Download Article

54 l Nursing2021 l Volume 51, Number 6 www.Nursing2021.com

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

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. In- 41%], dabigatran [n = 245, 39%], Interpreting the severity of a bleed tracranial hemorrhage (ICH) oc- and rivaroxaban [n = 131, 20%]), is critical for appropriate manage- curred in 0.3% to 0.5% of patients, was divided into two subcohorts ment.4 A 2017 American College of which was significantly lower than based on creatinine clearance Cardiology (ACC) task force devel- the warfarin arms.15-18 (See Major (CrCl): chronic kidney disease oped criteria to assess if a bleed is bleeding rates in NVAF trials of (CKD) (CrCl 15–59 mL/min, 219) categorized as major, where one or DOACs.) and non-CKD (CrCl 60–89 mL/ more conditions must be present: In the VTE trials, all DOACs min, 413).24 Those with CKD were • Bleeding in a critical site, defined were compared with a parenteral at higher ischemic and hemor- as intracranial, spinal, intraocular, anticoagulant with a bridge to war- rhagic risk compared with patients thoracic, retroperitoneal, intra- farin.19-22 In the RE-COVER I & II without CKD. Major bleeding, as abdominal, pericardial tamponade, and Hokusai-VTE trials, a paren- defined by the International Society airway (including posterior epistax- teral anticoagulant was used for at for Thrombosis and Haemostasis is), intra-articular, and intramuscular least 5 days prior to starting dabiga- (ISTH), occurred in 5.1% of pa- bleeds. (Intraluminal gastrointestinal tran and edoxaban, respectively.20,21 tients with no significant differ- bleeding is not considered to be a Major bleeding occurred in 0.6% to ences between patients with and critical site, but it may result in he- 1.4% of patients with ICH occur- without CKD.24 modynamic compromise.)

www.Nursing2021.com June l Nursing2021 l 57

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. • Hemodynamic instability, which Bleeding management correction of acidosis and hypother- includes an increased heart rate, a In 2017, the ACC published a con- mia, and blood transfusion if appro- systolic BP (SBP) under 90 mm Hg, a sensus statement regarding the man- priate.4 If a major bleed is considered decrease in SBP greater than 40 mm agement of bleeding in patients on life-threatening or located at a critical Hg, or orthostatic changes (an SBP oral anticoagulation.4 This provides a site, as defined previously, pharma- drop of 20 mm Hg or greater or a useful framework to aid in decision- cologic reversal is recommended. diastolic BP drop of 10 mm Hg or making regarding when to adminis- Timing of last ingestion of the DOAC greater upon standing), mean arterial ter a reversal agent to treat bleeds and renal function also play a critical pressure less than 65 mm Hg or associated with the use of DOACs. role in determining if a reversal agent signs of poor organ perfusion (for For major bleeds, the document rec- is needed versus supportive care example, urine output less than ommends stopping the DOAC, hold- alone.4 Standard coagulation assays 0.5 mL/kg/h). ing antiplatelet therapy if applicable, (such as INR and aPTT) are unreli- • Overt bleeding with hemoglobin and providing supportive care in- able for assessing patients on decreases of 2 g/dL or greater or ad- cluding aggressive volume resuscita- DOACs. Drug-specific anti-Xa assays ministration of 2 or more units of tion, local measures to control bleed- are not readily available and treat- packed red blood cells. ing (such as pressure or packing), ment should not be delayed for a pending result. For major bleeds that do not fall Defining major bleeds into the categories previously men- tioned, supportive care and surgical/ Classification Definition procedural management of the bleed • ≥ ISTH hemoglobin drop of 2 g/dL, are recommended. If these measures (major bleeding) • transfusion of ≥2 units packed red blood cells, fail, pharmacologic reversal may be • symptomatic bleed in a critical area,* or • fatal bleed. considered. In nonmajor bleeds, pharmacologic reversal is generally TIMI • hemoglobin drop of ≥5 g/dL, not recommended. (major bleeding) • ICH, or • fatal bleed. Dabigatran reversal BARC Type 3a Patients presenting with a bleed (type 3 bleeding) • overt bleeding plus hemoglobin drop of 3 to should have dabigatran and other <5 g/dL (provided hemoglobin drop is related to bleed) medications that could contribute to • any transfusion with overt bleeding. bleeding, such as antiplatelet agents, held. If the patient ingested dabiga- Type 3b tran within 2 to 4 hours of presenta- • ≥ overt bleeding plus hemoglobin drop of 5 g/dL tion, charcoal administration may be (provided hemoglobin drop is related to bleed) considered, although data for its use • cardiac tamponade • bleeding requiring surgical intervention for control are sparse and it should be adminis- (excluding dental/nasal/skin/hemorrhoid) tered only to patients with intact • bleeding requiring I.V. vasoactive agents. mental status due to risk of aspira- tion.4,29 Type 3c Idarucizumab is the only ap- • ICH (does not include microbleeds or hemorrhagic proved reversal agent for dabiga- transformation, does include intraspinal) • subcategories confirmed by autopsy or imaging or tran. It first received accelerated lumbar puncture approval in 2015 and now has full 30 • intraocular bleed compromising vision. approval. Idarucizumab is a hu- GUSTO • hemodynamic compromise requiring treatment, manized monoclonal antibody (severe/life- • ICH, or fragment indicated for dabigatran threatening bleeding) • fatal bleed. reversal in patients undergoing

Abbreviations: BARC, Bleeding Academic Research Consortium; GUSTO, Global Use of Strategies to Open emergency surgery/urgent proce- Occluded Arteries; TIMI, Thrombolysis in Myocardial Infarction dures or in the event of a life- *Critical areas include: intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intra- 31 muscular with compartment syndrome. threatening or uncontrolled bleed. Source: Bergmark BA, Kamphuisen PW, Wiviott SD, et al. Comparison of events across bleeding scales in the Although only limited data support ENGAGE AF-TIMI 48 Trial. Circulation. 2019;140(22):1792-1801. additional dosing, if reappearance

58 l Nursing2021 l Volume 51, Number 6 www.Nursing2021.com

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. of clinically relevant bleeding oc- 33 curs, along with re-elevation of co- RE-VERSE AD trial data agulation parameters, a repeat dose Group A (n = 301) Group B (n = 202) may be warranted.31,32 The Reversal Effects of Idaruci- Elevated baseline dTT (%) 244/301 (81.1%) 152/202 (75.2%) zumab on Active Dabigatran Elevated baseline ECT (%) 276/301 (91.7%) 185/202 (91.6%) (RE-VERSE AD) trial was a multi- Primary endpoint (maximum percent reversal within 4 hours of second infusion center prospective cohort study that of idarucizumab) led to the accelerated approval of Median, based on dTT or ECT 100% (95% CI, 100 to 100) 33 idarucizumab. There were two Secondary endpoints groups in this trial: Group A (n = Cessation of bleeding 134/203* (67.7%) N/A 301), which included patients with within 24 hours after Median time to uncontrollable or life-threatening administration of hemostasis: bleeding, and Group B (n = 202), idarucizumab 2.5 hours (95% CI, which included patients who need- 2.2–3.9) ed to undergo surgery or other inva- Normal periprocedural N/A 184/197** (93.4%) sive procedures that could not be hemostasis delayed for at least 8 hours and for *98 patients with intracranial bleeding were excluded because of dissociation between the clinical course which normal hemostasis was re- and the extent of bleeding, quired. In this trial, more than 95% **Procedure was canceled for 5 patients. of patients were receiving dabigatran for stroke prevention for AF. plasma (Group A, 19.3% versus lyzable, but it may be difficult to ob- The median age was 78 years and Group B, 11.9%), 3-factor prothrom- tain dialysis access on a bleeding pa- 43.3% of patients had a CrCl under bin complex concentrate, 4-factor tient. The current cost of idaruci- 50 mL/min. Approximately 62% of PCC (4F-PCC), factor VIIa, or acti- zumab 2.5 g/50 mL from the patients in both Groups A and B vated PCC (Group A, 6.6% versus authors’ institution’s wholesaler is had been treated with dabigatran Group B, 4.0%) and tranexamic acid $2,226, which makes the expense of 110 mg twice daily, which is not a (Group A, 11.6% versus Group B, a 5 g dose $4,452. If idarucizumab is therapeutic dose approved in the 4.0%). The 30-day and 90-day mor- unavailable, PCC or activated PCC US. The median time since the last tality in Group A were 13.5% and may be considered as an off-label dose of dabigatran (reported by the 18.8%, respectively. In Group B, the alternative option.4 patients) was 14.6 hours (Group A) 30-day and 90-day mortality were and 18 hours (Group B). The pri- 12.6% and 18.9%, respectively.33 Apixaban and mary efficacy endpoint was maxi- Some patients may experience a rivaroxaban reversal mum percentage reversal of dTT or re-elevation in coagulation param- Patients taking apixaban or rivar- ECT at any point from the end of eters between 12 and 24 hours after oxaban presenting with a major the first idarucizumab infusion until treatment with idarucizumab. This is bleed that meets criteria for phar- 4 hours after the end of the second most likely due to redistribution of macologic reversal should have infusion. The median maximum unbound dabigatran from the extra- their FXaI held.4 Similar to dabiga- percentage dabigatran reversal was vascular to the intravascular com- tran, charcoal can be administered 100% based on either dTT or ECT. partment.34 A second dose of idaru- if a patient ingested a dose of FXaI Clinical outcomes were secondary cizumab should not be considered within 2 to 4 hours of presenta- endpoints, including the extent of for this group unless there is a con- tion.4,29 There is some controversy bleeding per ISTH criteria for Group comitant bleed.33,35 Anti-idarucizumab regarding the agent of choice for A. (See RE-VERSE AD trial data.) antibodies were found in 28 (5.6%) pharmacologic reversal of the Hemostatic treatment, including of the 501 patients who were as- FXaIs. The two options currently whole blood and blood components, sessed. Of those 28 patients, 19 test- available for reversal are: plasma derivatives, and volume ex- ed positive for preexisting antibodies • coagulation factor Xa (FXa, recom- panders/prohemostatic agents, was before administration, and 9 had an- binant), inactivated-zhzo, also given to 201 (66.8%) patients in tibodies that developed during treat- known as andexanet alfa, the only Group A and 79 (39.1%) patients in ment. The preexisting antibodies agent that is FDA-approved for re- Group B. Specific agents included had no obvious effect on idaruci- versal of apixaban and rivaroxaban, but were not limited to fresh frozen zumab activity.33 Dabigatran is dia- and

www.Nursing2021.com June l Nursing2021 l 59

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. • 4F-PCC, which is used off-label for 41,42,44 reversal of FXaIs. 4F-PCC for reversal of FXaI-related bleeds Andexanet alfa. This modified Majeed, et al. Schulman, et. al. Piran, et al. human FXa decoy protein works by (n = 84) (n = 66) (n = 340) binding and sequestering FXaIs, causing their inactivation. The medi- Study characteristics cation is administered as a bolus 4F-PCC dose ~25 IU/kg 2,000 IU variable followed by a 2-hour infusion. The Patients w/ICH 70.2% 55% 74% dose of andexanet depends on the DOAC taken as well as the time of Effectiveness (ISTH criteria) last ingestion and dose of the Effective 69.1% 68% 69%* DOAC. The half-life of andexanet is Effectiveness for central nervous system bleeds** approximately 1 hour; anti-FXa activity begins to return to baseline Excellent or good not done 76%*** not done levels within 2 hours of infusion Safety outcomes at 30 days completion. Of note, andexanet carries a boxed warning for throm- Thromboembolism 2.4% 7.6% 4% boembolic risks, ischemic risks, Death 32% 14% 16% 36 sudden death, and cardiac arrest. *Only 2 studies analyzed used ISTH criteria. Of the other 8 studies, 77% of patients were deemed to have Andexanet received accelerated effective management of bleeding. **As defined by Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin approval for reversal of rivaroxaban complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234-1243 and modified by Schulman and apixaban in May 2018 based on et al.42 the results of two studies, ANNEXA- ***In an analysis of a subset of 33 patients who had repeat computed tomography (n = 30) or large central nervous system bleeds with early death (n = 3). A and ANNEXA-R, and the interim Source: Reversal agents for factor Xa inhibitors. Vizient. 2018. results of the ANNEXA-4 trial under the condition that a phase IV confir- matory randomized controlled trial than 60 cc, or a thrombotic event expected mortality within 30 days, be completed comparing andexanet within 2 weeks of enrollment were Glasgow Coma Scale score under 7, to the standard of care, PCCs. This excluded. and patients expected to need sur- trial is expected to be completed by In patients receiving apixaban or gery within 12 hours) and the lack October 2022 and submitted by rivaroxaban, the study found a 92% of a control group.40 April 2023.37 Initially, the FDA clini- reduction in anti-FXa levels at the PCCs. Like andexanet, there are cal reviewer and supervisor assigned end of the andexanet infusion, and no randomized placebo-controlled to review andexanet did not recom- among all patients, 82% were judged trials studying PCC for the reversal mend approval of the drug because to have excellent or good hemostatic of FXaI-related bleeds. There have they had concerns over the safety efficacy 12 hours after administration been two prospective cohort trials and efficacy data available. However, of andexanet. Overall, no relation- and a meta-analysis of 4F-PCC for this was overruled by the Director ship between reduction in anti-FXa reversal of FXaI-related bleeds. (See for the Office of Tissues and Ad- levels and hemostatic efficacy could 4F-PCC for reversal of FXaI-related vanced Therapies, who felt there be established. bleeds.) The first trial utilized 4F- could be a clinical benefit.38 Of note, 10% of patients had a PCC at a dose of approximately The ANNEXA-4 trial was an thromboembolic event and 14% 25 IU/kg for apixaban- and open-label, single group study of patients died within the 30-day rivaroxaban-associated major bleeds that included patients with acute follow-up. A postulated mechanism in 84 patients.41 Hemostatic effec- major bleeding who had taken for an increase in thromboembolic tiveness was achieved in 69.1% of apixaban, rivaroxaban, edoxaban, events is that andexanet binds to patients. Thromboembolism oc- or enoxaparin within 18 hours tissue factor pathway inhibitor, an curred in 2.4% of patients. Death of presentation.39 Patients with endogenous anticoagulant protein, occurred in 18% of patients within planned surgery within 12 hours of possibly increasing risk of thrombo- the first week of the major bleed andexanet administration, expected sis. Criticisms of the study design of and 32% of patients within 30 survival of less than 1 month, ICH ANNEXA-4 include the exclusion days. Of the patients who expired + Glasgow Coma Scale score less of patients considered at highest within the first week, 86.7% had than 7 or hematoma volume greater risk of death (including those with ICH.

60 l Nursing2021 l Volume 51, Number 6 www.Nursing2021.com

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. The second trial utilized 4F-PCC projected cost of andexanet, adjusted mularies.40 The results of the phase at a fixed dose of 2,000 IU.42 This for the Medicare NTAP, would be IV randomized control trial com- trial found effective control of $22,120 versus $5,670 for 4F-PCC, paring andexanet to PCC, which is bleeding in 68% of patients overall. while the median hospital payment an FDA requirement as part of the Excellent or good control of bleed- would be only $11,492. Further, approval of andexanet, will provide ing was seen in 76% of a subset of they found that in 74% of cases the more definitive data to guide patients who had repeat computed NTAP-adjusted projected andexanet choice of agent for the reversal tomography (n = 30) or large bleeds cost would exceed total hospital re- of FXaI. resulting in early death (n = 3). imbursement by a median of $7,604. Thromboembolism occurred in The cost of 4F-PCC was found to Resumption of 7.6% of patients and death oc- exceed total hospital reimbursement anticoagulation curred in 14% of patients. Of note, in only 7% of cases at a median of The aforementioned 2017 ACC PCCs carry a boxed warning for $0.45 consensus statement for manage- arterial and venous thromboem- Choice of agent. Several profes- ment of bleeding in patients on bolic complications.43 sional organizations have published oral anticoagulants also provides In addition to these prospective recommendations regarding agent useful guidance on when to re- studies, a meta-analysis of 10 studies of choice for reversal of the FXaIs start anticoagulation following of patients (n = 340) treated with in the setting of major bleeding. a bleeding event.4 It is useful to 4F-PCC has also been completed.44 The 2018 American Society of first reevaluate the indication for Both retrospective and prospective Hematology guideline for manage- anticoagulation and ensure the studies were included in the meta- ment of VTE recommends either patient still requires treatment. If analysis. In the two studies that uti- 4F-PCC or andexanet, both as not, the anticoagulant should be lized ISTH criteria for hemostasis, a “conditional recommendation discontinued. If the patient has 69% of patients were found to based on very low certainty in the continued need for anticoagulation, achieve effective hemostasis. In the evidence about effects.”46 The 2019 several factors should be evaluated other eight studies that used non- American Heart Association (AHA)/ to guide resumption of therapy. If ISTH hemostasis criteria, 77% of pa- ACC/Heart Rhythm Society (HRS) the bleed was not at a critical site, tients had effective hemostasis. Four Focused Update of the 2014 AHA/ the patient is not at high risk of percent of patients experienced VTE, ACC/HRS Guideline for the Man- rebleed or at high risk of death or and 16% of patients died. agement of Patients with Atrial disability with a rebleed, and there It is important to note that pa- Fibrillation states that “andexanet are no immediate invasive proce- tients who would have been exclud- alfa can be useful for the reversal dures planned, anticoagulation ed from ANNEXA-4 were included of rivaroxaban and apixaban” for may be restarted. Depending on in the 4F-PCC studies discussed life-threatening bleeding.47 Later the patient’s clinical status, tempo- above. For example, patients expect- in 2019, the American College of rary management with a parenteral ed to need surgery within 12 hours Emergency Physicians published anticoagulant may be warranted. and those with expected mortality “Anticoagulant Reversal Strategies Delayed resumption of anticoagula- within 30 days were excluded from in the Emergency Department Set- tion should be considered for pa- ANNEXA-4, but that was not part of ting,” which recommends reversal tients with a critical site bleed, high the exclusion criteria for the 4F-PCC of oral FXaIs with andexanet as a risk of rebleeding, or an invasive studies. This makes it difficult, if not “Tier 1” recommendation or PCC procedure planned. impossible, to compare the results of as a “Tier 2” recommendation.29 the ANNEXA-4 to the 4F-PCC trials. Although andexanet is FDA- Pipeline agents Cost considerations. A recent approved only for reversal of apixa- Ciraparantag (PER977). This cost comparison study was pub- ban and rivaroxaban, clinicians may small, water-soluble, cationic, syn- lished examining andexanet versus prescribe it off-label to reverse the thetic molecule binds directly to a 4F-PCC. The authors of the study other oral FXaIs. variety of anticoagulants, including calculated the cost of treatment with Given the lack of a head-to-head unfractionated heparin, LMWH, andexanet, considering the Medicare trial comparing the efficacy and and select DOACs (dabigatran, riva- New Technology Add-On Payment safety of andexanet to 4F-PCC and roxaban, apixaban, edoxaban).48-50 (NTAP) reimbursement for use of the cost associated with andexanet, Ciraparantag is thought to exhibit andexanet, versus the cost of treat- some clinicians challenge the addi- these effects through direct, nonco- ment with PCC. They found that the tion of andexanet to hospital for- valent hydrogen binding, although

www.Nursing2021.com June l Nursing2021 l 61

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. more recent data suggest that its reported adverse reactions were mi- noted 2 to 5 minutes postdose and mechanism in the DOACs may be nor and included facial flushing and returned to baseline within 2 hours. due to binding and modulation of dysgeusia, both of which resolved Increased D-dimer levels were ob- intrinsic factor IXa activity.51,52 shortly after administration of the served at higher doses of FXaI16L 2 Phase I and I/II clinical studies in study drug.49,53 to 4 hours postdose and returned to humans have shown that ciraparan- Factor X (FX) variants: baseline within 24 to 48 hours. PT/ tag completely reverses the antico- FXaI16L and chimeric FX. INR and Factor V activity were not agulant effects of enoxaparin, edoxa- FXaI16L is a human zymogen-like altered following administration of ban, rivaroxaban, and apixa- FX variant, which contains a single FXaI16L. No serious adverse reac- ban.49,50,53 This reversal was found amino acid substitution compared tions were reported, although naso- to be sustained over a 24-hour pe- with endogenous FX. This substitu- pharyngitis and oropharyngeal pain riod for the FXaI, which offers a pos- tion creates an altered active bind- were reported by several volunteers. sible advantage over treatments such ing site and prevents conversion of No neutralizing antibody produc- as andexanet.50,53 Of note, the pres- the molecule from zymogen to pro- tion was observed in any of the ence of sodium citrate, oxalate, tease, increasing its half-life in the volunteers.55 EDTA, or heparin, common chemi- serum and decreasing the potential Various chimeric FX molecules cals used in blood tubes to prevent for excess activation of the clotting have been synthesized by using whole blood coagulation, affects the cascade. It is theorized that in the FX variants found in the venom ciraparantag-anticoagulant complex, presence of Factor Va, which is acti- and liver of elapid snakes. One thus negating the effects of the vated at the site of damaged tissue, molecule, FX-C, has specifically ciraparantag in vitro. In addition, FXaI16L activity is “rescued” and been found to restore thrombin kaolin and celite-based assays, such restored to that of endogenous FX generation in plasma spiked with as the anti-Xa or aPTT tests, are un- only near the site of injury.54 It is apixaban and edoxaban, respec- usable because they bind ciraparan- postulated that these properties tively, without inducing in vitro tag, which reduces the active could make FXaI16L a useful by- hypercoaguability, indicating its concentration and therefore reversal passing agent for treatment of potential as a bypassing agent to effects of ciraparantag in vitro. For bleeds associated with FXaI. reverse FXaI anticoagulation. Ad- these reasons, whole blood clotting FXaI16L was studied in a phase I ditional in vivo studies are needed time is used to study the reversal trial to characterize its pharmacoki- to further elucidate the potential effects of ciraparantag.53 Clinical netic and pharmacodynamic prop- therapeutic application of these studies thus far have not identified erties. Forty-nine healthy male vol- molecules.56 any procoagulant effects of ci- unteers were administered doses raparantag as measured by serum ranging from 0.1 to 5 mcg/kg Nursing considerations D-dimer, prothrombin fragment 1.2, FXaI16L or placebo. Plasma con- Administration. Idarucizumab, and tissue factor pathway inhibitor centrations peaked within 2 to 5 the reversal agent for dabigatran, is concentrations.49,53 minutes postdose and were unde- given I.V. Prior to administration, Ciraparantag is administered via tectable within 40 minutes. Dose- the I.V. line should be flushed with slow I.V. injection.53 Commonly dependent decreases in aPTT were normal saline. It is typically ad-

Signs and symptoms of thromboembolic events*57-59

Deep vein thrombosis Pulmonary embolism Acute coronary syndromes 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 pain/tenderness discomfort or both arms, jaw, or difficulty understanding speech • Redness of • Hemoptysis neck • 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 • Diaphoresis cause

*NOTE: This is not an all-inclusive list

62 l Nursing2021 l Volume 51, Number 6 www.Nursing2021.com

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. Conclusion DOAC reversal summary As DOAC utilization continues to rise, knowledge of emergent reversal DOAC DOAC Reversal agent half-life* administration concerns strategies is paramount. Understand- ing when and how to use pharmaco- Direct thrombin inhibitor logic reversal is critical to successful Dabigatran 12–17 Idarucizumab management of the bleeding patient. • hours Flush line with normal saline pri- (See DOAC reversal summary.) ■ or to infusion • Administer through dedicated line REFERENCES FXaIs 1. Barnes GD, Ageno W, Ansell J, Kaatz S. Recommendation on the nomenclature for oral Apixaban 12 hours Andexanet alfa** anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(6):1154-1156. • Administer with 0.22 micron in- 2. Centers for Disease Control and Prevention. line filter Atrial fibrillation. 2020. www.cdc.gov/ Betrixaban 19–27 • Start infusion within 2 minutes of heartdisease/atrial_fibrillation.htm. hours bolus dose completion 3. Centers for Disease Control and Prevention. Data and statistics on venous thromboembolism. 2020. www.cdc.gov/ncbddd/dvt/data.html. Edoxaban 10–14 4F-PCC† hours • 4. Tomaselli GF, Mahaffey KW, Cuker A, et al. Administer through dedicated line 2017 ACC Expert consensus decision pathway • Blood should not be allowed to on management of bleeding in patients on Rivaroxaban 5–13 hours enter the infusion line as fibrin clot oral anticoagulants: a report of the American College of Cardiology Task Force on Expert may form. Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067. *Half-life may be prolonged in patients with renal impairment **Andexanet alfa is off-label for the reversal of betrixaban and edoxaban 5. Hellenbart EL, Faulkenberg KD, Finks SW. †4F-PCC is off-label for all FXaIs Evaluation of bleeding in patients receiving direct oral anticoagulants. Vasc Health Risk Manag. 2017;13:325-342. 6. Gosselin RC, Adcock DM, Bates SM, et al. ministered as a bolus I.V. injection prescribing clinician notified im- International Council for Standardization or I.V. infusion. Individual institu- mediately, and the reaction treated in Haematology (ICSH) recommendations for laboratory measurement of direct oral tions should have a standardized appropriately. Patients with heredi- anticoagulants. Thromb Haemost. 2018;118(03): method of administration to avoid tary fructose intolerance who have 437-450. confusion. received idarucizumab may due at 7. Connors JM. Testing and monitoring direct oral anticoagulants. . 2018;132(19):2009-2015. I.V. administration of andexanet an increased risk of adverse reac- Blood 8. Gosselin RC, Adcock DM, Douxfils J. An requires use of a 0.22 micron, low tions (such as hypoglycemia, hypo- update on laboratory assessment for direct protein binding, in-line filter. Dosing phosphatemia, metabolic acidosis, oral anticoagulants (DOACs). Int J Lab Hematol. 2019;41(Suppl. 1):33-39. is as an I.V. bolus followed by an I.V. increase in uric acid, acute liver 9. Cate HT, Henskens YM, Lancé MD. Practical infusion, which should be started failure, or death) due to the sorbitol guidance on the use of laboratory testing in the within 2 minutes of the bolus dose. content.31 management of bleeding in patients receiving direct oral anticoagulants. Vasc Health Risk Manag. The rate depends on the dosing Thromboembolic events. Pa- 2017;13:457-467. regimen.36 tients who take anticoagulants 10. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral Administration of 4F-PCC should are at a higher thrombotic risk direct thrombin inhibitor: interpretation of occur through a dedicated I.V. line. It because of their underlying indica- coagulation assays and reversal of anticoagulant is important that blood is not al- tion for anticoagulation. Following activity. Thromb Haemost. 2010;103(06):1116-1127. 11. Samuelson BT, Cuker A. Measurement and lowed to enter the infusion line reversal of any anticoagulant, the reversal of the direct oral anticoagulants. Blood Rev. because a fibrin clot may form.43 risk of thrombosis increases. It is 2017;31(1):77-84. Monitoring. Any of the reversal important to be aware of the signs 12. Jaffer IH, Chan N, Roberts R, Fredenburgh JC, Eikelboom JW, Weitz JI. Comparison of the ecarin agents can cause hypersensitivity and symptoms of thromboembolic chromogenic assay and diluted thrombin time reactions. Signs and symptoms of events (such as deep vein throm- for quantification of dabigatran concentrations. J Thromb Haemost. 2017;15(12):2377-2387. these reactions may include rash, bosis, pulmonary embolism, acute 13. Douxfils J, Dogné J-M, Mullier F, et al. hives, flushing, angioedema, bron- coronary syndromes, and ischemic Comparison of calibrated dilute thrombin time chospasm, wheezing, tachypnea, stroke) and to continually monitor and aPTT tests with LC-MS/MS for the therapeutic monitoring of patients treated with dabigatran hypotension, and nausea or vomit- patients for these events following etexilate. Thromb Haemost. 2013;110(03):543-549. ing. If a serious reaction occurs reversal of anticoagulation. (See 14. Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant during administration, the infu- Signs and symptoms of thromboembolic activity of the non-vitamin K oral anticoagulants. sion should be discontinued, the events.) J Am Coll Cardiol. 2014;64(11):1128-1139. www.Nursing2021.com June l Nursing2021 l 63

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. 15. Granger CB, Alexander JH, McMurray JJV, et sustained reversal of dabigatran. J Thromb Haemost. 49. Ansell JE, Laulicht BE, Bakhru SH, Hoffman al. Apixaban versus warfarin in patients with atrial 2017;15(7):1317-1321. M, Steiner SS, Costin JC. Ciraparantag safely fibrillation. N Engl J Med. 2011;365(11):981-992. 33. Pollack CV, Reilly PA, van Ryn J, et al. and completely reverses the anticoagulant effects 16. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Idarucizumab for dabigatran reversal: full cohort of low molecular weight heparin. Thromb Res. Dabigatran versus warfarin in patients with atrial analysis. N Engl J Med. 2017;377(5):431-441. 2016;146:113-118. fibrillation. N Engl J Med. 2009;361(12):1139-1151. 34. Moia M, Squizzato A. Reversal agents for oral 50. Laulicht B, Bakhru S, Steiner S, Ansell J. 17. Giugliano RP, Ruff CT, Braunwald E, et al. anticoagulant-associated major or life-threatening Ciraparantag safely and effectively reverses Edoxaban versus warfarin in patients with atrial bleeding. Intern Emerg Med. 2019;14(8):1233-1239. apixaban and rivaroxaban in age-matched healthy fibrillation. N Engl J Med. 2013;369(22):2093-2104. volunteers as measured by whole blood clotting 35. Eikelboom JW, Quinlan DJ, van Ryn J, Weitz time. Blood. 2018;132(Suppl. 1):987-987. 18. Patel MR, Mahaffey KW, Garg J, et al. JI. Idarucizumab: the antidote for reversal of Rivaroxaban versus warfarin in nonvalvular atrial dabigatran. Circulation. 2015;132(25):2412-2422. 51. Kalathottukaren MT, Creagh AL, Abbina S, et fibrillation. N Engl J Med. 2011;365(10):883-891. al. Comparison of reversal activity and mechanism 36. Andexxa [package insert]. Portola Pharmaceuti- of action of UHRA, andexanet, and PER977 19. Agnelli G, Buller HR, Cohen A, et al. Oral cals, Inc., San Francisco, CA; 2017. on heparin and oral FXa inhibitors. Blood Adv. apixaban for the treatment of acute venous 37. US Food and Drug Administration. Biologics 2018;2(16):2104–2114. thromboembolism. N Engl J Med. 2013;369(9): License Application Accelerated Approval to Portola 799-808. 52. Laulicht B, Bakhru S, Jiang X, et al. Antidote for Pharmaceuticals, Inc. Silver Spring, MD: FDA Center new oral anticoagulants: mechanism of action and 20. Schulman S, Kakkar AK, Goldhaber SZ, et for Biologics Evaluation and Research; 2018. STN: binding specificity of PER977: AS 47.1. J Thromb al. Treatment of acute venous thromboembolism BL 125586/0. Haemost. 2013;11. with dabigatran or warfarin and pooled analysis. 38. Bryan WW, US Food and Drug Administration. Circulation. 2014;129(7):764-772. 53. Ansell JE, Bakhru SH, Laulicht BE, et al. Single- Memorandum Director, Office of Tissues and Advanced dose ciraparantag safely and completely reverses 21. Büller HR, Décousus H, Grosso MA, et al. Therapies to Portola Pharmaceuticals, Inc. Silver anticoagulant effects of edoxaban. Thromb Haemost. Edoxaban versus warfarin for the treatment of Spring, MD: FDA Director, Office of Tissues and 2017;117(02):238-245. symptomatic venous thromboembolism. N Engl J Advanced Therapies; 2018. BLA 125586/0; Portola; Med. 2013;369(15):1406-1415. ANDEXXA. 54. Bunce MW, Toso R, Camire RM. Zymogen-like factor Xa variants restore thrombin generation and 22. Prins MH, Lensing AW, Bauersachs R, et 39. Connolly SJ, Crowther M, Eikelboom JW, et effectively bypass the intrinsic pathway in vitro. al. Oral rivaroxaban versus standard therapy al. ANNEXA-4 Investigators. Full study report of Blood. 2011;117(1):290-298. for the treatment of symptomatic venous andexanet alfa for bleeding associated with factor thromboembolism: a pooled analysis of the Xa inhibitors. N Engl J Med. 2019;380(14):1326- 55. Parsons-Rich D, Hua F, Li G, Kantaridis C, EINSTEIN-DVT and PE randomized studies. 1335. Pittman DD, Arkin S. Phase 1 dose-escalating Thromb J. 2013;11(1):21. study to evaluate the safety, pharmacokinetics, 40. Peled H, Dau NQ, Lau H. Key points to and pharmacodynamics of a recombinant 23. Datar M, Crivera C, Rozjabek H, et al. consider when evaluating Andexxa for formulary factor Xa variant (FXaI16L). J Thromb Haemost. Comparison of real-world outcomes in patients addition. Neurocrit Care. 2020;33(1):20-24. 2017;15(5):931-937. with nonvalvular atrial fibrillation treated with 41. Majeed A, Ågren A, Holmström M, et al. direct oral anticoagulant agents or warfarin. Am J 56. Verhoef D, Visscher KM, Vosmeer CR, et al. Management of rivaroxaban- or apixaban- Health Syst Pharm. 2019;76(5):275-285. Engineered factor Xa variants retain procoagulant associated major bleeding with prothrombin activity independent of direct factor Xa inhibitors. 24. Godino C, Melillo F, Rubino F, et al. Real-world complex concentrates: a cohort study. Blood. Nat Commun. 2017;8(1):528. 2-year outcome of atrial fibrillation treatment with 2017;130(15):1706-1712. dabigatran, apixaban, and rivaroxaban in patients 57. Centers for Disease Control and Prevention. with and without chronic kidney disease. Intern 42. Schulman S, Gross PL, Ritchie B, et al. On What is venous thromboembolism? 2020. www. Emerg Med. 2019;14(8):1259-1270. behalf of the study investigators. Prothrombin cdc.gov/ncbddd/dvt/facts.html. complex concentrate for major bleeding on factor 25. Kattoor AJ, Pothineni NV, Goel A, et al. Xa inhibitors: a prospective cohort study. Thromb 58.American Heart Association. Acute coronary Prescription patterns and outcomes of patients Haemost. 2018;118(05):842-851. syndrome. www.heart.org/en/health-topics/ with atrial fibrillation treated with direct oral heart-attack/about-heart-attacks/acute-coronary- anticoagulants and warfarin: a real-world analysis. 43. Kcentra [package insert]. CSL Behring LLC, syndrome. Kankakee, IL; October 2018. J Cardiovasc Pharmacol Ther. 2019;24(5):428-434. 59. Centers for Disease Control and Prevention. 26. Barnes GD, Lucas E, Alexander GC, 44. Piran S, Khatib R, Schulman S, et al. Stroke signs and symptoms. 2020. www.cdc.gov/ Goldberger ZD. National trends in ambulatory oral Management of direct factor Xa inhibitor- stroke/signs_symptoms.htm. anticoagulant use. Am J Med. 2015;128(12):1300. related major bleeding with prothrombin e2-1305.e2. complex concentrate: a meta-analysis. Blood Adv. 2019;3(2):158-167. 27. Xu Y, Gomes T, Wells PS, et al. Evaluation of definitions for oral anticoagulant-associated major 45. Frontera JA, Bhatt P, Lalchan R, et al. Cost bleeding: a population-based cohort study. Blood. comparison of andexanet versus prothrombin complex concentrates for direct factor Xa inhibitor Andrea Hafer is a critical care clinical pharmacist at 2018;132(Suppl. 1):426. Riddle Hospital in Media, Pa., and Lindsay McCann reversal after hemorrhage. J Thromb Thrombolysis. is a critical care clinical pharmacy specialist at Bryn 28. Mehran R, Rao SV, Bhatt DL, et al. Standardized 2020;49(1):121-131. bleeding definitions for cardiovascular clinical Mawr Hospital in Bryn Mawr, Pa. trials: a consensus report from the Bleeding 46. Witt DM, Nieuwlaat R, Clark NP, et al. Academic Research Consortium. Circulation. American Society of Hematology 2018 guidelines 2011;123(23):2736-2747. for management of venous thromboembolism: optimal management of anticoagulation therapy. 29. Baugh CW, Levine M, Cornutt D, et al. Blood Adv. 2018;2(22):3257-3291. Anticoagulant reversal strategies in the emergency The authors have disclosed no financial relationships department setting: recommendations of a 47. January CT, Wann LS, Calkins H, et al. 2019 related to this article. multidisciplinary expert panel. Ann Emerg Med. AHA/ACC/HRS focused update of the 2014 2019;S0196-0644(19)31181-31183. AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: a report of 30.Boehringer Ingelheim. FDA provides full the American College of Cardiology/American approval to Praxbind, specific reversal agent for Heart Association Task Force on Clinical Practice Pradaxa. www.boehringer-ingelheim.us/press- Guidelines and the Heart Rhythm Society This article was first published as: Hafer A, McCann release/fda-provides-full-approval-praxbind- in collaboration with the Society of Thoracic L. Direct oral anticoagulant reversal: an update. Nurs specific-reversal-agent-pradaxa. Surgeons. Circulation. 2019;140(2):e125-e151. Crit Care. 2020;15(6):18-29. 31. Praxbind [package insert]. Boehringer 48. Sullivan DW, Gad SC, Laulicht B, Bakhru Ingelheim, Ridgefield, CT; April 2018. S, Steiner S. Nonclinical safety assessment of 32. Simon A, Domanovits H, Ay C, Sengoelge G, PER977: a small molecule reversal agent for new Levy JH, Spiel AO. The recommended dose of oral anticoagulants and heparins. Int J Toxicol. idarucizumab may not always be sufficient for 2015;34(4):308-317. DOI-10.1097/01.NURSE.0000743104.69943.67

64 l Nursing2021 l Volume 51, Number 6 www.Nursing2021.com