Quality and Safety Issues of Direct Oral Anticoagulants in the Emergency Department

 

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Abstract

The direct oral anticoagulants (DOACs) are increasingly used in patients with atrial fibrillation and venous thromboembolism. The decision making of clinicians and especially emergency physicians for the appropriate management of patients taking DOACs entails a thorough understanding of pharmacologic profile, practical guidance on their usage, and management of bleeding and/or thrombotic events. The available evidence suggests that the bleeding complications observed in patients taking DOACs are less frequent and potentially less severe than those in patients taking vitamin K antagonists or heparins. This should be regarded as an advantage for emergency physicians, since it would decrease the admission rate of anticoagulated patients and probably require a less aggressive treatment in the emergency department (ED). The greatest challenge of DOACs is so far represented by the lack of clinically usable antidotes, since these (i.e., idarucizumab, andexanet alfa, and aripazine) are in different phases of development. A second major concern is the current lack of consensus about laboratory monitoring for these drugs. Although there is widespread perception that patients on DOACs do not require dose adjustment based on laboratory testing, in some selected clinical situations, laboratory testing may be taken into consideration in the ED. The type of laboratory diagnostics needed for emergency management should hence include tests that are promptly available, affordable to all stat laboratories, and cost effective. The aim of this article is to provide a personal overview on quality and safety issues of DOACs with an ED perspective.

• References

• 1 Elg M, Gustafsson D, Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 1999; 94 (3) 187-197
  CrossrefPubMedGoogle Scholar
• 2 Haycraft JB. Über die Einwirkung eines Sekretes des officinellen Blutegels auf die Gerinnbarkeit des Bluts. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 1894; 18: 209-217
  PubMedGoogle Scholar
• 3 Bergmann C, Dodt J, Köhler S, Fink E, Gassen HG. Chemical synthesis and expression of a gene coding for hirudin, the thrombin-specific inhibitor from the leech Hirudo medicinalis. Biol Chem Hoppe Seyler 1986; 367 (8) 731-740
  CrossrefPubMedGoogle Scholar
• 4 Harvey RP, Degryse E, Stefani L , et al. Cloning and expression of a cDNA coding for the anticoagulant hirudin from the bloodsucking leech, Hirudo medicinalis. Proc Natl Acad Sci U S A 1986; 83 (4) 1084-1088
  CrossrefPubMedGoogle Scholar
• 5 Rydel TJ, Ravichandran KG, Tulinsky A , et al. The structure of a complex of recombinant hirudin and human alpha-thrombin. Science 1990; 249 (4966) 277-280
  CrossrefPubMedGoogle Scholar
• 6 Harenberg J, Jörg I, Weiss C. Observations of alanine aminotransferase and aspartate aminotransferase in THRIVE studies treated orally with ximelagatran. Int J Toxicol 2006; 25 (3) 165-169
  CrossrefPubMedGoogle Scholar
• 7 Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI ; American College of Chest Physicians. Parenteral anticoagulants: American College of Chest Physicians evidence-based clinical practice guidelines (8th). Chest 2008; 133 (6, Suppl): 141S-159S
  CrossrefPubMedGoogle Scholar
• 8 Koller F. History of factor X. Thromb Diath Haemorrh 1960; 4 (Suppl): 58-65
  PubMedGoogle Scholar
• 9 Leadley Jr RJ. Coagulation factor Xa inhibition: biological background and rationale. Curr Top Med Chem 2001; 1 (2) 151-159
  CrossrefPubMedGoogle Scholar
• 10 Brown DL, Kouides PA. Diagnosis and treatment of inherited factor X deficiency. Haemophilia 2008; 14 (6) 1176-1182
  CrossrefPubMedGoogle Scholar
• 11 Tuszynski GP, Gasic TB, Gasic GJ. Isolation and characterization of antistasin. An inhibitor of metastasis and coagulation. J Biol Chem 1987; 262 (20) 9718-9723
  PubMedGoogle Scholar
• 12 Waxman L, Smith DE, Arcuri KE, Vlasuk GP. Tick anticoagulant peptide (TAP) is a novel inhibitor of blood coagulation factor Xa. Science 1990; 248 (4955) 593-596
  CrossrefPubMedGoogle Scholar
• 13 Becker RC, Alexander J, Dyke CK, Harrington RA. Development of DX-9065a, a novel direct factor Xa antagonist, in cardiovascular disease. Thromb Haemost 2004; 92 (6) 1182-1193
  PubMedGoogle Scholar
• 14 Sato K, Kawasaki T, Taniuchi Y, Hirayama F, Koshio H, Matsumoto Y. YM-60828, a novel factor Xa inhibitor: separation of its antithrombotic effects from its prolongation of bleeding time. Eur J Pharmacol 1997; 339 (2-3) 141-146
  CrossrefPubMedGoogle Scholar
• 15 Roehrig S, Straub A, Pohlmann J , et al. Discovery of the novel antithrombotic agent 5-chloro-N-((5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-ylmethyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem 2005; 48 (19) 5900-5908
  CrossrefPubMedGoogle Scholar
• 16 Perzborn E, Strassburger J, Wilmen A , et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct factor Xa inhibitor. J Thromb Haemost 2005; 3 (3) 514-521
  CrossrefPubMedGoogle Scholar
• 17 Adam SS, McDuffie JR, Ortel TL, Williams Jr JW. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med 2012; 157 (11) 796-807
  CrossrefPubMedGoogle Scholar
• 18 Kazmi RS, Lwaleed BA. New anticoagulants: how to deal with treatment failure and bleeding complications. Br J Clin Pharmacol 2011; 72 (4) 593-603
  CrossrefPubMedGoogle Scholar
• 19 Lippi G, Favaloro EJ. Recent guidelines and recommendations for laboratory assessment of the direct oral anticoagulants (DOACs): is there consensus?. Clin Chem Lab Med 2015; 53 (2) 185-197
  PubMedGoogle Scholar
• 20 Favaloro EJ, Lippi G. Laboratory testing in the era of the direct or non-vitamin K antagonist oral anticoagulants (NOACs): a practical guide to measuring their activity and avoiding diagnostic errors. Semin Thromb Hemost 2015; 41 (2) 208-227
  Article in Thieme ConnectPubMedGoogle Scholar
• 21 Godman B, Malmström RE, Diogene E , et al. Dabigatran—a continuing exemplar case history demonstrating the need for comprehensive models to optimize the utilization of new drugs. Front Pharmacol 2014; 5: 109
  PubMedGoogle Scholar
• 22 Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol 2013; 70 (12) 1486-1490
  PubMedGoogle Scholar
• 23 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 (20) 2141-2147
  CrossrefPubMedGoogle Scholar
• 24 Piccini JP, Garg J, Patel MR , et al; ROCKET AF Investigators. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J 2014; 35 (28) 1873-1880
  CrossrefPubMedGoogle Scholar
• 25 Majeed A, Hwang HG, Connolly SJ , et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013; 128 (21) 2325-2332
  CrossrefPubMedGoogle Scholar
• 26 Fontaine GV, Mathews KD, Woller SC, Stevens SM, Lloyd JF, Evans RS. Major bleeding with dabigatran and rivaroxaban in patients with atrial fibrillation: a real-world setting. Clin Appl Thromb Hemost 2014; 20 (7) 665-672
  CrossrefPubMedGoogle Scholar
• 27 Berger R, Salhanick SD, Chase M, Ganetsky M. Hemorrhagic complications in emergency department patients who are receiving dabigatran compared with warfarin. Ann Emerg Med 2013; 61 (4) 475-479
  CrossrefPubMedGoogle Scholar
• 28 Wasserlauf G, Grandi SM, Filion KB, Eisenberg MJ. Meta-analysis of rivaroxaban and bleeding risk. Am J Cardiol 2013; 112 (3) 454-460
  CrossrefPubMedGoogle Scholar
• 29 Sardar P, Chatterjee S, Lavie CJ , et al. Risk of major bleeding in different indications for new oral anticoagulants: insights from a meta-analysis of approved dosages from 50 randomized trials. Int J Cardiol 2015; 179: 279-287
  CrossrefPubMedGoogle Scholar
• 30 Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G ; American College of Chest Physicians. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e44S-e88S
  CrossrefPubMedGoogle Scholar
• 31 Schulman S, Furie B. How I treat poisoning with vitamin K antagonists. Blood 2015; 125 (3) 438-442
  CrossrefPubMedGoogle Scholar
• 32 Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124 (14) 1573-1579
  CrossrefPubMedGoogle Scholar
• 33 Levi M, Moore KT, Castillejos CF , et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost 2014; 12 (9) 1428-1436
  CrossrefPubMedGoogle Scholar
• 34 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 (1) 82-90
  CrossrefPubMedGoogle Scholar
• 35 Glund S, Stangier J, Schmohl M , et al. A specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in healthy male volunteers. Circulation 2013; 128: A17765
  PubMedGoogle Scholar
• 36 Van RJ, Schmoll M, Pillu H , et al. Effect of dabigatran on the ability to generate fibrin at a wound site and its reversal by idarucizumab, the antidote to dabigatran, in healthy volunteers: an exploratory marker of blood loss. Circulation 2014; 130: A18403
  PubMedGoogle Scholar
• 37 Crowther M, Lu G, Conley P , et al. Sustained reversal of apixaban anticoagulation with andexanet alfa using a bolus plus infusion regimen in a phase 2 placebo controlled trial. Eur Heart J 2014; 35 (Suppl. 01) 738
  PubMedGoogle Scholar
• 38 Laulicht B, Bakhru S, Lee C , et al. Small molecule antidote for anticoagulants. Circulation 2012; 126: A11395
  PubMedGoogle Scholar
• 39 Ansell JE, Bakhru SH, Laulicht BE , et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; 371 (22) 2141-2142
  CrossrefPubMedGoogle Scholar
• 40 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 (6) 1116-1127
  Article in Thieme ConnectPubMedGoogle Scholar
• 41 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 (4) 596-605
  Article in Thieme ConnectPubMedGoogle Scholar
• 42 Ward C, Conner G, Donnan G, Gallus A, McRae S. Practical management of patients on apixaban: a consensus guide. Thromb J 2013; 11 (1) 27
  CrossrefPubMedGoogle Scholar
• 43 Siegal DM, Garcia DA, Crowther MA. How I treat target-specific oral anticoagulant-associated bleeding. Blood 2014; 123 (8) 1152-1158
  CrossrefPubMedGoogle Scholar
• 44 Franchini M, Crestani S, Frattini F, Sissa C, Bonfanti C. Hemostatic agents for bleeding: recombinant-activated factor VII and beyond. Semin Thromb Hemost 2015; 41 (3) 342-347
  Article in Thieme ConnectPubMedGoogle Scholar
• 45 Siegal DM, Cuker A. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis 2013; 35 (3) 391-398
  CrossrefPubMedGoogle Scholar
• 46 Harenberg J, Kraemer S, Du S , et al. Determination of direct oral anticoagulants from human serum samples. Semin Thromb Hemost 2014; 40 (1) 129-134
  Article in Thieme ConnectPubMedGoogle Scholar
• 47 Tripodi A, Di Iorio G, Lippi G, Testa S, Manotti C. Position paper on laboratory testing for patients taking new oral anticoagulants. Consensus document of FCSA, SIMeL, SIBioC and CISMEL1). Clin Chem Lab Med 2012; 50 (12) 2137-2140
  PubMedGoogle Scholar
• 48 Harenberg J, Du S, Weiss C, Krämer R, Hoppensteadt D, Walenga J ; working party: methods to determine apixaban of the Subcommittee on Control of Anticoagulation of the International Society of Thrombosis and Haemostasis. Report of the Subcommittee on Control of Anticoagulation on the determination of the anticoagulant effects of apixaban: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12 (5) 801-804
  CrossrefPubMedGoogle Scholar
• 49 Lippi G, Ardissino D, Quintavalla R, Cervellin G. Urgent monitoring of direct oral anticoagulants in patients with atrial fibrillation: a tentative approach based on routine laboratory tests. J Thromb Thrombolysis 2014; 38 (2) 269-274
  CrossrefPubMedGoogle Scholar
• 50 Heidbuchel H, Verhamme P, Alings M , et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013; 34 (27) 2094-2106
  CrossrefPubMedGoogle Scholar
• 51 Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J 2013; 34 (7) 489-498b
  CrossrefPubMedGoogle Scholar
• 52 Tran H, Joseph J, Young L , et al; Australasian Society of Thrombosis and Haemostasis. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Intern Med J 2014; 44 (6) 525-536
  CrossrefPubMedGoogle Scholar