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Download Article 54 l Nursing2021 l Volume 51, Number 6 www.Nursing2021.com Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. Direct oral anticoagulant reversal: An update BY ANDREA HAFER, PharmD, BCPS, CACP, AND LINDSAY McCANN, PharmD, BCCP Abstract: The rise in direct oral anticoagulant (DOAC) use means nurses must understand the reversal of these agents in case of bleeding. Depending on bleed severity, as well as other criteria, pharmacologic reversal can be considered in place of supportive care alone. Knowl- edge of literature surrounding DOAC reversal is crucial. Keywords: andexanet alfa, direct oral anticoagulant, DOAC, idarucizumab, PCC, pharmacologic reversal, prothrombin complex concentrate ANTICOAGULATION IS the foun- ally, up to 900,000 people could dation for the treatment and preven- experience a VTE event.2,3 Effective tion of thromboembolic events. For anticoagulation requires a delicate over 50 years, warfarin, a vitamin K balance between thrombosis preven- antagonist, was the only oral antico- tion and bleeding prevention. When agulant on the market in the US. prescribing these agents, the charac- Since 2010, newer anticoagulants teristics of the drug and the patient’s have been approved with various risk of bleeding should be assessed. indications. The preferred terminol- Effective prescribing includes consid- ogy for these agents is direct oral anti- eration of drug interactions, assess- coagulant (DOAC). This has replaced ment of ability to adhere to once- the previous term novel/non-vitamin K versus twice-daily dosing, patient oral anticoagulant (NOAC) due to re- barriers (such as inability to obtain ports of the abbreviation NOAC frequent lab draws or financial con- being misinterpreted to mean no cerns), and an understanding of each anticoagulation.1 DOACs include the agent’s pharmacokinetic properties.4 only oral direct thrombin inhibitor, A patient’s risk of bleeding can be dabigatran etexilate, as well as the assessed by using validated scoring factor Xa inhibitors (FXaIs) apixa- systems such as HEMORR2HAGES, ban, betrixaban, edoxaban, and riva- HAS-BLED, and ATRIA for AF, and roxaban. RIETE and CHEST for VTE.5 Atrial fibrillation (AF) and venous thromboembolism (VTE) are among Monitoring: SHUTTERSTOCK the two most common indications Coagulation assays / for prescribing an anticoagulant. In One of the advantages of using a RIBOLDI the US, AF is estimated to occur in DOAC over warfarin is the lack of STUDIOMOLEKUUL/SHUTTERSTOCK BRITTANY 2.7 to 6.1 million people. Addition- monitoring associated with these www.Nursing2021.com June l Nursing2021 l 55 Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. medications. Although this is ad- FXaIs tend to prolong the PT more molecular weight heparin (LMWH) vantageous in certain situations, this than the aPTT.8 However, normal PT or a specific FXaI. When calibrated may also be a limitation when trying levels may still result while the to detect heparin or LMWH, this to evaluate if reversal is needed. patient is on an FXaI depending on assay is considered qualitative for Lab assessments can be either qual- the sensitivity of the reagent used. the evaluation of DOAC levels. itative or quantitative. Qualitative The aPTT is prolonged in the pres- However, if the assay is calibrated tests, which detect the presence or ence of dabigatran and exhibits a specific to one of the FXaIs, the absence of a drug, include prothrom- concentration-response curve that assay is considered quantitative bin time (PT), activated partial throm- flattens at higher concentrations and will provide a linear concentra- boplastin time (aPTT), and thrombin (≥200 ng/mL).9 It can be useful in tion-dependent relationship.7 time (TT). Quantitative tests show the determining supratherapeutic levels Ecarin-based assays include ECT amount of drug present and include of dabigatran, but the aPTT should and ecarin chromogenic assay. Ecarin diluted thrombin time (dTT), ecarin be evaluated with caution because a is a snake venom that cleaves pro- chromogenic assay, ecarin clotting normal value may result despite the thrombin to form meizothrombin, time (ECT), anti-Xa assay, and liquid presence of dabigatran.7,10 which is an intermediate of throm- chromatography-tandem mass spec- TT directly measures thrombin bin.7,14 These assays are sensitive to trometry (LC-MS/MS).6 activity and is highly sensitive to dabigatran but limited due to lack Qualitative assays. DOACs may dabigatran. A normal TT suggests of standardization among different prolong the PT in a concentration- that little or no dabigatran is present, lots.14 dependent manner, but this varies but an elevated TT does not neces- LC-MS/MS displays a high degree based on reagents used.7 The PT is sarily mean there is a high dabigatran of specificity, sensitivity, selectivity, less sensitive to dabigatran than the concentration.11 and reproducibility, and is consid- aPTT. The PT can be expressed as an Quantitative assays. dTT is a ered the gold standard method for international normalized ratio (INR) clot-based assay that correlates with DOAC measurement.6 It is often for patients receiving vitamin K an- dabigatran concentrations measured used to assess the pharmacokinetics tagonists; however, the PT should by mass spectrometry.12 The use of of DOACs in clinical development not be expressed as an INR for pa- diluted plasma allows a wider range but is not practical for clinical lab tients receiving DOACs because the of dabigatran concentrations to be use.6,7 Many institutions may not international sensitivity index is not measured.13 have quantitative assays available or based on DOAC sensitivity. In gen- Anti-Xa assays are chromogenic the results are not immediately avail- eral, dabigatran normally prolongs assays that are calibrated to detect able, which limits their use in the the aPTT more than the PT while either unfractionated heparin/low early assessment of a critical bleed. Major bleeding rates in NVAF trials of DOACs15-18 ARISTOTLE RE-LY ENGAGE AF-TIMI 48 ROCKET AF HR (95% CI) RR (95% CI) HR (95% CI) HR (95% CI) Apixaban Warfarin Dabigatran Warfarin Edoxaban Warfarin Rivaroxaban Warfarin 150 mg 60 mg Major 2.13% 3.09% 3.11% 3.36% 2.75% 3.43% 3.6% 3.4% bleeding 0.69 (0.60–0.80) 0.93 (0.81–1.07) 0.80 (0.71–0.91) 1.04 (0.90–1.20) P < .001 P = .31 P < .001 P = .58 ICH 0.33% 0.80% 0.30% 0.74% 0.39% 0.85% 0.5% 0.7% 0.42 (0.30–0.58) 0.40 (0.27–0.60) 0.47 (0.34–0.63) 0.67 (0.47–0.93) P < .001 P < .001 P < .001 P = .02 Gastro- 0.76% 0.86% 1.51% 1.02% 1.51% 1.23% 3.2% 2.2% intestinal 0.89 (0.70–1.15) 1.50 (1.19–1.89) 1.23 (1.02–1.50) P < .001 bleed P = .37 P < .001 P = .03 Abbreviations: HR, hazard ratio; RR, relative risk Major bleeding was defined according to the ISTH criteria. 56 l Nursing2021 l Volume 51, Number 6 www.Nursing2021.com Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. Major bleeding rates in VTE trials of DOACs19-22 AMPLIFY RE-COVER* HOKUSAI-VTE EINSTEIN** Apixaban Warfarin Dabigatran Warfarin Edoxaban Warfarin Rivaroxaban Warfarin Major bleeding 0.6% 1.8% 1.4% 2.0% 1.4% 1.6.% 1.0% 1.7% RR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) 0.31 (0.17–0.55) 0.73 (0.48–1.11) 0.84 (0.59–1.21) 0.54 (0.37–0.79) P < .001 P = .35 P = .002 ICH*** 0.1% 0.2% 0.1% 0.2% 0.1% 0.4% 0.1% 0.3% Gastrointestinal 0.3% 0.7% NR NR NR NR NR NR bleed Abbreviations: NR, not reported; HR, hazard ratio; RR, relative risk *Pooled analysis of RE-COVER and RE-COVER II **Pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies ***ICH including both fatal and nonfatal where data available. Bleeding data ring at a lesser frequency. (See National data show that the rate Bleeding data for DOACs can be Major bleeding rates in VTE trials of of anticoagulant prescribing is ris- extrapolated from clinical trials as DOACs.) ing; specifically, use of DOACs is well as from real-world statistics. Datar and colleagues evaluated increasing compared with warfa- Unfortunately, there are no head-to- over 16,000 patients with AF receiv- rin.25,26 This increase in DOAC use head trials between DOACs, so ing DOACs (n = 8,227) versus those makes it extremely important that bleeding data from the trials cannot receiving warfarin (n = 8,227). In nurses understand when and how be directly compared. Randomized this study, the bleeding risk was as- to effectively reverse the anticoagu- clinical trials that evaluated DOACs sessed by the Cunningham algorithm lant effect. for the prevention of stroke and and bleeding occurred in 81 (0.98%) systemic embolism in nonvalvular patients on DOACs versus 72 Categorizing a major bleed AF (NVAF) were compared with (0.87%) patients on warfarin and There are different classification warfarin targeted to an INR of 2.0 was not statistically significant (haz- systems used to define major to 3.0.15-18 It is important to note ard ratio [HR], 0.85; 95% confidence bleeding. (See Defining major that the CHADS2 scores and time interval [CI], 0.71–1.01).23 bleeds.) ISTH criteria are used to in therapeutic range differed in The INSigHT registry, which standardize the definition of major each NVAF trial. Major bleeding evaluated patients receiving DOACs bleeding in clinical trials for non- among DOACs occurred in 2.13% for NVAF (apixaban [n = 256, surgical patients.27,28 to 3.6% of patients with NVAF.
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