Copyright © 2020 Wolters Kluwer Health, Inc. All Rights Reserved. Direct Oral Anticoagulant Reversal: an Update

STUDIOMOLEKUUL/SHUTTERSTOCK

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By Andrea Hafer, PharmD, BCPS, CACP and Lindsay McCann, PharmD, BCCP

Abstract: The rise in direct oral anticoagulant (DOAC) use means critical care 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. Knowledge of literature surrounding DOAC reversal is crucial.

Keywords: andexanet alfa, direct oral anticoagulant (DOAC), idarucizumab, prothrombin complex concentrate (PCC), reversal

Anticoagulation is the foundation 900,000 people could experience for the treatment and preven- a VTE event.2,3 Effective anti- tion of thromboembolic events. coagulation requires a delicate For over 50 years, warfarin, a balance between thrombosis pre- vitamin K antagonist (VKA), was vention and bleeding prevention. the only oral anticoagulant on When prescribing these agents, the market in the US. Since 2010, the characteristics of the drug newer anticoagulants have been and the patient’s risk of bleeding approved with various indica- should be assessed. Effective pre- tions. The preferred terminology scribing includes consideration of for these agents is direct oral drug interactions, assessment of anticoagulant (DOAC). This has ability to adhere to once- versus replaced the previous term novel/ twice-daily dosing, patient bar- non-vitamin K oral anticoagulant riers (such as inability to obtain (NOAC) due to reports of the frequent lab draws or financial abbreviation NOAC being misin- concerns), and understanding of terpreted to mean no anticoagu- each agent’s pharmacokinetic lation.1 The DOACs include the properties.4 A patient’s risk of only oral direct thrombin inhibi- bleeding can be assessed by using tor, dabigatran etexilate, as well validated scoring systems such as as factor Xa inhibitors (FXaIs) HEMORR2HAGES, HAS-BLED, apixaban, betrixaban, edoxaban, and ATRIA for AF, and RIETE and rivaroxaban. and CHEST for VTE.5 Atrial fibrillation (AF) and venous thromboembolism (VTE) Monitoring: Coagulation are among the two most com- assays mon indications for prescribing One of the advantages of using a an anticoagulant. In the US, AF DOAC over warfarin is the lack is estimated to occur in 2.7 to 6.1 of monitoring associated with million people. Additionally, up to these medications. Although www.nursingcriticalcare.com November l Nursing2020CriticalCare l 19

this is advantageous in certain as INRs for patients receiving Quantitative assays. dTT is situations, this may also be a DOACs because the international a clot-based assay that correlates limitation when trying to evalu- sensitivity index is not based on with dabigatran concentrations ate if reversal is needed. Lab DOAC sensitivity. In general, measured by mass spectrometry.12 assessments can be either qualita- dabigatran normally prolongs the The use of diluted plasma allows tive or quantitative. Qualitative aPTT more than the PT while a wider range of dabigatran con- tests, which detect the presence FXaIs tend to prolong the PT more centrations to be measured.13 or absence of a drug, include: than the aPTT.8 However, normal Anti-Xa assays are chromo- prothrombin time (PT), activated PT levels may still result while genic assays that are calibrated partial thromboplastin time on an FXaI depending on the sen- to detect either unfractionated (aPTT), and thrombin time (TT); sitivity of the reagent used. heparin (UFH)/low molecular whereas quantitative tests show The aPTT is prolonged in weight heparin (LMWH) or a the amount of drug present and the presence of dabigatran and specific FXaI. When calibrated include: diluted thrombin time exhibits a concentration-response to detect heparin or LMWH, this (dTT), ecarin chromogenic assay curve that flattens at higher con- assay is considered qualitative for (ECA), ecarin clotting time (ECT), centrations (≥200 ng/mL).9 It can the evaluation of DOAC levels. anti-Xa assay, and liquid chroma- be useful in determining supra- However, if the assay is calibrated tography-tandem mass spectrom- therapeutic levels of dabigatran, specific to one of the FXaIs, the etry (LC-MS/MS).6 but the aPTT should be evaluated assay is considered quantitative Qualitative assays. DOACs with caution as a normal value and will provide a linear concen- may prolong the PT in a concen- may result despite presence of tration-dependent relationship.7 tration-dependent manner, but dabigatran.7,10 Ecarin-based assays include ECT this varies based on reagents TT directly measures thrombin and ECA. Ecarin is a snake venom used.7 The PT is less sensitive activity and therefore, is highly that cleaves prothrombin to form to dabigatran than the aPTT. PT sensitive to dabigatran. A normal meizothrombin, which is an inter- can be expressed as an interna- TT suggests that little or no dabiga- mediate of thrombin.7,14 These tional normalized ratio (INR) for tran is present, but an elevated TT assays are sensitive to dabigatran patients receiving VKAs; how- does not necessarily mean there is but limited due to lack of standard- ever, PTs should not be expressed a high dabigatran concentration.11 ization among different lots.14

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 GIB 0.76% 0.86% 1.51% 1.02% 1.51% 1.23% 3.2% 2.2%

0.89 (0.70-1.15) 1.50 (1.19-1.89) 1.23 (1.02-1.50) P < .001 P = .37 P < .001 P = .03

Abbreviations: NVAF, nonvalvular atrial fibrillation; ICH, Intracranial hemorrhage; GIB, gastrointestinal bleed; HR, hazard ratio; RR, relative risk Major bleeding was defined according to the ISTH criteria.

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Copyright © 2020 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% GIB 0.3% 0.7% NR NR NR NR NR NR

Abbreviations: VTE, venous thromboembolism; ICH, Intracranial hemorrhage; GIB, gastrointestinal bleed; 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.

LC-MS/MS displays a high each NVAF trial. Major bleeding was not statistically significant degree of specificity, sensitivity, among DOACs occurred in 2.13% (hazard ratio [HR], 0.85; 95% selectivity, and reproducibility, to 3.6% of patients with NVAF. confidence interval [CI], 0.71- and is considered the gold stan- Intracranial hemorrhage occurred 1.01).23 dard method for DOAC measure- in about 0.3% to 0.5% of patients, The INSigHT registry, which ment.6 It is often used to assess which was significantly lower evaluated patients receiving pharmacokinetics of DOACs in than the warfarin arms.15-18 (See DOACs for NVAF [apixaban clinical development, but is not Major bleeding rates in NVAF trials (n = 256, 41%), dabigatran practical for clinical lab use.6,7 of DOACs.) (n = 245, 39%), and rivar- Many institutions may not have In the VTE trials, all DOACs oxaban (n = 131, 20%)], was quantitative assays available or were compared with a parenteral divided into two subcohorts the results are not immediately anticoagulant with a bridge to based on creatinine clearance available, which limits their use warfarin.19-22 In the RE-COVER (CrCl): (1) chronic kidney dis- in the early assessment of a criti- I & II and Hokusai-VTE trials, ease (CKD) (CrCl 15-59 mL/ cal bleed. a parenteral anticoagulant was min, 219) and (2) non-CKD used for at least 5 days prior to (CrCl 60-89 mL/min, 413).24 Bleeding data starting dabigatran and edoxaban, Those with CKD were at higher Bleeding data for the DOACs respectively.20,21 Major bleed- ischemic and hemorrhagic risk, can be extrapolated from clinical ing occurred in 0.6% to 1.4% of compared to patients without trials as well as real world statis- patients with intracranial hemor- CKD. Major bleeding, as defined tics. Unfortunately, there are no rhage (ICH) occurring at a lesser by the International Society for head-to-head trials between the frequency. (See Major bleeding Thrombosis and Haemostasis DOACs, so bleeding data from rates in VTE trials of DOACs.) (ISTH), occurred in 5.1% of the trials cannot be directly com- Datar and colleagues evalu- patients with no significant differ- pared. Randomized clinical trials ated over 16,000 patients with ences between patients with and that evaluated the DOACs for the AF receiving DOACs (n = 8,227) without CKD.24 prevention of stroke and systemic versus those receiving warfarin National data show that the embolism in nonvalvular AF (n = 8,227). In this study, the rate of anticoagulant prescribing (NVAF) were compared with war- bleeding risk was assessed by is rising; specifically, use of the farin targeted to an INR of 2.0 to the Cunningham algorithm and DOACs is increasing compared 3.0.15-18 It is important to note bleeding occurred in 81 (0.98%) with warfarin.25,26 This increase that the CHADS2 scores and time patients on DOACs versus 72 in DOAC use makes it extremely in therapeutic range differed in (0.87%) patients on warfarin and important that critical care nurses www.nursingcriticalcare.com November l Nursing2020CriticalCare l 21

understand when and how to Interpreting the severity of a pericardial tamponade, airway effectively reverse the anticoagu- bleed is critical for appropriate (including posterior epistaxis), lant effect. management.4 A 2017 American intra- articular, and intramuscular College of Cardiology (ACC) task bleeds (Intraluminal gastrointestinal Categorizing a major bleed force developed criteria to assess bleeding is not considered to be There are different classification if a bleed is categorized as major, a critical site, but it may result in systems used to define major where one or more conditions hemodynamic compromise.) bleeding. (See Defining major must be present: • Hemodynamic instability, bleeds.) ISTH criteria are used • Bleeding in a critical site, which includes: an increased to standardize the definition of defined as intracranial, spinal, heart rate, a systolic blood major bleeding in clinical trials intraocular, thoracic, retro- pressure (SBP) <90 mm Hg, a for nonsurgical patients.27,28 peritoneal, intra-abdominal, decrease in SBP >40 mm Hg, or orthostatic changes (SBP drop ≥20 mm Hg or a diastolic blood Defining major bleeds pressure drop ≥10 mm Hg upon Classification Definition standing), mean arterial pressure ISTH • hemoglobin drop of ≥2 g/dL, <65 mm Hg or signs of poor (major bleeding) • transfusion of ≥2 units pRBCs, organ perfusion (for example, • symptomatic bleed in a critical area*, or urine output <0.5 mL/kg/h) • fatal bleed. • overt bleeding with hemoglobin TIMI • hemoglobin drop of ≥5 g/dL, decreases of ≥2 g/dL or adminis- (major bleeding) • intracranial hemorrhage, or tration of ≥2 units of packed red • fatal bleed. blood cells. BARC Type 3a (Type 3 bleeding) • overt bleeding plus hemoglobin drop of 3 to <5 g/dL Bleeding management (provided hemoglobin drop is related to bleed) In 2017, the ACC published a • any transfusion with overt bleeding. consensus statement regarding Type 3b the management of bleeding in • overt bleeding plus hemoglobin drop ≥5 g/dL (pro- patients on oral anticoagulation.4 vided hemoglobin drop is related to bleed) This provides a useful framework • cardiac tamponade to aid in decision-making regard- • bleeding requiring surgical intervention for control ing when to administer a reversal (excluding dental/nasal/skin/hemorrhoid) agent to treat bleeds associated • bleeding requiring I.V. vasoactive agents. with the use of the DOACs. For Type 3c major bleeds, the document rec- • intracranial hemorrhage (does not include micro- ommends stopping the DOAC, bleeds or hemorrhagic transformation, does holding antiplatelet therapy if include intraspinal) applicable, and providing sup- • subcategories confirmed by autopsy or imaging or portive care including aggressive lumbar puncture volume resuscitation, local mea- • intraocular bleed compromising vision. sures to control bleeding (such as GUSTO • Hemodynamic compromise requiring treatment, pressure or packing), correction • (severe/life- intracranial hemorrhage, or of acidosis and hypothermia, and threatening bleeding) • fatal bleed. blood transfusion if appropriate.4 Abbreviations: BARC, Bleeding Academic Research Consortium; GUSTO, Global Use of Strategies to Open Occluded Arteries; ISTH, International Society for Thrombosis and Haemostasis; pRBC, packed red If a major bleed is considered blood cells; TIMI, Thrombolysis in Myocardial Infarction life-threatening or located at a *Critical areas include: intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome. critical site, as defined previously, Source: Bergmark BA, Kamphuisen PW, Wiviott SD, et al. Comparison of events across bleeding scales pharmacologic reversal is recom- in the ENGAGE AF-TIMI 48 Trial. Circulation. 2019;140(22):1792-1801. mended. Timing of last ingestion

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. of the DOAC and renal function 33 also play a critical role in deter- RE-VERSE AD trial data mining if a reversal agent is need- Group A (n = 301) Group B (n = 202) 4 ed versus supportive care alone. Elevated baseline dTT (%) 244/301 (81.1%) 152/202 (75.2%) Standard coagulation assays (such Elevated baseline ECT (%) 276/301 (91.7%) 185/202 (91.6%) as INR and aPTT) are unreliable Primary Endpoint (maximum percent reversal within 4 hours of 2nd infusion for assessing patients on DOACs. of idarucizumab) Drug-specific anti-Xa assays are not readily available and treat- Median, based on dTT or ECT 100% (95% CI, 100 to 100) ment should not be delayed for a Secondary Endpoints pending result. Cessation of bleeding 134/203* (67.7%) NA For major bleeds that do not within 24 hours after Median time to hemostasis: fall into the categories previously administration of 2.5 hours (95% CI, 2.2 to 3.9) mentioned, supportive care and idarucizumab surgical/procedural management Normal periprocedural NA 184/197** of the bleed are recommended. hemostasis (93.4%) If these measures fail, pharmaco- Abbreviations: dTT, diluted thrombin time; ECT, ecarin clotting time; CI, confidence interval *98 patients with intracranial bleeding were excluded because of dissociation between the clinical logic reversal may be considered. course and the extent of bleeding, In nonmajor bleeds, pharmaco- **Procedure was canceled for 5 patients. logic reversal is generally not recommended. tional dosing, if reappearance been treated with dabigatran of clinically relevant bleeding 110 mg twice daily, which is Dabigatran reversal occurs, along with reelevation of not a therapeutic dose approved Patients presenting with a bleed coagulation parameters, a repeat in the US. The median time should have dabigatran and other dose may be warranted.31,32 The since the last dose of dabigatran medications that could contribute Reversal Effects of Idarucizumab (reported by the patients) was to bleeding, such as antiplate- on Active Dabigatran (RE-VERSE 14.6 hours (Group A) and 18 let agents, held. If the patient AD) trial was a multicenter hours (Group B). The primary ingested dabigatran within 2 to prospective cohort study that efficacy end point was maximum 4 hours of presentation, charcoal led to the accelerated approval percentage reversal of dTT or administration may be consid- of idarucizumab.33 There were ECT at any point from the end of ered although data for its use two groups in this trial: Group the first idarucizumab infusion are sparse and it should only be A (n = 301), which included until 4 hours after the end of the administered for patients with patients with uncontrollable second infusion. The median intact mental status due to risk of or life-threatening bleeding, maximum percentage dabigatran aspiration.4,29 and Group B (n = 202), which reversal was 100% (95% CI: Idarucizumab is the only included patients who needed to 100,100) based on either dTT approved reversal agent for dabi- undergo surgery or other inva- or ECT. Clinical outcomes were gatran. It first received accelerat- sive procedures that could not secondary end points, included approval in 2015 and now has be delayed for at least 8 hours ing the extent of bleeding per full approval.30 Idarucizumab and for which normal hemosta- ISTH criteria for Group A. (See is a humanized monoclonal sis was required. In this trial, RE-VERSE AD trial data.) antibody fragment indicated for more than 95% of patients were Hemostatic treatment, includ- dabigatran reversal in patients receiving dabigatran for stroke ing whole blood and blood undergoing emergency surgery/ prevention for AF. The median components, plasma derivatives, urgent procedures or in the age was 78 years and 43.3% of and volume expanders/prohe- event of a life-threatening or patients had a CrCl <50 mL/min. mostatic agents was given to 201 uncontrolled bleed.31 Although Approximately 62% of patients (66.8%) patients in Group A and only limited data support addi- in both Groups A and B had 79 (39.1%) patients in Group B. www.nursingcriticalcare.com November l Nursing2020CriticalCare l 23

Specific agents included but were Apixaban and rivaroxaban ANNEXA-R, and the interim not limited to fresh frozen plasma reversal results of the ANNEXA-4 trial (Group A, 19.3%, versus Group Patients taking apixaban or riva- under the condition that a phase B, 11.9%), 3-factor prothrombin roxaban presenting with a major 4 confirmatory randomized con- complex concentrate (3F-PCC), bleed that meets criteria for trolled trial (RCT) be completed 4- factor PCC (4F-PCC), factor pharmacologic reversal should comparing andexanet to the VIIa (FVIIa), or activated PCC have their FXaI held.4 Similar standard of care, PCCs. This trial (aPCC) (Group A, 6.6%, versus to dabigatran, charcoal can be is expected to be completed by Group B, 4.0%) and tranexamic administered if a patient ingested October 2022 and submitted by acid (Group A, 11.6%, versus a dose of FXaI within 2 to 4 April 2023.37 Initially, the FDA Group B, 4.0%). The 30-day and hours of presentation.4,29 There clinical reviewer and supervisor 90-day mortality in Group A is some controversy regarding the assigned to review andexanet did were 13.5% and 18.8%, respec- agent of choice for pharmacologic not recommend approval of the tively. In Group B, the 30-day reversal of the FXaIs. The two drug because they had concerns and 90-day mortality were 12.6% options currently available for over the safety and efficacy data and 18.9%, respectively.33 reversal are: available. However, this was Some patients may experi- • coagulation factor Xa (recom- overruled by the Director for the ence a reelevation in coagula- binant), inactivated-zhzo, also Office of Tissues and Advanced tion parameters between 12 known as andexanet alfa, the Therapies, who felt there could and 24 hours after treatment only agent that is FDA-approved be a clinical benefit.38 with idarucizumab. This is most for reversal of apixaban and riva- The ANNEXA-4 trial was an likely due to redistribution of roxaban, and open-label, single group study unbound dabigatran from the • 4F-PCC, which is used off-label that included patients with acute extravascular to the intravascular for reversal of FXaIs. major bleeding who had taken compartment.34 A second dose Andexanet alfa. Andexanet apixaban, rivaroxaban, edoxaban, of idarucizumab should not be alfa is a modified human factor or enoxaparin within 18 hours considered for this group unless Xa decoy protein that works by of presentation.39 Patients with there is a concomitant bleed.33,35 binding and sequestering FXaIs, planned surgery within 12 hours Anti-idarucizumab antibodies causing their inactivation. The of andexanet administration, were found in 28 (5.6%) of the medication is administered as expected survival of less than 501 patients who were assessed. a bolus followed by a 2-hour 1 month, ICH + Glasgow Coma Of those 28 patients, 19 tested infusion. The dose of andexanet Scale score <7 or hematoma positive for preexisting antibod- depends on the DOAC taken as volume >60 cc, or a thrombotic ies before administration, and 9 well as the time of last ingestion event within 2 weeks of enroll- had antibodies that developed and dose of the DOAC. The half- ment were excluded. during treatment. The preexist- life of andexanet is approximately In patients receiving apixaban ing antibodies had no obvious 1 hour; antifactor Xa activity or rivaroxaban, the study found effect on idarucizumab activity.33 begins to return to baseline lev- a 92% reduction in antifactor Xa Dabigatran is dialyzable, how- els within 2 hours of infusion levels at the end of the andexanet ever it may be difficult to obtain completion. Of note, andexanet infusion, and among all patients, dialysis access on a bleeding carries a boxed warning for 82% were judged to have excel- patient. The current cost of ida- thromboembolic risks, ischemic lent or good hemostatic efficacy rucizumab 2.5 g/50 mL from our risks, sudden death, and cardiac 12 hours after administration of institution’s wholesaler is $2,226, arrest.36 andexanet. Overall, no relation- which makes the expense of a 5 g Andexanet received acceler- ship between reduction in anti- dose $4,452. If idarucizumab is ated approval for reversal of factor Xa levels and hemostatic unavailable, PCC or aPCC may rivaroxaban and apixaban in efficacy could be established. be considered as an off-label May 2018 based on the results Of note, 10% of patients had a alternative option.4 of two studies, ANNEXA-A and thromboembolic event and 14%

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. of patients died within the 30-day 41,42,44 follow-up. A postulated mecha- 4F-PCC for reversal of FXaI-related bleeds nism for an increase in thrombo- Majeed, et al Schulman, et al Piran, et al embolic events is that andexanet (N = 84) (N = 66) (N = 340) binds to tissue factor pathway Study Characteristics inhibitor, an endogenous anti- 4F-PCC dose ~25 IU/kg 2,000 IU variable coagulant protein, possibly increasing risk of thrombosis. Patients w/ICH 70.2% 55% 74% Criticisms of the study design of Effectiveness (ISTH criteria) ANNEXA-4 include the exclusion Effective 69.1% 68% 69%* of patients considered at high- est risk of death, including those Effectiveness for CNS bleeds** with expected mortality within Excellent or Good Not done 76%*** Not done 30 days, Glasgow Coma Scale Safety Outcomes at 30 Days score <7, and patients expected to need surgery within 12 hours, Thromboembolism 2.4% 7.6% 4% 40 and the lack of a control group. Death 32% 14% 16%

PCCs. Like andexanet, there *Only 2 studies analyzed used ISTH criteria. Of the other 8 studies, 77% of patients were deemed to are no randomized placebo- have effective management of bleeding. **As defined by Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin controlled trials studying PCC complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, for the reversal of FXaI-related plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234-1243 and modified by Schulman et al.42 ***In an analysis of a subset of 33 patients who had repeat computed tomography (n = 30) or large CNS bleeds. There have been two bleeds with early death (n = 3). prospective cohort trials and Abbreviations: CNS, central nervous system; ISTH, International Society on Thrombosis and Haemostasis; ICH, intracranial hemorrhage a meta-analysis of 4F-PCC for Source: Reversal agents for factor Xa inhibitors. Vizient. 2018. reversal of FXaI-related bleeds. (See 4F-PCC for reversal of FXaI- related bleeds.) The first trial death (n = 3). Thromboembolism It is important to note that utilized 4F-PCC at a dose of occurred in 7.6% of patients and patients who would have been approximately 25 IU/kg for apixa- death occurred in 14% of patients. excluded from ANNEXA-4 were ban- and rivaroxaban-associated Of note, PCCs carry a boxed included in the 4F-PCC studies major bleeds in 84 patients.41 warning for arterial and venous discussed above. For example, Hemostatic effectiveness was thromboembolic complications.43 patients expected to need sur- achieved in 69.1% of patients. In addition to these prospec- gery within 12 hours and those Thromboembolism occurred in tive studies, a meta-analysis of 10 with expected mortality within 2.4% of patients. Death occurred studies of patients (N = 340) treat- 30 days were excluded from in 18% of patients within the first ed with 4F-PCC has also been ANNEXA-4, however that was week of the major bleed and 32% completed.44 Both retrospective not part of the exclusion crite- of patients within 30 days. Of the and prospective studies were ria for the 4F-PCC studies. This patients who expired within the included in the meta-analysis. In makes it difficult, if not impossi- first week, 86.7% had ICH. The the two studies that utilized ISTH ble, to compare the results of the second trial utilized 4F-PCC at criteria for hemostasis, 69% of ANNEXA-4 to the 4F-PCC trials. a fixed dose of 2,000 IU.42 This patients were found to achieve Cost considerations. A recent trial found effective control of effective hemostasis. In the other cost comparison study was bleeding in 68% of patients over- eight studies which used non- published examining andexanet all. Excellent or good control of ISTH hemostasis criteria, 77% of versus 4F-PCC. The authors of bleeding was seen in 76% of a patients had effective hemostasis. the study calculated the cost subset of patients who had repeat Four percent of patients experi- of treatment with andexanet, computed tomography (n = 30) enced VTE, and 16% of patients considering the Medicare New or large bleeds resulting in early died. Technology Add-On Payment www.nursingcriticalcare.com November l Nursing2020CriticalCare l 25

(NTAP) reimbursement for use is only FDA-approved for reversal patients with a critical site bleed, of andexanet, versus the cost of of apixaban and rivaroxaban, cli- high risk of rebleeding, or an treatment with PCC. They found nicians may prescribe it off-label invasive procedure planned. that the projected cost of andex- to reverse the other oral FXaIs. anet, adjusted for the Medicare Given the lack of a head-to- Pipeline agents NTAP, would be $22,120 versus head trial comparing the effi- Ciraparantag (PER977). $5,670 for 4F-PCC, while the cacy and safety of andexanet to Ciraparantag is a small, water- median hospital payment would 4F-PCC and the cost associated soluble, cationic, synthetic mol- be only $11,492. Further, they with andexanet, some clinicians ecule that binds directly to a vari- found that in 74% of cases the challenge the addition of andex- ety of anticoagulants, including NTAP-adjusted projected andexanet to hospital formularies.40 UFH, LMWH, and select DOACs anet cost would exceed total hos- The results of the phase 4 RCT (dabigatran, rivaroxaban, apixa- pital reimbursement by a median comparing andexanet to PCC, ban, edoxaban).48-50 Ciraparantag of $7,604. The cost of 4F-PCC which is an FDA requirement as is thought to exhibit these effects was found to exceed total hospi- part of the approval of andexanet, through direct, noncovalent tal reimbursement in only 7% of will provide more definitive data hydrogen binding, although more cases at a median of $0.45 to guide choice of agent for the recent data suggest that its mech- Choice of agent. Several reversal of FXaI. anism in the DOACs may be due professional organizations have to binding and modulation of published recommendations Resumption of intrinsic factor IXa activity.51,52 regarding agent of choice for anticoagulation Phase 1 and 1/2 clinical stud- reversal of the FXaIs in the set- The aforementioned 2017 ACC ies in humans have shown that ting of major bleeding. The 2018 consensus statement for manage- ciraparantag completely reverses American Society of Hematology ment of bleeding in patients on the anticoagulant effects of enoxa- guideline for management of oral anticoagulants also provides parin, edoxaban, rivaroxaban, VTE recommends either 4F-PCC useful guidance on when to and apixaban.49,50,53 This reversal or andexanet, both as a “condi- restart anticoagulation following was found to be sustained over a tional recommendation based a bleeding event.4 It is useful to 24-hour time period for the FXaI, on very low certainty in the first reevaluate the indication for which offers a possible advantage evidence about effects.”46 The anticoagulation and ensure the over treatments such as andex- 2019 American Heart Association patient still requires treatment. If anet.50,53 Of note, the presence (AHA)/ACC/Heart Rhythm not, the anticoagulant should be of sodium citrate, oxalate, EDTA, Society (HRS) Focused Update discontinued. If the patient does or heparin, common chemicals of the 2014 AHA/ACC/HRS have continued need for anticoag- used in blood tubes to prevent Guideline for the Management of ulation, several factors should be whole blood coagulation, affects Patients with Atrial Fibrillation evaluated to guide resumption of the ciraparantag-anticoagulant states that “andexanet alfa can therapy. If the bleed was not at a complex, thus negating the effects be useful for the reversal of critical site, patient is not at high of the ciraparantag in vitro. In rivaroxaban and apixaban” for risk of rebleed or at high risk of addition, kaolin and celite-based life-threatening bleeding.47 Later death or disability with a rebleed, assays, such as the anti-Xa or in 2019, the American College of and there are no immediate inva- aPTT tests, are unusable because Emergency Physicians published sive procedures planned, anti- they bind ciraparantag, which “Anticoagulant Reversal Strategies coagulation may be restarted. reduces the active concentration in the Emergency Department Depending on the clinical status and therefore reversal effects of Setting,” which recommends of the patient, temporary man- ciraparantag in vitro. For these reversal of oral FXaIs with andex- agement with a parenteral anti- reasons, whole blood clotting anet as a “Tier 1” recommenda- coagulant may be warranted. time is used to study the reversal tion or PCC as a “Tier 2” recom- Delayed resumption of anticoagu- effects of ciraparantag.53 Clinical mendation.29 Although andexanet lation should be considered for studies thus far have not identi-

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. fied any procoagulant effects 2 to 5 minutes postdose and in-line filter. Dosing is as an I.V. of ciraparantag as measured by returned to baseline within bolus followed by an I.V. infu- serum D-dimer, prothrombin frag- 2 hours. Increased D-dimer levels sion, which should be started ment 1.2, and tissue factor path- were observed at higher doses of within 2 minutes of the bolus way inhibitor concentrations.49,53 FXaI16L 2 to 4 hours postdose and dose. The rate depends on the Ciraparantag is adminis- returned to baseline within 24 to dosing regimen.36 tered via slow I.V. injection.53 48 hours. PT/INR and Factor V Administration of 4F-PCC Commonly reported adverse (FV) activity were not altered fol- should occur through a dedicated reactions were minor and includ- lowing administration of FXaI16L. I.V. line. It is important that ed facial flushing and dysgeusia, No serious adverse events were blood is not allowed to enter the both of which resolved shortly reported, although nasopharyngi- infusion line as fibrin clot may after administration of the study tis and oropharyngeal pain were form.43 drug.49,53 reported by several volunteers. Monitoring. Hypersensitivity Factor X (FX) variants: No neutralizing antibody produc- reactions. Any of the reversal FXaI16L and chimeric FX. tion was observed in any of the agents can cause hypersensitiv- FXaI16L is a human zymogen- volunteers.55 ity reactions. Signs and symp- like FX variant, which contains Various chimeric FX mol- toms of these reactions may a single amino acid substitution ecules have been synthesized include rash, hives, flushing, compared with endogenous by using FX variants found in angioedema, bronchospasm, FX. This substitution creates an the venom and liver of Elapid wheezing, tachypnea, hypoten- altered active binding site and snakes. One molecule, FX-C, sion, and nausea or vomiting. prevents conversion of the mol- has specifically been found to If a serious reaction occurs dur- ecule from zymogen to protease, restore thrombin generation in ing administration, the infusion thus increasing its half-life in plasma spiked with apixaban should be discontinued, the the serum and decreasing the and edoxaban, respectively, prescribing clinician should be potential for excess activation of without inducing in vitro hyper- notified immediately, and the the clotting cascade. It is theo- coaguability, indicating its reaction should be treated appro- rized that in the presence of FVa, potential as a bypassing agent priately. Patients with hereditary which is activated at the site of to reverse FXaI anticoagula- fructose intolerance who have damaged tissue, FXaI16L activity tion. Further in-vivo studies are received idarucizumab may due is “rescued” and restored to that needed to further elucidate the at an increased risk of adverse of endogenous FX only near the potential therapeutic application reactions (such as hypoglycemia, site of injury.54 It is postulated of these molecules.56 hypophosphatemia, metabolic that these properties could make acidosis, increase in uric acid, FXaI16L a useful bypassing agent Nursing considerations acute liver failure, or death) due for treatment of bleeds associated Administration. Idarucizumab to the sorbitol content.31 with FXaI. is the reversal agent for dabiga- Thromboembolic events. Patients FXaI16L was studied in a tran and it is given intravenously. who take anticoagulants are at a phase 1 trial to characterize its Prior to administration, the I.V. higher thrombotic risk because pharmacokinetic and pharmaco- line should be flushed with nor- of their underlying indication dynamic properties. Forty-nine mal saline. Dosing is typically as for anticoagulation. Following healthy male volunteers were a bolus I.V. injection or as an I.V. reversal of any anticoagulant, the administered doses ranging from infusion. Individual institutions risk of thrombosis increases. It is 0.1-5 mcg/kg FXaI16L or placebo. should have a standardized meth- important for critical care nurses Plasma concentrations peaked od of administration, to avoid to be aware of the signs and within 2 to 5 minutes postdose confusion. symptoms of thromboembolic and were undetectable within I.V. administration of andex- events (such as deep vein throm- 40 minutes. Dose-dependent anet requires use of a 0.22 bosis, pulmonary embolism, decreases in aPTT were noted micron, low protein binding, acute coronary syndrome, and www.nursingcriticalcare.com November l Nursing2020CriticalCare l 27

Signs and symptoms of thromboembolic events*57-59 DVT PE ACS Stroke • Extremity • Dyspnea • Dyspnea • Sudden numbness or weakness in the face, swelling • Tachycardia • Chest pain/pressure arm, or leg, especially on one side of the body • Extremity • Chest pain/ • Pain or discomfort in one • Sudden confusion, trouble speaking, or dif- pain/tenderness discomfort or both arms, jaw, neck, ficulty understanding speech • Redness of • Hemoptysis back, or stomach • Sudden trouble seeing in one or both eyes the skin • Hypotension • Dizziness or • Sudden trouble walking, dizziness, loss of • Lightheadedness lightheadedness balance, or lack of coordination • Syncope • Nausea • Sudden severe headache with no known • Sweating cause

*NOTE: This is not an all-inclusive list Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; ACS, acute coronary syndrome

2. Centers for Disease Control and Prevention. DOAC reversal summary Atrial Fibrillation. 2020. www.cdc.gov/heart disease/atrial_fibrillation.htm. DOAC DOAC Reversal agent 3. Centers for Disease Control and Prevention. half-life* administration concerns Data and Statistics on Venous Thromboembo- lism. 2020. www.cdc.gov/ncbddd/dvt/data.html. Direct thrombin inhibitor 4. Tomaselli GF, Mahaffey KW, Cuker A, et al. Dabigatran (Pradaxa) 12-17 hours Idarucizumab (Praxbind) 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral • Flush line with normal saline Anticoagulants: A Report of the American Col- prior to infusion lege of Cardiology Task Force on Expert Con- • sensus Decision Pathways. J Am Coll Cardiol. Administer through dedicated line 2017;70(24):3042-3067. Factor Xa inhibitors 5. Hellenbart EL, Faulkenberg KD, Finks SW. Evaluation of bleeding in patients receiving di- Apixaban (Eliquis) 12 hours Andexanet alfa (Andexxa)** rect oral anticoagulants. Vasc Health Risk Manag. • Administer with 0.22 micron in- 2017;13:325-342. line filter 6. Gosselin RC, Adcock DM, Bates SM, et al. Betrixaban (Bevyxxa) 19-27 hours • International Council for Standardization in Hae- Start infusion within 2 minutes matology (ICSH) Recommendations for Labora- of bolus dose completion tory Measurement of Direct Oral Anticoagulants. Thromb Haemost. 2018;118(03):437-450. Edoxaban (Savaysa) 10-14 hours 4F-PCC (Kcentra)† 7. Connors JM. Testing and monitoring direct oral anticoagulants. Blood. 2018;132(19):2009-2015. • Administer through dedicated line 8. Gosselin RC, Adcock DM, Douxfils J. An • Blood should not be allowed to Rivaroxaban (Xarelto) 5-13 hours update on laboratory assessment for direct oral enter the infusion line as fibrin anticoagulants (DOACs). Int J Lab Hematol. 2019; clot may form. 41(Suppl. 1):33-39. 9. Cate HT, Henskens YM, Lancé MD. Practical *Half-life—may be prolonged in patients with renal impairment guidance on the use of laboratory testing in the **Andexanet alfa is off-label for the reversal of betrixaban and edoxaban management of bleeding in patients receiving di- †4F-PCC is off-label for all FXaIs rect oral anticoagulants. Vasc Health Risk Manag. 2017;13:457-467. 10. van Ryn J, Stangier J, Haertter S, et al. Dabi- gatran etexilate--a novel, reversible, oral direct ischemic stroke) and to continu- amount. Understanding when and thrombin inhibitor: interpretation of coagulation ally monitor patients for these how to use pharmacologic reversal assays and reversal of anticoagulant activity. events following reversal of anti- is critical to successful manage- Thromb Haemost. 2010;103(06):1116-1127. 11. Samuelson BT, Cuker A. Measurement and coagulation. (See Signs and symp- ment of the bleeding patient. (See reversal of the direct oral anticoagulants. Blood toms of thromboembolic events.) DOAC reversal summary.) ■ Rev. 2017;31(1):77-84. 12. Jaffer IH, Chan N, Roberts R, Fredenburgh JC, Eikelboom JW, Weitz JI. Comparison of the Conclusion REFERENCES ecarin chromogenic assay and diluted thrombin In conclusion, as DOAC utilization 1. Barnes GD, Ageno W, Ansell J, Kaatz S. Rec- time for quantification of dabigatran concentra- ommendation on the nomenclature for oral anti- tions. J Thromb Haemost. 2017;15(12):2377-2387. continues to rise, knowledge of coagulants: communication from the SSC of the 13. Douxfils J, Dogné J-M, Mullier F, et al. Com- emergent reversal strategies is par- ISTH. J Thromb Haemost. 2015;13(6):1154-1156. parison of calibrated dilute thrombin time and

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. aPTT tests with LC-MS/MS for the therapeutic multidisciplinary expert panel. Ann Emerg Med. bolism: optimal management of anticoagulation monitoring of patients treated with dabigatran 2019;S0196-0644(19)31181-3. therapy. Blood Adv. 2018;2(22):3257-3291. etexilate. Thromb Haemost. 2013;110(03):543-549. 30. FDA Provides Full Approval to Praxbind, 47. January CT, Wann LS, Calkins H, et al. 2019 14. Cuker A, Siegal DM, Crowther MA, Garcia Specific Reversal Agent for Pradaxa. www.boeh AHA/ACC/HRS focused update of the 2014 DA. Laboratory measurement of the anticoagu- ringer-ingelheim.us/press-release/fda-provides-full- AHA/ACC/HRS Guideline for the Management lant activity of the non-vitamin K oral anticoagu- approval-praxbind-specific-reversal-agent-pradaxa. of Patients With Atrial Fibrillation: a report of lants. J Am Coll Cardiol. 2014;64(11):1128-1139. 31. Praxbind [package insert]. Boehringer Ingel- the American College of Cardiology/American Heart Association Task Force on Clinical Practice 15. Granger CB, Alexander JH, McMurray JJV, heim, Ridgefield, CT; April 2018. Guidelines and the Heart Rhythm Society in col- et al. Apixaban versus warfarin in patients with 32. Simon A, Domanovits H, Ay C, Sengoelge laboration with the Society of Thoracic Surgeons. atrial fibrillation. N Engl J Med. 2011;365(11): G, Levy JH, Spiel AO. The recommended dose Circulation. 2019;140(2):e125-e151. 981-992. of idarucizumab may not always be sufficient 48. Sullivan DW, Gad SC, Laulicht B, Bakhru S, 16. Connolly SJ, Ezekowitz MD, Yusuf S, et al. for sustained reversal of dabigatran. J Thromb Steiner S. Nonclinical safety assessment of Dabigatran versus warfarin in patients with atrial Haemost. 2017;15(7):1317-1321. PER977: a small molecule reversal agent for fibrillation. N Engl J Med. 2009;361(12):1139-1151. 33. Pollack CV, Reilly PA, van Ryn J, et al. Ida- new oral anticoagulants and heparins. Int J 17. Giugliano RP, Ruff CT, Braunwald E, et al. rucizumab for dabigatran reversal: full cohort Toxicol. 2015;34(4):308-317. analysis. N Engl J Med. 2017;377(5):431-441. Edoxaban versus warfarin in patients with atrial 49. Ansell JE, Laulicht BE, Bakhru SH, Hoffman fibrillation. N Engl J Med. 2013;369(22):2093-2104. 34. Moia M, Squizzato A. Reversal agents for oral M, Steiner SS, Costin JC. Ciraparantag safely 18. Patel MR, Mahaffey KW, Garg J, et al. Ri- anticoagulant-associated major or life-threatening and completely reverses the anticoagulant effects varoxaban versus warfarin in nonvalvular atrial bleeding. Intern Emerg Med. 2019;14(8):1233-1239. of low molecular weight heparin. Thromb Res. fibrillation. N Engl J Med. 2011;365(10):883-891. 35. Eikelboom JW, Quinlan DJ, van Ryn J, Weitz 2016;146:113-118. 19. Agnelli G, Buller HR, Cohen A, et al. Oral JI. Idarucizumab: the antidote for reversal of 50. Laulicht B, Bakhru S, Steiner S, Ansell J. Ci- apixaban for the treatment of acute venous throm- dabigatran. Circulation. 2015;132(25):2412-2422. raparantag safely and effectively reverses apixa- boembolism. N Engl J Med. 2013;369(9):799-808. 36. Andexxa [package insert]. Portola Pharma- ban and rivaroxaban in age-matched healthy volunteers as measured by whole blood clotting 20. Schulman S, Kakkar AK, Goldhaber SZ, et ceuticals, Inc., San Francisco, CA; 2017. time. Blood. 2018;132(Suppl. 1):987-987. al. Treatment of acute venous thromboembolism 37. U.S. Food & Drug Administration. Biolog- with dabigatran or warfarin and pooled analysis. ics License Application Accelerated Approval 51. Kalathottukaren MT, Creagh AL, Abbina Circulation. 2014;129(7):764-772. to Portola Pharmaceuticals, Inc. Silver Spring, S, et al. Comparison of reversal activity and mechanism of action of UHRA, andexanet, and 21. Büller HR, Décousus H, Grosso MA, et al. MD: FDA Center for Biologics Evaluation and PER977 on heparin and oral FXa inhibitors. Edoxaban versus warfarin for the treatment of Research; 2018. STN: BL 125586/0. Blood Adv. 2018;2(16):2104-2114. symptomatic venous thromboembolism. N Engl 38. Bryan WW. U.S. Food & Drug Administra- J Med. 2013;369(15):1406-1415. tion. Memorandum Director, Office of Tissues 52. Laulicht B, Bakhru S, Jiang X, et al. Antidote for new oral anticoagulants: mechanism of ac- 22. Prins MH, Lensing AW, Bauersachs R, et al. and Advanced Therapies to Portola Pharma- ceuticals, Inc. Silver Spring, MD: FDA Director, tion and binding specificity of PER977: AS 47.1. Oral rivaroxaban versus standard therapy for the J Thromb Haemost. 2013;11. treatment of symptomatic venous thromboembo- Office of Tissues and Advanced Therapies; 2018. lism: a pooled analysis of the EINSTEIN-DVT and BLA 125586/0; Portola; ANDEXXA. 53. Ansell JE, Bakhru SH, Laulicht BE, et al. Single-dose ciraparantag safely and completely PE randomized studies. Thromb J. 2013;11(1):21. 39. Connolly SJ, Crowther M, Eikelboom JW, reverses anticoagulant effects of edoxaban. et al. ANNEXA-4 Investigators. Full study 23. Datar M, Crivera C, Rozjabek H, et al. Thromb Haemost. 2017;117(02):238-245. Comparison of real-world outcomes in patients report of andexanet alfa for bleeding associ- 54. Bunce MW, Toso R, Camire RM. Zymogen- with nonvalvular atrial fibrillation treated with ated with factor Xa inhibitors. N Engl J Med. like factor Xa variants restore thrombin genera- direct oral anticoagulant agents or warfarin. Am 2019;380(14):1326-1335. tion and effectively bypass the intrinsic pathway J Health Syst Pharm. 2019;76(5):275-285. 40. Peled H, Dau NQ, Lau H. Key points to con- in vitro. Blood. 2011;117(1):290-298. 24. Godino C, Melillo F, Rubino F, et al. Real- sider when evaluating Andexxa for formulary 55. Parsons-Rich D, Hua F, Li G, Kantaridis C, world 2-year outcome of atrial fibrillation treat- addition. Neurocrit Care. 2020;33(1):20-24. Pittman DD, Arkin S. Phase 1 dose-escalating ment with dabigatran, apixaban, and rivaroxa- 41. Majeed A, Ågren A, Holmström M, et study to evaluate the safety, pharmacokinet- ban in patients with and without chronic kidney al. Management of rivaroxaban- or apixaban- ics, and pharmacodynamics of a recombinant disease. Intern Emerg Med. 2019;14(8):1259-1270. associated major bleeding with prothrombin factor Xa variant (FXaI16L). J Thromb Haemost. 25. Kattoor AJ, Pothineni NV, Goel A, et al. Pre- complex concentrates: a cohort study. Blood. 2017;15(5):931-937. 2017;130(15):1706-1712. scription patterns and outcomes of patients with 56. Verhoef D, Visscher KM, Vosmeer CR, et atrial fibrillation treated with direct oral anti- 42. Schulman S, Gross PL, Ritchie B, et al. On al. Engineered factor Xa variants retain proco- coagulants and warfarin: a real-world analysis. behalf of the study investigators. Prothrombin agulant activity independent of direct factor Xa J Cardiovasc Pharmacol Ther. 2019;24(5):428-434. complex concentrate for major bleeding on fac- inhibitors. Nat Commun. 2017;8(1):528. 26. Barnes GD, Lucas E, Alexander GC, Gold- tor Xa inhibitors: a prospective cohort study. Thromb Haemost. 2018;118(05):842-851. 57. Centers for Disease Control and Prevention. berger ZD. National trends in ambulatory oral What is venous thromboembolism? 2020. www. anticoagulant use. Am J Med. 2015;128(12):1300. 43. Kcentra [package insert]. CSL Behring LLC, cdc.gov/ncbddd/dvt/facts.html. e2-1305.e2. Kankakee, IL; October 2018. 58. Acute Coronary Syndrome. www.heart.org/ 27. Xu Y, Gomes T, Wells PS, et al. Evaluation 44. Piran S, Khatib R, Schulman S, et al. Manage- en/health-topics/heart-attack/about-heart-attacks/ of definitions for oral anticoagulant-associated ment of direct factor Xa inhibitor-related major acute-coronary-syndrome. major bleeding: a population-based cohort study. bleeding with prothrombin complex concentrate: 59. Centers for Disease Control and Prevention. Blood. 2018;132(Suppl. 1):426-. a meta-analysis. Blood Adv. 2019;3(2):158-167. Stroke signs and symptoms. 2020. www.cdc.gov/ 28. Mehran R, Rao SV, Bhatt DL, et al. Stan- 45. Frontera JA, Bhatt P, Lalchan R, et al. Cost stroke/signs_symptoms.htm. dardized bleeding definitions for cardiovascular comparison of andexanet versus prothrombin Andrea Hafer is a critical care clinical pharmacist at clinical trials: a consensus report from the Bleed- complex concentrates for direct factor Xa Riddle Hospital, Media, Pa. ing Academic Research Consortium. Circulation. inhibitor reversal after hemorrhage. J Thromb Lindsay McCann is a critical care clinical pharmacy 2011;123(23):2736-2747. Thrombolysis. 2020;49(1):121-131. specialist at Bryn Mawr Hospital, Bryn Mawr, Pa. 29. Baugh CW, Levine M, Cornutt D, et al. 46. Witt DM, Nieuwlaat R, Clark NP, et al. The authors have disclosed no financial relationships Anticoagulant reversal strategies in the emer- American Society of Hematology 2018 guide- related to this article. gency department setting: recommendations of a lines for management of venous thromboem- DOI-10.1097/01.CCN.0000718332.38919.36 www.nursingcriticalcare.com November l Nursing2020CriticalCare l 29