Management of bleeding in patients receiving direct oral anticoagulants
- David A Garcia, MD
David A Garcia, MD
- Professor of Medicine, Division of Hematology
- University of Washington School of Medicine
- Mark Crowther, MD, MSc
Mark Crowther, MD, MSc
- Professor of Medicine and Pathology & Molecular Medicine
- St Joseph’s Hospital and McMaster University
- Section Editors
- Lawrence LK Leung, MD
Lawrence LK Leung, MD
- Editor-in-Chief — Hematology
- Section Editor — Disorders of Hemostasis and Coagulation
- Professor of Medicine
- Stanford University School of Medicine
- Maria E Moreira, MD
Maria E Moreira, MD
- Section Editor — Adult Trauma
- Associate Professor, Department of Emergency Medicine
- University of Colorado Denver School of Medicine
- Residency Program Director
- Denver Health Residency in Emergency Medicine
The use of any anticoagulant is associated with an increased risk of bleeding, and bleeding complications can be life-threatening. Bleeding is especially concerning with the direct oral anticoagulants (DOACs) because antidotes or specific reversal agents for some of the DOACs are lacking. Additionally, routine coagulation tests cannot be used to determine the degree of anticoagulation, making it more challenging to determine when the anticoagulant effect has resolved.
This topic discusses our approach to managing bleeding in patients receiving DOACs. Specific indications for these agents, details of administration and monitoring, and perioperative management of these agents are presented separately. (See "Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse effects" and "Atrial fibrillation: Anticoagulant therapy to prevent embolization" and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Perioperative management of patients receiving anticoagulants" and "Venous thromboembolism: Initiation of anticoagulation (first 10 days)".)
TERMINOLOGY AND SITES OF ACTION
Terminology for oral anticoagulants has been in flux as individual agents become more familiar (less new) and additional agents become available. We use the following terminology:
●Direct oral anticoagulants (DOACs) – DOACs are oral medications that inhibit a specific enzyme in the coagulation cascade. A consensus document regarding terminology for these agents has been published; although no single term emerged as the obviously best term, DOAC was preferred by the most experts surveyed . These medications are also called target-specific oral anticoagulants (TSOACs), oral direct inhibitors (ODIs), or referred to by their individual names or the enzyme they inhibit. We prefer to avoid the terms "novel oral anticoagulant" and "new(er) oral anticoagulant" (NOAC) because over time each agent ceases to be novel or new. Some clinicians refer to this group of agents as "non-vitamin K antagonist oral anticoagulants", to retain the NOAC acronym.
Available agents include those that directly inhibit thrombin (factor IIa) or factor Xa. The positions of these enzymes in the coagulation cascade are illustrated in the figure (figure 1) and discussed in detail separately. (See "Overview of hemostasis".)
- Barnes GD, Ageno W, Ansell J, et al. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13:1154.
- Chai-Adisaksopha C, Hillis C, Isayama T, et al. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015; 13:2012.
- Kakkos SK, Kirkilesis GI, Tsolakis IA. Editor's Choice - efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials. Eur J Vasc Endovasc Surg 2014; 48:565.
- Majeed A, Hwang HG, Connolly SJ, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013; 128:2325.
- Koretz RL. Neither dabigatran nor rivaroxaban were linked to increased GI bleeding compared with warfarin. Ann Intern Med 2015; 163:JC13.
- Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013; 368:1272.
- Sharma M, Cornelius VR, Patel JP, et al. Efficacy and Harms of Direct Oral Anticoagulants in the Elderly for Stroke Prevention in Atrial Fibrillation and Secondary Prevention of Venous Thromboembolism: Systematic Review and Meta-Analysis. Circulation 2015; 132:194.
- Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014; 124:2450.
- Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383:955.
- 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.
- Piccini JP, Garg J, Patel MR, et al. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J 2014; 35:1873.
- Patel MR, Hellkamp AS, Fox KA, ROCKET AF Executive Committee and Investigators. Point-of-Care Warfarin Monitoring in the ROCKET AF Trial. N Engl J Med 2016; 374:785.
- Lopes RD, Guimarães PO, Kolls BJ, et al. Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy. Blood 2017; 129:2980.
- Hernandez I, Baik SH, Piñera A, Zhang Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med 2015; 175:18.
- Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015; 131:157.
- Beyer-Westendorf J, Ebertz F, Förster K, et al. Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost 2015; 113:1247.
- Tamayo S, Frank Peacock W, Patel M, et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol 2015; 38:63.
- Graham DJ, Reichman ME, Wernecke M, et al. Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation. JAMA Intern Med 2016; 176:1662.
- van der Hulle T, Kooiman J, den Exter PL, et al. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014; 12:320.
- 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.
- Fihn SD, Callahan CM, Martin DC, et al. The risk for and severity of bleeding complications in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics. Ann Intern Med 1996; 124:970.
- Sardar P, Chatterjee S, Chaudhari S, Lip GY. New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. J Am Geriatr Soc 2014; 62:857.
- Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet 2013; 52:69.
- Eller T, Busse J, Dittrich M, et al. Dabigatran, rivaroxaban, apixaban, argatroban and fondaparinux and their effects on coagulation POC and platelet function tests. Clin Chem Lab Med 2014; 52:835.
- Herrmann R, Thom J, Wood A, et al. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost 2014; 111:989.
- Neyens R, Bohm N, Cearley M, et al. Dabigatran-associated subdural hemorrhage: using thromboelastography (TEG(®)) to guide decision-making. J Thromb Thrombolysis 2014; 37:80.
- Xu Y, Wu W, Wang L, et al. Differential profiles of thrombin inhibitors (heparin, hirudin, bivalirudin, and dabigatran) in the thrombin generation assay and thromboelastography in vitro. Blood Coagul Fibrinolysis 2013; 24:332.
- Casutt M, Konrad C, Schuepfer G. Effect of rivaroxaban on blood coagulation using the viscoelastic coagulation test ROTEM™. Anaesthesist 2012; 61:948.
- Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J 2013; 34:489.
- Siegal DM, Garcia DA, Crowther MA. How I treat target-specific oral anticoagulant-associated bleeding. Blood 2014; 123:1152.
- Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012; 87 Suppl 1:S141.
- 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; 108:217.
- Wong H, Keeling D. Activated prothrombin complex concentrate for the prevention of dabigatran-associated bleeding. Br J Haematol 2014; 166:152.
- Htun KT, McFadyen J, Tran HA. The successful management of dabigatran-associated critical end-organ bleeding with recombinant factor VIIa. Ann Hematol 2014; 93:1785.
- Ross B, Miller MA, Ditch K, Tran M. Clinical experience of life-threatening dabigatran-related bleeding at a large, tertiary care, academic medical center: a case series. J Med Toxicol 2014; 10:223.
- Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in life-threatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med 2013; 41:e42.
- Dumkow LE, Voss JR, Peters M, Jennings DL. Reversal of dabigatran-induced bleeding with a prothrombin complex concentrate and fresh frozen plasma. Am J Health Syst Pharm 2012; 69:1646.
- Maurice-Szamburski A, Graillon T, Bruder N. Favorable outcome after a subdural hematoma treated with feiba in a 77-year-old patient treated by rivaroxaban. J Neurosurg Anesthesiol 2014; 26:183.
- Perzborn E, Gruber A, Tinel H, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost 2013; 110:162.
- Lambourne MD, Eltringham-Smith LJ, Gataiance S, et al. Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J Thromb Haemost 2012; 10:1830.
- Pragst I, Zeitler SH, Doerr B, et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 2012; 10:1841.
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery (Accessed on October 16, 2015).
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/761025lbl.pdf (Accessed on October 19, 2015).
- Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med 2015; 373:511.
- Bauer KA. Targeted Anti-Anticoagulants. N Engl J Med 2015; 373:569.
- Glund S, Stangier J, Schmohl M, 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, double-blind phase 1 trial. Lancet 2015; 386:680.
- Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121:3554.
- Getta B, Muller N, Motum P, et al. Intermittent haemodialysis and continuous veno-venous dialysis are effective in mitigating major bleeding due to dabigatran. Br J Haematol 2015; 169:603.
- Chai-Adisaksopha C, Hillis C, Lim W, et al. Hemodialysis for the treatment of dabigatran-associated bleeding: a case report and systematic review. J Thromb Haemost 2015; 13:1790.
- Stangier J, Rathgen K, Stähle 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.
- Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013; 109:596.
- 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.
- Wanek MR, Horn ET, Elapavaluru S, et al. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 2012; 46:e21.
- Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 2015; 131:82.
- http://www.bayerresources.com.au/resources/uploads/PI/file9466.pdf (Accessed on May 21, 2014).
- http://packageinserts.bms.com/pi/pi_eliquis.pdf (Accessed on May 21, 2014).
- Camm AJ, Bounameaux H. Edoxaban: a new oral direct factor xa inhibitor. Drugs 2011; 71:1503.
- Parasrampuria DA, Marbury T, Matsushima N, et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost 2015; 113:719.
- 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.
- 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.
- Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost 2014; 111:189.
- Dibu JR, Weimer JM, Ahrens C, et al. The Role of FEIBA in Reversing Novel Oral Anticoagulants in Intracerebral Hemorrhage. Neurocrit Care 2016; 24:413.
- Honickel M, Maron B, van Ryn J, et al. Therapy with activated prothrombin complex concentrate is effective in reducing dabigatran-associated blood loss in a porcine polytrauma model. Thromb Haemost 2016; 115:271.
- Gruber A, Marzek UM, Buetehorn U, et al. Haematologica 2009; 92 (Suppl 2):181 (abstract 0449).
- Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19:446.
- Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med 2016; 375:1131.
- Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med 2015; 373:2413.
- Laulicht B, Bakhru S, Jiang X, et al. Antidote for new oral anticoagulants: Mechanism of action and binding specificity of PER977. ISTH abstract 2013; :AS 47.1.
- Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; 371:2141.
- Thalji NK, Ivanciu L, Davidson R, et al. A rapid pro-hemostatic approach to overcome direct oral anticoagulants. Nat Med 2016; 22:924.
- TERMINOLOGY AND SITES OF ACTION
- BLEEDING RISKS FROM DOACs
- Clinical outcomes
- Risk of bleeding
- PATIENT ASSESSMENT
- Initial assessment
- Assessment of bleeding
- Assessment of anticoagulation status
- - Interval since last dose
- - Renal and hepatic function
- - Coagulation testing
- Other limited laboratory testing
- MAJOR BLEEDING
- Overview of management
- Anticoagulant reversal
- - Overview of reversal strategy
- - Dabigatran reversal
- - Rivaroxaban, apixaban, edoxaban (reversal)
- Clotting factor products
- Antifibrinolytics and other pro-hemostatic therapies
- Transfusions if needed
- MINOR BLEEDING
- SURGERY/INVASIVE PROCEDURE
- RESUMPTION OF ANTICOAGULATION
- ANTIDOTES UNDER DEVELOPMENT
- SUMMARY AND RECOMMENDATIONS