Hindawi Advances in Hematology Volume 2020, Article ID 7636104, 10 pages https://doi.org/10.1155/2020/7636104 Review Article An Update on the Reversal of Non-Vitamin K Antagonist Oral Anticoagulants Mark Terence P. Mujer,1 Manoj P. Rai ,1 Varunsiri Atti,1 Ian Limuel Dimaandal,2 Abigail S. Chan ,3 Shiva Shrotriya,1 Krishna Gundabolu,4,5 and Prajwal Dhakal4,5 1Department of Medicine, Michigan State University, East Lansing, MI, USA 2Department of Internal Medicine, University of Connecticut, Farmington, CT, USA 3Department of Internal Medicine, Sinai Hospital of Baltimore, Baltimore, MD, USA 4Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA 5Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA Correspondence should be addressed to Manoj P. Rai; [email protected] Received 8 May 2019; Revised 26 August 2019; Accepted 25 September 2019; Published 27 January 2020 Academic Editor: Erwin Strasser Copyright © 2020 Mark Terence P. Mujer et al. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Non-vitamin K antagonist oral anticoagulants (NOACs) include thrombin inhibitor dabigatran and coagulation factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and betrixaban. NOACs have several benefits over warfarin, including faster time to the achieve effect, rapid onset of action, fewer documented food and drug interactions, lack of need for routine INR monitoring, and improved patient satisfaction. Local hemostatic measures, supportive care, and withholding the next NOAC dose are usually sufficient to achieve hemostasis among patients presenting with minor bleeding. +e administration of reversal agents should be considered in patients on NOAC’s with major bleeding manifestations (life-threatening bleeding, or major uncontrolled bleeding), or those who require rapid anticoagulant reversal for an emergent surgical procedure. +e Food and Drug Ad- ministration (FDA) has approved two reversal agents for NOACs: idarucizumab for dabigatran and andexanet alfa for apixaban and rivaroxaban. +e American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) have released an updated guideline for the management of patients with atrial fibrillation that provides indications for the use of these reversal agents. In addition, the final results of the ANNEXA-4 study that evaluated the efficacy and safety of andexanet alfa were recently published. Several agents are in different phases of clinical trials, and among them, ciraparantag has shown promising results. However, their higher cost and limited availability remains a concern. Here, we provide a brief review of the available reversal agents for NOACs (nonspecific and specific), recent updates on reversal strategies, lab parameters (including point-of-care tests), NOAC resumption, and agents in development. 1. Introduction RE-LY trial compared Dabigatran, which is the first de- veloped NOAC with warfarin in patients with nonvalvular atrial Non-vitamin K antagonist oral anticoagulants (NOACs) fibrillation. +e higher 150 mg dose was associated with a lower have become the cornerstone in the prevention and treat- rate of stroke and systemic embolism (SE) but a similar rate in ment of venous thromboembolism (VTE) in nonvalvular major bleeding compared to warfarin. A lower 110 mg dose was atrial fibrillation. For years, vitamin K antagonists (VKA) similar to warfarin in the prevention of stroke and SE and was and heparin derivatives were the only available anticoagu- associated with a lower rate of major bleeding. Patients with age lants. From 1954 until the advent of non-vitamin K an- <75 years were reported to have a lower rate of major bleeding tagonist oral anticoagulants (NOACs) in 2010, warfarin was and major extracranial bleeding compared to warfarin for both the only available oral agent (see Figure 1). doses of dabigatran [1]. +e results from the ROCKET-AF trial 2 Advances in Hematology 1940 1954 1990’s 2009 2011 2013 2015 2017 2018 Dicoumarol or Approval of Clinical trials RE-LY ROCKET-AF ENGAGE FDA approves FDA dicumarol was warfarin for evaluating dabigatran rivaroxaban AF-TIMI idarucizumab approves FDA approves discovered oral warfarin ARISTOTLE 48 betrixaban andexanet alfa anticoaglation versus apixaban edoxaban placebo Figure 1: Oral anticoagulants and NOAC reversal agents’ timeline. showed rivaroxaban to be noninferior to warfarin for the by the FDA for VTE prophylaxis in acutely ill medical prevention of stroke or SE [2]. Rivaroxaban was associated with patients. However, betrixaban has not been studied in acute less frequent intracranial and fatal bleeding, but there was no VTE or in the prevention of VTE recurrence. significant group difference in the risk of major bleeding. +e NOACs have several advantages over warfarin including ARISTOTLE trial found that apixaban was superior to warfarin faster time to achieve the anticoagulant effect, a shorter plasma in preventing stroke or SE. Also, it was associated with a lower half-life, lack of need for routine INR monitoring, and im- rate of major bleeding and lower mortality [3]. +e ENGAGE proved patient satisfaction [12]. +ere have been concerns AF-TIMI 48 showed that once-daily edoxaban (either 30 mg or about achieving hemostasis among patients on NOACs with 60 mg) was non-inferior to warfarin in the prevention of stroke bleeding episodes since there were no specific reversal agents or systemic embolism. Edoxaban was associated with a dose- available until 2015. Two reversal agents were recently ap- dependent decrease in the rate of major bleeding, intracranial proved by FDA, the American College of Cardiology (ACC), bleeding, and life-threatening bleeding. However, a higher dose American Heart Association (AHA), and Heart Rhythm So- of edoxaban caused a higher rate of gastrointestinal bleeding ciety (HRS) (ACC/AHA/HRS) released guidelines on their compared to warfarin [4]. appropriate use. We mainly discuss the management of For the treatment of acute VTE, six clinical trials have bleeding episodes with NOACs, including the use of non- compared dabigatran, rivaroxaban, apixaban, and edox- specific and specific reversal agents, application of lab pa- aban with conventional therapy (parenteral anticoagulation rameters, and resumption of NOAC. Also, we briefly touch followed by VKA) [5]. In the dabigatran and the edoxaban base upon agents in development. trials, patients in both the NOAC and conventional therapy arm received 5 days of parenteral anticoagulation before 2. Initiation of NOAC starting either dabigatran or edoxaban. However, in the rivaroxaban and the apixaban trials, the agents were ini- Prior to the initiation of NOACs, comorbidities and come- tiated without prior parenteral anticoagulation. +e pri- dications (with emphasis on P-glycoprotein and CYP3A4 mary efficacy outcomes for all four NOACs were non- interacting medicines) should be carefully reviewed [13–15]. inferior to conventional treatment—dabigatran (HR 1.09; Baseline laboratory workup, namely, hemoglobin, liver, and 95% CI: 0.76 to 1.57) [6, 7], rivaroxaban (HR: 0.89; 95% CI: renal function as well as a coagulation panel should be or- 0.66 to 1.19) [8], apixaban (relative risk (RR): 0.84; 95% CI: dered to assess if a patient is an appropriate candidate for the 0.60 to 1.18) [9], and edoxaban (HR: 0.89; 95% CI: 0.70 to initiation of NOAC or if dosing adjustment is needed. Older 1.13) [6] in the referenced phase III clinical trials. Apixaban age with increased fall risk, previous major bleed, ongoing was associated with a significant reduction in major heavy alcohol use, and coronary artery disease requiring bleeding compared with conventional treatment (RR: 0.31; percutaneous coronary intervention are concerning factors 95% CI: 0.17 to 0.55) [9]. +e outcome was similar for for initiation of NOACs. +e data on drug-drug interactions rivaroxaban in the pulmonary embolism study but not in in patients on NOACs is limited [13]. Based on the available the deep vein thrombosis (DVT) trial [10]. Edoxaban, data, concurrent use of amiodarone, fluconazole, rifampin, or dabigatran and rivaroxaban were safer than conventional phenytoin with NOACs has been reported to be associated treatment with lower clinically relevant bleeding (HR: 0.81; with an increased predisposition for major bleeding [13]. 95% CI: 0.71 to 0.94) [11], and (HR: 0.62; 95% CI: 0.50 to +erefore, physicians should use caution when prescribing 0.76) [7], and (HR: 0.93; 95% CI: 0.81 to 1.06) respectively the above medications in patients on NOAC. Additionlly, the [8]. +e reduction in intracranial hemorrhage with all International Society of +rombosis and Haemostasis does NOACs was statistically non-significant, and not ade- not support the use of NOACs in patients with a BMI of quately sized to show a definitive effect. +ere was a sig- >40 kg/m2 or weight of >120 kg due to concern for decreased nificant reduction in fatal bleeding in the Hokusai study drug exposure and risk of underdosing [16]. which compared edoxaban with warfarin (2 events vs. 10 events; odds ratio (OR): 0.20; 95% CI: 0.04 to 0.91) [11]. 3. Indications for Reversal Agents Unfortunately, there is no definitive data available on the incidence of gastrointestinal or mucosal bleeding with +e most recent American Heart Association/American NOACs. Twice-daily apixaban could be preferred for its College of Cardiology/Heart Rhythm Society (ACC/AHA/ safety profile, as shown by the 69% reduction in major HRS) guidelines define major bleeding as all major bleeds bleeding [9], also since United States Food and Drug that are associated with either hemodynamic compromise, Administration (FDA) recently approved generics of bleed in a critical organ site (e.g., intracranial and peri- apixaban making it more affordable. Betrixaban, which is cardial), a drop in hemoglobin >2 g/dL (when baseline is the fifth oral, direct factor Xa inhibitor, has been approved unknown), or a need for 2 units of whole blood or red cells Advances in Hematology 3 [17].