Direct Oral Anticoagulant Reversal

Transcription

1 08 June 2018 No. 08 Direct Oral Anticoagulant Reversal M Khattab Moderator: E Hodgson School of Clinical Medicine Discipline of Anaesthesiology and Critical Care

2 CONTENTS INTRODUCTION... 3 Pharmacokinetics and characteristics of common DOACs and warfarin(2) Strategies for DOAC reversal... 3 Specific reversal agents for DOAC... 5 Idarucizumab... 5 Andexanet alfa... 5 Ciraparantag... 5 Who should receive reversal agents?... 6 Resuming anticoagulation... 7 Risk stratification and decision making... 8 CONCLUSION REFERENCES Page 2 of 11

3 Direct Oral Anticoagulant Reversal INTRODUCTION Direct oral anticoagulants (DOAC) were recently introduced (late 2010) as effective agents in preventing and treating venous thromboembolism and preventing stroke in patient with nonvalvular atrial fibrillation(1), these agents demonstrated similar or superior efficacy to vitamin K antagonists such as warfarin in prevention and treatment of thromboembolic events. DOAC have several advantages over vitamin K antagonists like fixed dosing, fewer drug-drug and drug-food interactions in addition to administration without the need for regular coagulation monitoring(1). Similar to all other anticoagulants there is a concern regarding risk of bleeding, but overall risk of major bleeding with DOAC is similar to, or better than, that of warfarin(1). All DOAC have shorter half-lives compared to warfarin and most bleeding associated with DOAC can be managed simply by withholding them. Similarly because of the relatively short half-lives of these agents elective procedures can be timed easily after the withdrawal of the agent(1). However in some situations such as life-threatening bleeding or emergency invasive surgery, reversal agents for DOAC become a must(1). Pharmacokinetics and characteristics of common DOACs and warfarin(2). Strategies for DOAC reversal Prior to development of specific reversal agents for DOACs the management of DOACassociated bleeding was based on non-specific supportive measures in addition to withholding of the DOAC(3). These strategies lack supportive evidence of their efficacy in addition to the risk of thrombosis with some of these strategies(3). Strategies include: -Activated charcoal: works by reducing absorption of the drug from gastrointestinal tract if ingested within 2 hours(4). -Haemodialysis: reverses the effect of dabigatran but not factor Xa inhibitors because of their high protein binding(4). Page 3 of 11

4 -Theoretically DOAC can also be reversed by the use of nonspecific agents which include recombinant factor VIIa, prothrombin complex concentrate, and pctivated prothrombin complex concentrate. None of these agents has been studied prospectively in bleeding patients(4). Table 2: Non-specific strategies considered in DOAC patients presenting with serious bleeding(3) Table 3: Summary of reversal strategies for common anticoagulants, including specific reversal agents:(2) Page 4 of 11

5 Specific reversal agents for DOAC Idarucizumab First drug approved by FDA in October 2015 as a reversal agent for the direct factor IIa inhibitor dabigatran(5). Idarucizumab is a humanized monoclonal antibody fragment that binds to dabigatran with an affinity more than 350-fold higher than that of thrombin administered at a 1:1 molar ratio(5). It binds dabigatran irreversibly with maximum effect within 4 hours without any prothrombotic properties despite the similarity in structure to thrombin(5). The total dose of Idarucizumab is 5 g intravenously which can be given as single dose or two consecutive intravenous infusions of 2.5 g(4). Andexanet alfa Is an agent in development for the reversal of direct (apixaban, edoxaban, and rivaroxaban) and indirect (enoxaparin and fondaparinux) factor Xa inhibitors(5). Andexanet alfa is a modified recombinant form of the human coagulation factor X that lacks any coagulant activity, and does not interfere with normal factor Xa activity(5). Ciraparantag Ciraparantag is a universal agent for reversal of direct and indirect factor factor Xa inhibitors in addition to factor II inhibitors. It is a small water-soluble molecule that binds directly to DOACs and heparin through noncovalent hydrogen bonding and charge-charge interactions to neutralize anticoagulant activity(5). Phase II clinical studies of ciraparantag are ongoing. Therefore, sufficient research data to evaluate ciraparantag s safety and effects in a large patient population are not available(5). Table 4: Agents reversing effects of various anticoagulant(5) Page 5 of 11

6 Who should receive reversal agents? The fact that DOACs have short half-lives and a lower risk of bleeding compared with warfarin means there is a relatively limited need for reversal of these agents. Indeed, before the introduction of reversal agents, data suggested that up to a third of patients with DOACassociated major bleeding can be managed without haemostatic agents or blood products(4). Nevertheless there are some conditions in which rapid reversal of these agents is necessary which include trauma, emergency invasive procedures and major bleeding(4). The following table proposed by the International Society on Thrombosis and Haemostasis provides some guidance for when patient taking DOACs should receive specific reversal agents(4). Table 5: Indications for the use of specific reversal agents for DOACs(4) The following figure also provides an algorithm for management of patients with a DOACs who present with, moderate-to-severe, or life-threatening bleeding or who require emergency surgery(4). Page 6 of 11

7 Figure1: Algorithm for management of patients with DOAC-associated bleeding or requiring emergency surgery (4) Resuming anticoagulation While some patients should not resume their anticoagulation after haemorrhage, those patients are in the minority. Patients do not die of recurrent hemorrhage, but die of thromboembolic complications by failing to resume anticoagulation promptly after bleeding events(2). Clinical judgment is required in determining the individual bleeding and thrombotic risks of each patient on a case-by-case basis(2). Page 7 of 11

8 Risk stratification and decision making The overall risk of major haemorrhage for patients receiving oral anticoagulants must be weighed against the risk of thromboembolic complications in the absence of any anticoagulant therapy(6). Several risk-stratification tools are available to evaluate and understand the risks and benefits of oral anticoagulant therapy for different patients: CHA2DS2-VASc score to assess risk of stroke and HASBLED score to assess risk of bleeding are the most commonly used tools as recommended by current guidelines(6). Table 6: Risk-stratification tools for risk of stroke in patients with atrial fibrillation(6) Page 8 of 11

9 Table 7: HAS-BLED score for risk of bleeding in atrial fibrillation(6) The decision to restart oral anticoagulation therapy must recognize when the increasing risk of thromboembolism outweighs the decreasing risk of recurrent haemorrhage. Therefore factors in favour of restarting anticoagulant therapy earlier include: patients with prosthetic heart valves and stabilised GI bleeding, and later with patients with intracranial haemorrhage (ICH) or low risk of thromboembolic complications(6). Recommendations vary widely on when to start anticoagulants, a recent review by Hofmeijer et al concluded that treatment with anticoagulants should be resumed after 1-2 weeks in patients with deep ICH and high risk of cerebral ischaemia such as patients with non-valvular atrial fibrillation and CHA2DS2-VASc of >3 or mechanical heart valve but should be restarted later (after 4 weeks) in other patients(7). Page 9 of 11

10 CONCLUSION Reversal agents for DOACs, whether those that currently approved for use such as idarucizumab, or those under clinical trial such as ciraparantag and andexanet alfa, present the potential for effective and reliable treatment options whenever uncontrolled or life-threatening DOAC-associated bleeding occurs or when an emergency procedure is required in patients on DOAC therapy(5). Page 10 of 11

11 REFERENCES 1. Pollack CV. Introduction to direct oral anticoagulants and rationale for specific reversal agents. The American Journal of Emergency Medicine. 2016;34(11, Supplement): Weinberger J, Cipolle M. Optimal reversal of novel anticoagulants in trauma. Critical care clinics. 2017;33(1): Monagle S, Eikelboom JW, Ng KH, Bhagirath VC. Clinical implications of reversal agents for direct oral anticoagulants. Future cardiology. 2017;13(2): Ageno W, Büller H, Falanga A, Hacke W, Hendriks J, Lobban T, et al. Anticoagulation Education Task Force White Paper. Thrombosis and haemostasis. 2016;116(6): Riley TR, Gauthier-Lewis ML, Sanchez CK, Douglas JS. Role of agents for reversing the effects of target-specific oral anticoagulants. American Journal of Health-System Pharmacy. 2016:ajhp Milling TJ, Spyropoulos AC. Re-initiation of dabigatran and direct factor Xa antagonists after a major bleed. The American journal of medicine. 2016;129(11):S54-S Hofmeijer J, Kappelle L, Klijn C. Antithrombotic treatment and intracerebral haemorrhage: between Scylla and Charybdis. Practical neurology. 2015:practneurol Page 11 of 11