Management of Hemorrhage Related to Direct Action Oral Anticoagulant Medication

Manejo das Hemorragias Relacionadas aos Anticoagulantes Orais de Ação Direta

Authors

  • Isabela Ramos Ali Ganem
  • Luiz Claudio Behrmann Martins
  • Carlos Eduardo Mendonça Tomé

Keywords:

Atrial fibrillation, Blood coagulation, Pharmaceuticals, Efeitos dos fármacos

Abstract

Introduction: Direct Oral Anticoagulant – DOACs) are a new class of anticoagulant that directly inhibit the trombine (dabigatrane) or Xa factor (rivaroxabane, edoxabane and apixabane) in the coagulation cascade. These medications are being more frequently used for the treatment and prevention of thrombolytic events, mainly in patients with atrial fibrillation, in substitute to varfrine or other vitamin K antagonists (VKAs). Although the incidence of hemorrhage is higher in AVKs than in DOACs, these events may also occur in this group, even in the form of intracranial hemorrhage (ICH), with risk of death. Nowadays, DOACs indications have progressively enhanced and the availability of their specific reverse agents certainly will enhance the safety of their usage. Idarucizumab, reverse agent of dabigatrane, and alpha andexanet, reverse agent of Xa factor, have been approved by the Food and Drug Administration in the United States and ciraparantag may be approved in a near future. Objective: To review the literature on the manage of hemorrhage related to the use of DOACs. Methods: Review of literature that used articles from 1998 to 2017, from several platforms and journals. Conclusion: DOACs constitute a great advance in prophylaxis and treatment of thrombolytic diseases, which presents elevated morbid mortality, and hemorrhages are the main adverse events related to their usage, being rarely necessary the immediate reverse of the anticoagulation. However, the existence of DOACs specific reverse agents enhances the safety of patients, whose anticoagulation may be rapidly reversed if necessary. 

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References

Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am

J Med. 2015;128(12):1300-5.e2. https://doi.org/10.1016/j.amjmed.2015.05.044

Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics–2016 update: a report from American Heart Association. Circulation. 2016;133:e38-360. https://doi.org/10.1161/

CIR.0000000000000350

Reilly PA, van Ryn J, Grottke O, Glund S, Stangier J. Idarucizumab, a specific reversal agent for Dabigatran:

Mode of action, Pharmacokinetics and pharmacodynamics, and safety and efficacy in fase 1 subjects. The American Journal of Medicine. 2016. http://dx.doi.org/10.1016/J.amjmed.2016.06.007

Suryanarayan D, Schulman S. Potencial antidotos for reversal of old and new oral anticoagulants. Tirombaço

Res. 2014;133(Suppl 2):S158-66. https://doi.org/10.1016/S0049-3848(14)50026-6

Marques SP. Velhos e novos anticoagulantes orais. Perspectiva farmacológica. Rev Port Cardiol. 2012;31(1):6-

https://doi.org/10.1016/S0870-2551(12)70034-3

Dager WE, Gosselin RC, Kitchen S, Dwyre D. Dabigatran effects on the international normalized ratio, activated

partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother.

;46:1627. https://doi.org/10.1345/aph.1R179

Reilly PA, Lehr T, Haertter S, Conolly SJ, Yusuf S, Eikelboom JW, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63:321-38. https://doi.org/10.1016/j.jacc.2013.07.104

Douros A, Azoulay L, Yin H, Suissa S, Renoux C. Non-vitamin K antagonist oral anticoagulants and risk of serious liver injury. J Am Coll Cardiol. 2018;71:1105. https://doi.org/10.1016/j.jacc.2018.01.009

Poulsen BK, Grove EL, Husted SE. New oral anticoagulants: a review of the literature with particular emphasis on patients with impaired renal function. Drugs. 2012;72:1739. https://doi.org/10.2165/11635730-000000000-00000

Turpie AG, Kreutz R, Llau J, Norrving B, Haas S. Management consensus guidance for the use of rivaroxaban – an oral, direct factor Xa inhibitor. Thromb Haemost. 2012;108:876. https://doi.org/10.1160/TH12-03-0209

Gulseth MP, Wittkowsky AK, Fanikos J, Spinler SA, Dager WE, Nutescu EA, et al. Dabigatran etexilate in clinical practice: confronting challenges to improve safety and effectiveness. Pharmacotherapy. 2011;31:1232. https://doi.org/10.1592/phco.31.12.1232

Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011;31:326. https://doi.org/10.1007/s11239-011-0561-1

Powell JR. Are new oral anticoagulant dosing recommendations optimal for all patients? JAMA.

;313:1013. https://doi.org/10.1001/jama.2015.59

Bristol-Myers Squibb Pharma Company. Highlights of prescribing information. Disponível em: http://

packageinserts.bms.com/pi/pi_eliquis.pdf

Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, et al. DU-176b, a potent and orally active fator Xa inhibitor: in vitro and in vivo pharmacological profiles. Thromb Haemost. 2008;6(9):1542-9. https://doi.org/10.1111/j.1538-7836.2008.03064.x

Zafar MU, Vorchheimer DA, Gaztanaga J, Velez M, Yadegar D, Moreno PR, et al. Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-1 study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber. Thromb Haemost. 2007;98(4):883-8. https://doi.org/10.1160/TH07-04-0312

Lixiana. Summary of product characteristics. (European Medicines Agency). Disponível em: http://www.ema.

europa.eu/ema/index.jsp?curl=Pages/medicines/human/medicines/002629/human_med_001874.

jsp&mid=WC0b01ac058001d124

Masumoto H, Yoshigae Y, Watanabe K, Takakusa H, Okazaki O, Izumi T, et al. In vitro metabolism of edoxaban and the enzymes involved in the oxidativo metabolism of edoxaban. AAPS J. 2010;12:1

Salazar DE, Mendell J, Kastrissios H, Green M, Carrothers TJ, Song S, et al. Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation. Thromb Haemost 2012;107(5):925-36. https://doi.org/10.1160/TH11-08-0566

Ruff CT, Giugliano RP, Antman EM, Crugnale SE, Bocanegra T, Mercuri M, et al. Evaluation of the novel factor Xa inhibitor edoxaban compares with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation - Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J. 2010;160(4):635-41. https://doi.org/10.1016/j.ahj.2010.06.042

Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes. J Am Coll Cardiol. 2014;63:2141. https://doi.org/10.1016/j.jacc.2014.02.549

Garcia DA, Crowther M. Management of bleeding in patients receiving direct oral anticoagulants. UpToDate.2018

Carson JL, Guyatt G, Heddle NM, Grossman BJ, Cohn CS, Fung MK, et al. Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage. JAMA. 2016;316:2025-35. https://doi.org/10.1001/jama.2016.9185

Contreras M. Consensus conferenc on platelet transfusion. Final statement. Blood Rev. 1998;12:239-40. https://doi.org/10.1016/S0268-960X(98)90005-4

Tummala R, Kavtaradze A, Gupta A, Ghosh RK.Specific antidotes against direct oral anticoagulants- a comprehensive review of clinical trials data. Int J Cardiol. 2016;214:292-8. https://doi.org/10.1016/j.ijcard.2016.03.056

Wong H, Keeling D. Activate prothrombin complex concentrate for the prevention of dabigatran-associated bleeding. Br J Haematol. 2014;166:152-3. https://doi.org/10.1111/bjh.12831

Dibu JR, Weimer JM, Ahrens C, Manno E, Frontera JA.The role of FEIBA in reversing novel oral anticoagulants in

intracerebral hemorrhage. Neurocrit Care. 2016;24:413-9. https://doi.org/10.1007/s12028-015-0213-y

Van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M. Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb

Haemost. 2010;103:1116-27. https://doi.org/10.1160/TH09-11-0758

Stangier J, Rathgen K, Stahle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate. Clin Pharmaokinet. 2010;49:259-

https://doi.org/10.2165/11318170-000000000-00000

Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, Nar H, et al. A specific antidote for dabigatran, funcional and structural characterization. Blood. 2013;121:3554-62. https://doi.org/10.1182/blood-2012-11-468207

Glund S, Stangier J, Schmohl M, Ganser D, Norris S, van Ryn J, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, doubleblind phase 1 trial. Lancet. 2015;386:680-90. https://doi.

org/10.1016/S0140-6736(15)60732-2

Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat

Med. 2013;19:446-51. https://doi.org/10.1038/nm.3102

Connolly SJ, Milling TJ, Eikelboom JW, Gibson CM, Gold A, Curnutte JT, et al. Andexanet alfa for acute major

bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-41. https://doi.org/10.1056/

NEJMoa1607887

Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413-24. https://doi.org/10.1056/NEJMoa1510991

Quintard H, Viard D, Drici MD, Ruetsch C, Samama CM, Ichai C. Idarucizumab administration for reversing dabigatran effect in na acute kidney injured patient with bleeding. Thromb Haemost. 2017;117(1):196-7. https://doi.org/10.1160/TH16-06-0445

Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, Dishy V, et al. Use of PER977 to reverse the anticoagulants effect of edoxaban. N Engl J Med 2014; 371: 2141-2

J. E. Ansell, S. H. Bakhru, B. E. Laulicht et al., “Use of PER977 to reverse the anticoagulant effect of edoxaban,” New England Journal of Medicine, vol. 371, no. 22, pp. 2141-2142, 2014

Published

2019-10-19

How to Cite

Ganem, I. R. A. ., Martins, L. C. B. ., & Tomé, C. E. M. . (2019). Management of Hemorrhage Related to Direct Action Oral Anticoagulant Medication: Manejo das Hemorragias Relacionadas aos Anticoagulantes Orais de Ação Direta. JOURNAL OF CARDIAC ARRHYTHMIAS, 32(2), 89–96. Retrieved from https://jca.org.br/jca/article/view/26

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Section

Clinical Arrythmia

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