anticoagulants. Int J Stroke. 9:627–632PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Samama MM, Martinoli JL, Le Flem L, Guinet C, Plu-Bureau G, Depasse F, Perzborn E (2010) Assessment of laboratory assays to measure rivaroxaban—an oral, direct Factor Xa inhibitor. Thromb Haemost 103:815–825CrossRefPubMedGoogle Scholar
  10. 10.
    Mueck W, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, Kälebo P, Muelhofer E, Misselwitz F, Eriksson BI (2008) Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost 100:453–461PubMedGoogle Scholar
  11. 11.
    van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A (2010) Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103:1116–1127CrossRefPubMedGoogle Scholar
  12. 12.
    Barrett YC, Wang J, Knabb R, Mohan P (2011) Apixaban decreases coagulation activity in patients with acute deep-vein thrombosis. Thromb Haemost 105:181–189CrossRefPubMedGoogle Scholar
  13. 13.
    Frost C, Nepal S, Wang J, Schuster A, Byon W, Boyd RA, Yu Z, Shenker A, Barrett YC, Mosqueda-Garcia R, Lacreta F (2013) Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol 76:776–786PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Hawes EM, Deal AM, Funk-Adcock D, Gosselin R, Jeanneret C, Cook AM, Taylor JM, Whinna HC, Winkler AM, Moll S (2013) Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 11:1493–1502CrossRefPubMedGoogle Scholar
  15. 15.
  16. 16.
    Baglin T, Keeling D, Kitchen S (2012) Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: guidance from the British Committee for Standards in Haematology. Br J Haematol 159:427–429CrossRefPubMedGoogle Scholar
  17. 17.
    Mueck W, Stampfuss J, Kubitza D, Becka M (2014) Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 53:1–16PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Samama MM, Contant G, Spiro TE, Perzborn E, Le Flem L, Guinet C, Gourmelin Y, Rohde G, Martinoli JL (2013) Laboratory assessment of rivaroxaban: a review. Thromb J 11:11PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Cuker A, Siegal DM, Crowther MA, Garcia DA (2014) Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 64:1128–1139PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Jessica Kepplinger
    • 1
  • Alexandra Prakapenia
    • 1
  • Kristian Barlinn
    • 1
  • Gabriele Siegert
    • 2
  • Siegmund Gehrisch
    • 2
  • Charlotte Zerna
    • 1
  • Jan Beyer-Westendorf
    • 3
  • Volker Puetz
    • 1
  • Heinz Reichmann
    • 1
  • Timo Siepmann
    • 1
  • Ulf Bodechtel
    • 1
  1. 1.Department of NeurologyCarl Gustav Carus University Hospital, Technische Universität DresdenDresdenGermany
  2. 2.Institute of Clinical Chemistry and Laboratory MedicineCarl Gustav Carus University Hospital, Technische Universität DresdenDresdenGermany
  3. 3.Department of Internal MedicineCarl Gustav Carus University Hospital, Technische Universität DresdenDresdenGermany

Personalised recommendations