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Direct Oral Anticoagulant Reversal: How, When and Issues Faced М Mikhail S

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Expert Review of Hematology ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20 У Direct oral anticoagulant reversal: how, when and issues faced М Mikhail S. Dzeshka, Daniele Pastori & Gregory Y.H. Lip Г To cite this article: Mikhail S. Dzeshka, Daniele Pastori & Gregory Y.H. Lip (2017) Direct oral anticoagulant reversal: how, when and issues faced, Expert Review of Hematology, р10:11, 1005-1022, DOI: 10.1080/17474086.2017.1379896 To link to this article: http://dx.doi.org/10.1080/17474086.2017.1379896Г Accepted author version posted online: 13 Sep 2017. й Published online: 22 Sep 2017. Submit your article to this journal и Article views: 72 р View related articles о т View Crossmark data и з о п е Р Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierr20 Download by: [Dr Mikhail Dzeshka] Date: 29 October 2017, At: 04:40 EXPERT REVIEW OF HEMATOLOGY, 2017 VOL. 10, NO. 11, 1005–1022 https://doi.org/10.1080/17474086.2017.1379896 REVIEW Direct oral anticoagulant reversal: how, when and issues faced Mikhail S. Dzeshkaa,b, Daniele Pastoria,c and Gregory Y.H. Lipa,d aInstitute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK; bGrodno State Medical University, Grodno, Belarus; cDepartmentУ of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; dAalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark ABSTRACT ARTICLE HISTORY Introduction: The number of atrial fibrillation (AF) patients requiring thrombo-prophylaxis with oral Received 2 AugustМ 2017 anticoagulation is greatly increasing. The introduction of non-vitamin K oral anticoagulants (NOACs) in Accepted 12 September 2017 addition to standard therapy with dose-adjusted warfarin has increased the therapeutic options for AF KEYWORDS patients. Despite a generally better safety profile of the NOACs, the risk of major bleedings still persists, Non-vitaminГ K oral and the management of serious bleeding is a clinical challenge. anticoagulants; bleeding; Areas covered: In the current review, risk of major bleeding in patients taking NOACs and general reversal agents; approaches to manage bleeding depending on severity, with a particular focus on specific reversal idarucizumab; andexanet α; agents, are discussed. рciraparantag; prothrombin Expert commentary: Due to short half-life of NOACs compared to warfarin, discontinuation of drug, complex concentrate mechanical compression, and volume substitution are considered to be sufficient measures in most of bleeding cases. In case of life-threatening bleeding or urgent surgery, hemostasis can be achieved with non-specific reversal agents (prothrombin complex concentrates) in patients treated with factorГ Xa inhibitor until specific antidotes (andexanet α and ciraparantag) will receive approval. Thus far, idar- ucizumab has been the only reversal agent approved for dabigatran. й 1. Introduction The fixed-dose non-vitamin K oral anticoagulants (NOACs) were developed to overcome these issues and to improve Atrial fibrillation (AF) is the most common sustained arrhyth- adherenceи to OAC. Thus far, the NOACs included a direct mia, and it confers increased risk of stroke and systemic thrombin inhibitor dabigatran etexilate and factor Xa (FXa) embolism when one or more additional stroke risk factors inhibitors, namely, rivaroxaban, apixaban, and edoxaban are present [1,2]. The CHA DS -VASc score includes a cluster 2 2 р[9,11]. The safety and efficacy of each of the NOACs were of clinical risk factors associated with increased risk of throm- compared to warfarin in large phase 3 prospective rando- boembolism, such as congestive heart failure, hypertension, mized clinical trials [12–15]. All the NOACs showed to be at older age, diabetes mellitus, history of stroke or systemic о least as effective as warfarin for stroke prevention, along with embolism, vascular disease, and female sex [3]. This score is a better safety profile [12–15]. Thus, a significant reduction in recommended by guidelines as the preferred decision-making the rate of intracranial hemorrhage (ICH) was found for all tool to identify patients requiring oral anticoagulationт (OAC); Downloaded by [Dr Mikhail Dzeshka] at 04:40 29 October 2017 NOACs compared to warfarin (Table 1). Despite this favorable the use of CHA DS -VASc over CHADS score significantly 2 2 2 profile of NOACs, unavailability of specific reversal agents to improved stroke risk stratification in AF [4] by identifying manage life-threatening bleeding or to proceed without truly low-risk patients (rate of thromboembolic events < 1%/ и delays with emergency surgery has been raised as a clinical year) who do not need antithrombotic therapy [5,6]. issue [9,11]. Other indications for treatment with NOACs are Stroke prevention is pivotal component of AF management represented by acute [17] and chronic venous thromboembo- with OAC being the only effective treatmentз [5–7]. While OAC lism [18], where NOACs showed broadly similar effectiveness with warfarin is still a valid option for AF patients when quality compared to warfarin, with lower bleeding events [19–21]as of anticoagulant control is good (i.e. time in therapeutic range well as prophylaxis of venous thromboembolism in adult >70%) [8], many limitationsо of therapy with warfarin were patients hospitalized for an acute medical illness who are at acknowledged. Indeed, clinical challenges for warfarin therapy risk for thromboembolic complications [22]. are represented by its narrow therapeutic range, variability of Indications for the NOACs can be further expanded after anticoagulant effectп over time, requirement of regular labora- results of ongoing trials addressing OAC in peripheral artery tory monitoring, numerous drug interactions, slow onset, and disease, heart failure, and secondary prevention of recurrent prolonged half-life [7,9]. As result, a significant proportion of strokes in patients with ischemic stroke of undetermined AF patients withе indication to receive OAC are not adequately source will become available [23]. treatedР or not treated at all [10]. CONTACT Gregory Y.H. Lip [email protected] Institute of Cardiovascular Sciences, University of Birmingham, City Hospital, Birmingham B18 7QH, UK © 2017 Informa UK Limited, trading as Taylor & Francis Group У М Г 1006 р M. S. DZESHKA ET AL. Г Table 1. Summary of bleedings in phase 3 clinical trials with NOACs in AF patients. NOAC Dabigatran [12,16] Rivaroxaban [13] Apixaban [14] Edoxaban [15] Patients (n) 18.113 й 14.264 18.201 21.105 Age (years) 71 73 70 72 CHADS2 score 2.1 3.5 2.1 2.8 Dosing arm (mg) 110 bid 150 bid 20 (15) qd 5 (2.5) bid 30 (15) qd 60 (30) qd Prior vitamin K antagonist treatment (%) 50 и 62 57 59.2 58.8 Mean TTR, warfarin arm (%) 64 55 62 68.4 % of patients per year and HR (95% CI) for NOACs vs. warfarin Major bleeding NOAC 2.92 3.4 3.6 2.13 1.61 2.75 Warfarin 3.61 р 3.61 3.4 3.09 3.43 3.43 HR (95%CI) 0.80 (0.70–0.93) 0.94 (0.82–1.08) 1.04 (0.90–1.20) 0.69 (0.60–0.80) 0.47 (0.41–0.55) 0.80 (0.71–0.91) Major or clinically relevant nonmajor bleeding NOAC NA NA 14.9 4.07 7.97 11.10 Warfarin 14.5 6.01 13.02 13.02 HR (95%CI) о 1.03 (0.96–1.11) 0.68 (0.61–0.75) 0.62 (0.57–0.67) 0.86 (0.80–0.92) Life-threatening bleeding NOAC 1.27 1.52 0.8 NR 0.25 0.40 Warfarin 1.87 1.87 1.2a 0.78 0.78 HR (95%CI) 0.67 (0.55–0.83) 0.81 (0.67–0.99) 0.69 (0.53–0.91) 0.32 (0.23–0.46) 0.51 (0.38–0.70) Intracranial hemorrhage NOAC т 0.23 0.3 0.5 0.33 0.26 0.39 Downloaded by [Dr Mikhail Dzeshka] at 04:40 29 October 2017 Warfarin 0.74 0.74 0.70 0.80 0.85 0.85 HR (95%CI) 0.30 (0.19–0.45) 0.41 (0.28–0.60) 0.67 (0.47–0.93) 0.42 (0.30–0.58) 0.30 (0.21–0.43) 0.47 (0.34–0.63) Gastrointestinal bleeding NOAC 1.12 1.51 3.2 0.76 0.82 1.51 Warfarinи 1.02 1.02 2.20 0.86 1.23 1.23 HR (95%CI) 1.09 (0.85–1.39) 1.49 (1.19–1.88) 1.47 (1.20–1.81) 0.88 (0.67–1.14) 0.67 (0.53–0.83) 1.23 (1.02–1.50) Any bleeding NOAC 14.62 16.42 NR 18.1 10.68 14.15 зWarfarin 18.15 18.15 25.8 16.40 16.40 HR (95%CI) 0.78 (0.74–0.83) 0.91 (0.86–0.97) 0.71 (0.68–0.75) 0.66 (0.62–0.71) 0.87 (0.82–0.92) aCritical bleeding. bid: twice daily; CHADS2: congestive heart failure, hypertension, age >75 years, diabetes mellitus, stroke or transient ischemic attack (2 points); CI: confidence interval; NOAC: non-vitamin K oral anticoagulant; NR: not reported; qd: once daily; TTR: time in therapeuticо range. п е Р EXPERT REVIEW OF HEMATOLOGY 1007 The aim of the current review is to provide a summary of Real-world data further reaffirmed the safety and efficacy of current knowledge on (1) assessment of risk of major bleeding the NOACs observed in the randomized trials [20,21,28,39–42]. in patients taking NOACs, (2) management of bleeding with a However, high bleeding risk is not a reason to give up OAC particular focus on use of specific reversal agents, and (3) the with the purpose of stroke prevention [5].
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  • Reversal Agents

    Reversal Agents

    R E V E R S A L A G E N T S Opioids Nalaxone (Narcan) Opioid effects may outlast the reversal's duration of action Continue monitoring 3-4 hrs Benzodiazepines Flumazenil (Romazicon) May lower seizure threshold May cause confusion, agitation, hypertension, and alterations in heart rate Beta Blockers Glucagon Monitor for hyperglycemia May cause hypokalemia Heparin Protamine Sulfate May cause hypotension Risk for anaphylaxis Has weak anticoagulant effect Risk for thrombotic event Warfarin PCC - Vitamin K - FFP Treatment based on severity of bleeding An exhibitImiomne tdoiauter - oPnCC R aandp Vhita Kel Joo's mostF aisct o- FnFiPc works! Within 6 hrs - Vitamin K Risk for thrombotic event Factor Xa Inhibitors Andexanet alfa Risk for thrombotic event May cause cardiogenic shock, heart failure exacerbations, UTI, acute respiratory failure, and pneumonia © Digital Health Media LLC R E F E R E N C E S APSF. (2018, August 5). New Factor Xa Inhibitor (Xarelto®) (Eliquis®) Reversal Agent. Retrieved from Anesthesia Patient Safety Foundation website: https://www.apsf.org/news- updates/new-factor-xa-inhibitor-xarelto-eliquis-reversal-agent/ CHEMM. (n.d.). Naloxone. Retrieved from https://chemm.nlm.nih.gov/countermeasure _naloxone.htm#adminHanley, Deglin, J. H., & Vallerand, A. H. (2007). Davis’s drug guide for nurses (11th ed.). Philadelphia, PA: F. A. Davis Company J. P. (2004). Warfarin reversal. Journal of Clinical Pathology, 57(11), 1132–1139 https://doi.org /10.1136/jcp.2003.008904 Kang, M., & Ghassemzadeh, S. (2019). Benzodiazepine Toxicity. In StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK482238/ Ni Ainle, F., Preston, R.