Management of bleeding and reversal strategies for oral anticoagulants: Clinical practice considerations

American Journal of Health-System Pharmacy

Volumn 70, Issue 21, 2013, Pages 1914-1929

  Nutescu, Edith A ^a,b   Dager, William E ^c,d   Kalus, James S ^e,f   Lewin, John J ^g,h   Cipolle, Mark D ⁱ  

^a UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

^b UNIVERSITY OF ILLINOIS HOSPITAL AND HEALTH SCIENCES SYSTEM   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

^e HENRY FORD HOSPITAL   (United States)

^f WAYNE STATE UNIVERSITY   (United States)

^g JOHNS HOPKINS HOSPITAL   (United States)

^h UNIVERSITY OF MARYLAND SCHOOL OF PHARMACY   (United States)

ⁱ CHRISTIANA CARE HEALTH SYSTEM   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICOAGULANT AGENT; APIXABAN; DABIGATRAN; MULTIDRUG RESISTANCE PROTEIN; RIVAROXABAN; WARFARIN; ANTITHROMBIN; BLOOD CLOTTING FACTOR 10A;

ANTICOAGULANT THERAPY; BLEEDING; CLINICAL PRACTICE; DRUG ELIMINATION; DRUG HALF LIFE; DRUG PROTEIN BINDING; EMERGENCY CARE; GERIATRIC PATIENT; HOSPITALIZATION; HUMAN; INVASIVE PROCEDURE; LABORATORY TEST; PARTIAL THROMBOPLASTIN TIME; PHARMACODYNAMICS; PROTHROMBIN TIME; REVIEW; RISK ASSESSMENT; SURGERY; THROMBIN TIME; URINARY EXCRETION; ADULT; AGE; AGED; CHEMICALLY INDUCED DISORDER; DRUG ANTAGONISM; ORAL DRUG ADMINISTRATION;

ADMINISTRATION, ORAL; ADULT; AGE FACTORS; AGED; ANTICOAGULANTS; ANTITHROMBINS; FACTOR XA; HEMORRHAGE; HUMANS; WARFARIN;

EID: 84901730044     PISSN: 10792082     EISSN: 15352900     Source Type: Journal    
DOI: 10.2146/ajhp130243     Document Type: Review

References (85)

1. U.S. Department of Health and Human Services. Aging statistics. www.aoa.gov/AoARoot/Aging-Statistics/index.aspx (accessed 2013 Jun 28).
2. Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011; 31:326-43.
3. Budnitz DS, Lovegrove MC, Shehab N et al. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011; 365:2002-12.
4. Institute for Safe Medication Practices. QuarterWatch monitoring FDA Med-Watch reports: anticoagulants the leading reported drug risk in 2011. www.ismp.org/QuarterWa tch/pdfs/2011Q4.pdf (accessed 2013 Jun 28).
5. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361:1139-51.
6. Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365:883-91.
7. Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011; 365:981-92.
8. Harinstein LM, Morgan JW, Russo N. Treatment of dabigatran-associated bleeding: case report and review of the literature. J Pharm Pract. 2013; 26:264-9.
9. Food and Drug Administration. FDA drug safety communication: update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran). www.fda.gov/Drugs/DrugSafety/ucm326580.htm#data (accessed 2013 Jun 28).
10. Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med. 2013; 368:1272-4.
11. Institute for Safe Medication Practices. QuarterWatch monitoring FDA MedWatch reports: update on anticoagulants. www.ismp.org/quarterwatch/pdfs/2012Q2.pdf (accessed 2013 Jun 28).
12. Holbrook A, Schulman S, Witt DM et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(suppl 2):e152S-184S.
13. Neel S. Essential warfarin knowledge. In: Gulseth M, ed. Managing anticoagulation patients in the hospital. Bethesda, MD: American Society of Health-System Pharmacists; 2007:133-75.
14. Pradaxa (dabigatran etexilate mesylate) prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2013 Apr.
15. Xarelto (rivaroxaban) prescribing information. Titusville, NJ: Janssen Pharmaceuticals; 2013 Mar.
16. Eliquis (apixaban) prescribing information. New York, NY: Pfizer; 2012 Dec.
17. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet. 2009; 48:1-22.
18. 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):S141-5.
19. Stangier J, Rathgen K, Stähle 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; 49:259-68.
20. Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost. 2010; 103:572-85.
21. Haynes LM, Orfeo T, Mann KG. Rivaroxaban delivery and reversal at a venous flow rate. Arterioscler Thromb Vasc Biol. 2012; 32:2877-83.
22. Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health-Syst Pharm. 2012; 69:1473-84.
23. Palladino M, Thomson L, Swift B et al. Implementing the new oral anticoagulants into the hospital formulary. Am J Hematol. 2012; 87(suppl 1):S127-32.
24. Dager WE, Gosselin RC, Kitchen S et al. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother. 2012; 46:1627-36.
25. Avecilla ST, Ferrell C, Chandler WL et al. Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy. Am J Clin Pathol. 2012; 137:572-4.
26. Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis. 2012; 23:138-43.
27. Dager WE. Developing a management plan for oral anticoagulant reversal. Am J Health-Syst Pharm. 2013; 70(suppl 1):S21-31.
28. Aniara. Biophen rivaroxaban plasma calibrator (12x1 mL). www.aniara.com/PROD/A222701.html (accessed 2013 Jun 28).
29. 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(5):e42-6.
30. Van Ryn J, Litzenburger T, Waterman A et al. An antibody selective to dabigatran safely neutralizes both dabigatran-induced and anticoagulant and bleeding activity in in vitro and in vivo models. J Thromb Haemost. 2011; 9(suppl 2): P-MO-166. Abstract.
31. 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; 19:446-51.
32. Laulicht B, Bakhru S, Lee C et al. Small molecule antidote for anticoagulants. Circulation. 2012; 126:A11395. Abstract.
33. Kalus JS. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health-Syst Pharm. 2013; 70(suppl 1):S12-21.
34. Holland L, Warkentin TE, Refaai M et al. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009; 49:1171-7.
35. FEIBA NF (anti-inhibitor coagulant complex) product monograph. Baxter Corporation: Mississauga, Ontario, Canada; 2011 Jul.
36. Kcentra (prothrombin complex concentrate, human) prescribing information. Kankakee, IL: CSL Behring LLC; 2013 Apr.
37. Peacock WF, Gearhart MM, Mills RM. Emergency management of bleeding associated with old and new oral anticoagulants. Clin Cardiol. 2012; 35:730-7.
38. Sørensen B, Spahn DR, Innerhofer P et al. Clinical review: prothrombin complex concentrates - evaluation of safety and thrombogenicity. Crit Care. 2011; 15:201.
39. Escolar Albaladejo G. Reversal of apixaban induced alterations of hemostasis by different coagulation factor concentrates: studies in vitro with circulating human blood. http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@smd/documents/downloadable/ucm-441681.pdf (accessed 2013 Jun 28).
40. Imberti D, Barillari G, Biasioli C et al. Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus. 2011; 9:148-55.
41. Baggs JH, Patanwala AE, Williams EM et al. Dosing of 3-factor prothrombin complex concentrate for international normalized ratio reversal. Ann Pharmacother. 2012; 46:51-6.
42. Levi M, Moore T, Castillejos C et al. Effects of three-factor and four-factor prothrombin complex concentrates on the pharmacodynamics of rivaroxaban. www.eventure-online.com/eventure/publicAbstractViewdo?id=217276&congressId=6839 (accessed 2013 Jun 28).
43. Pabinger I, Brenner B, Kalina U et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008; 6:622-31.
44. Sarode R, Milling TJ, Refaai MA et al. Integrated safety analysis of a 4-factor prothrombin complex concentrate versus plasma in phase III clinical trials. http://cdn.f1000.com/posters/docs/249931755 (accessed 2013 Jun 28).
45. 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; 108:217-24.
46. 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; 124:1573-9.
47. Dinkelaar J, Molenaar PJ, Ninivaggi M et al. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for rivaroxaban. J Thromb Haemost. 2013; 11:1111-8.
48. Dager WE, King JH, Regalia RC et al. Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin. Pharmacotherapy. 2006; 26:1091-8.
49. Nishijima DK, Dager WE, Schrot RJ et al. The efficacy of factor VIIa in emergency department patients with warfarin use and traumatic intracranial hemorrhage. Acad Emerg Med. 2010; 17:244-51.
50. Pinner NA, Hurdle AC, Oliphant C et al. Treatment of warfarin-related intracranial hemorrhage: a comparison of prothrombin complex concentrate and recombinant activated factor VII. World Neurosurg. 2010; 74:631-5.
51. Wójcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med. 2009; 2:217-25.
52. Sarode R, Matevosyan K, Bhagat R et al. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage. J Neurosurg. 2012; 116:491-7.
53. Zhou W, Schwarting S, Illanes S et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011; 42:3594-9.
54. 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; 116:94-102.
55. 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. http://online.haematologica.org/eha13/browserecord.php?-action=browse&-recid=1923 (accessed 2013 Jun 28).
56. Gruber A, Marzek UM, Buetehorn U et al. Potential of activated prothrombin complex concentrate and activated factor VII to reverse the anticoagulant effects of rivaroxaban in primates. http://abstracts.hematologylibrary.org/cgi/content/abstract/112/11/3825?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=gruber&searchid=1&FIRSTINDEX=0&volume=112&issue=11&resourcetype=HWCIT (accessed 2013 Jun 28)
57. Clinicaltrials.gov. Study in healthy volunteers of the reversion by haemostatic drugs of the anticoagulant effect of new anti-thrombotics (REVNEWANTICO). www.clinicaltrials.gov/ct2/show/NCT01210755?term=rivaroxaban+dabigatran+reversal&rank=2 (accessed 2013 Jun 28).
58. Henry DA, Carless PA, Moxey AJ et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011; 1:CD001886.
59. Gage BF, Waterman AD, Shannon W et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001; 285:2864-70.
60. Lip GY, Nieuwlaat R, Pisters R et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest. 2010; 137:263-72.
61. Douketis JD, Spyropoulos AC, Spencer FA et al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(suppl 2):e326S-50S.
62. Falck-Ytter Y, Francis CW, Johanson NA et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(suppl 2):e278S-325S.
63. Gould MK, Garcia DA, Wren SM et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(suppl 2):e227S-77S.
64. Kearon C, Akl EA, Comerota AJ et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(suppl 2):e419S-994S.
65. Caprini JA. Identification of patient venous thromboembolism risk across the continuum of care. Clin Appl Thromb Hemost. 2011; 17:590-9.
66. Wanek MR, Horn ET, Elapavaluru S et al. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother. 2012; 46:e21.
67. Chang DN, Dager WE, Chin AI. Removal of dabigatran by hemodialysis. Am J Kidney Dis. 2013; 61:487-9.
68. Tsu LV, Dienes JE, Dager WE. Vitamin K dosing to reverse warfarin based on INR, route of administration, and home war-farin dose in the acute/critical care setting. Ann Pharmacother. 2012; 46:1617-26.
69. Meehan R, Tavares M, Sweeney J. Clinical experience with oral versus intravenous vitamin K for warfarin reversal (CME). Transfusion. 2013; 53:491-8.
70. Burbury KL, Milner A, Snooks B et al. Short-term warfarin reversal for elective surgery - using low-dose intravenous vitamin K: safe, reliable and convenient. Br J Haematol. 2011; 154:626-34.
71. Song MM, Warne CP, Crowther MA. Prothrombin complex concentrate (PCC, Octaplex) in patients requiring immediate reversal of vitamin K antagonist anticoagulation. Thromb Res. 2012; 129:526-9.
72. Switzer JA, Rocker J, Mohorn P et al. Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage. Stroke. 2012; 43:2500-2.
73. Leissinger CA, Blatt PM, Hoots WK et al. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol. 2008; 83:137-43.
74. Dager WE. Using prothrombin complex concentrates to rapidly reverse oral anticoagulant effects. Ann Pharmacother. 2011; 45:1016-20.
75. Chapman SA, Irwin ED, Beal AL et al. Prothrombin complex concentrate versus standard therapies for INR reversal in trauma patients receiving warfarin. Ann Pharmacother. 2011; 45:869-75.
76. Ilyas C, Beyer GM, Dutton RP et al. Recombinant factor VIIa for warfarin-associated intracranial bleeding. J Clin Anesth. 2008; 20:276-9.
77. Viles-Gonzalez JF, Fuster V, Halperin JL. New anticoagulants for prevention of stroke in patients with atrial fibrillation. J Cardiovasc Electrophysiol. 2011; 22:948-55.
78. Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood. 2012; 119:3016-23.
79. 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; 103:1116-27.
80. Nutescu EA. Oral anticoagulant therapies: balancing the risks. Am J Health-Syst Pharm. 2013; 70(suppl 1):S3-11.
81. Cotton B, McCarthy M, Holcomb J. Acutely injured patients on dabigatran. N Engl J Med. 2011; 365:2039-40.
82. 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; 109:596-605.
83. Singh T, Maw TT, Henry BL et al. Extra-corporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol. Epub ahead of print. 2013 May 23 (DOI 10.2215/CJN.01570213).
84. Warkentin TE, Margetts P, Connolly SJ et al. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood. 2012; 119:2172-4.
85. Harrison TD, Laskosky J, Jazaeri O et al. "Low-dose" recombinant activated factor VII results in less blood and blood product use in traumatic hemorrhage. J Trauma. 2005; 59:150-4.