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Direct oral anticoagulant reversal

An update

Hafer, Andrea PharmD, BCPS, CACP; McCann, Lindsay PharmD, BCCP

Author Information
doi: 10.1097/01.CCN.0000718332.38919.36
  • Free

Figure
Figure

Anticoagulation is the foundation for the treatment and prevention of thromboembolic events. For over 50 years, warfarin, a vitamin K antagonist (VKA), was the only oral anticoagulant on the market in the US. Since 2010, newer anticoagulants have been approved with various indications. The preferred terminology for these agents is direct oral anticoagulant (DOAC). This has replaced the previous term novel/non-vitamin K oral anticoagulant (NOAC) due to reports of the abbreviation NOAC being misinterpreted to mean no anticoagulation.1 The DOACs include the only oral direct thrombin inhibitor, dabigatran etexilate, as well as factor Xa inhibitors (FXaIs) apixaban, betrixaban, edoxaban, and rivaroxaban.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are among the two most common indications for prescribing an anticoagulant. In the US, AF is estimated to occur in 2.7 to 6.1 million people. Additionally, up to 900,000 people could experience a VTE event.2,3 Effective anticoagulation requires a delicate balance between thrombosis prevention and bleeding prevention. When prescribing these agents, the characteristics of the drug and the patient's risk of bleeding should be assessed. Effective prescribing includes consideration of drug interactions, assessment of ability to adhere to once- versus twice-daily dosing, patient barriers (such as inability to obtain frequent lab draws or financial concerns), and understanding of each agent's pharmacokinetic properties.4 A patient's risk of bleeding can be assessed by using validated scoring systems such as HEMORR2HAGES, HAS-BLED, and ATRIA for AF, and RIETE and CHEST for VTE.5

Monitoring: Coagulation assays

One of the advantages of using a DOAC over warfarin is the lack of monitoring associated with these medications. Although this is advantageous in certain situations, this may also be a limitation when trying to evaluate if reversal is needed. Lab assessments can be either qualitative or quantitative. Qualitative tests, which detect the presence or absence of a drug, include: prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT); whereas quantitative tests show the amount of drug present and include: diluted thrombin time (dTT), ecarin chromogenic assay (ECA), ecarin clotting time (ECT), anti-Xa assay, and liquid chromatography-tandem mass spectrometry (LC-MS/MS).6

Qualitative assays. DOACs may prolong the PT in a concentration-dependent manner, but this varies based on reagents used.7 The PT is less sensitive to dabigatran than the aPTT. PT can be expressed as an international normalized ratio (INR) for patients receiving VKAs; however, PTs should not be expressed as INRs for patients receiving DOACs because the international sensitivity index is not based on DOAC sensitivity. In general, dabigatran normally prolongs the aPTT more than the PT while FXaIs tend to prolong the PT more than the aPTT.8 However, normal PT levels may still result while on an FXaI depending on the sensitivity of the reagent used.

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ARISTOTLE RE-LY ENGAGE AF-TIMI 48 ROCKET AF
HR (95% CI) RR (95% CI) HR (95% CI) HR (95% CI)
Apixaban Warfarin Dabigatran 150 mg Warfarin Edoxaban 60 mg Warfarin Rivaroxaban Warfarin
Major bleeding 2.13% 3.09% 3.11% 3.36% 2.75% 3.43% 3.6% 3.4%
0.69 (0.60-0.80) P < .001 0.93 (0.81-1.07) P = .31 0.80 (0.71-0.91) P < .001 1.04 (0.90-1.20) 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) P < .001 0.40 (0.27-0.60) P < .001 0.47 (0.34-0.63) P < .001 0.67 (0.47-0.93) 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) P = .37 1.50 (1.19-1.89) P < .001 1.23 (1.02-1.50) P = .03 P < .001
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.

The aPTT is prolonged in the presence of dabigatran and exhibits a concentration-response curve that flattens at higher concentrations (≥200 ng/mL).9 It can be useful in determining supratherapeutic levels of dabigatran, but the aPTT should be evaluated with caution as a normal value may result despite presence of dabigatran.7,10

TT directly measures thrombin activity and therefore, is highly sensitive to dabigatran. A normal TT suggests that little or no dabigatran is present, but an elevated TT does not necessarily mean there is a high dabigatran concentration.11

Quantitative assays. dTT is a clot-based assay that correlates with dabigatran concentrations measured by mass spectrometry.12 The use of diluted plasma allows a wider range of dabigatran concentrations to be measured.13

Anti-Xa assays are chromogenic assays that are calibrated to detect either unfractionated heparin (UFH)/low molecular weight heparin (LMWH) or a specific FXaI. When calibrated to detect heparin or LMWH, this assay is considered qualitative for the evaluation of DOAC levels. However, if the assay is calibrated specific to one of the FXaIs, the assay is considered quantitative and will provide a linear concentration-dependent relationship.7

Ecarin-based assays include ECT and ECA. Ecarin is a snake venom that cleaves prothrombin to form meizothrombin, which is an intermediate of thrombin.7,14 These assays are sensitive to dabigatran but limited due to lack of standardization among different lots.14

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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)0.31 (0.17-0.55) P < .001 HR (95% CI)0.73 (0.48-1.11) HR (95% CI)0.84 (0.59-1.21) P = .35 HR (95% CI)0.54 (0.37-0.79) 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 degree of specificity, sensitivity, selectivity, and reproducibility, and is considered the gold standard method for DOAC measurement.6 It is often used to assess pharmacokinetics of DOACs in clinical development, but is not practical for clinical lab use.6,7 Many institutions may not have quantitative assays available or the results are not immediately available, which limits their use in the early assessment of a critical bleed.

Bleeding data

Bleeding data for the DOACs can be extrapolated from clinical trials as well as real world statistics. Unfortunately, there are no head-to-head trials between the DOACs, so bleeding data from the trials cannot be directly compared. Randomized clinical trials that evaluated the DOACs for the prevention of stroke and systemic embolism in nonvalvular AF (NVAF) were compared with warfarin targeted to an INR of 2.0 to 3.0.15-18 It is important to note that the CHADS2 scores and time in therapeutic range differed in each NVAF trial. Major bleeding among DOACs occurred in 2.13% to 3.6% of patients with NVAF. Intracranial hemorrhage occurred in about 0.3% to 0.5% of patients, which was significantly lower than the warfarin arms.15-18 (See Major bleeding rates in NVAF trials of DOACs.)

In the VTE trials, all DOACs were compared with a parenteral anticoagulant with a bridge to warfarin.19-22 In the RE-COVER I & II and Hokusai-VTE trials, a parenteral anticoagulant was used for at least 5 days prior to starting dabigatran and edoxaban, respectively.20,21 Major bleeding occurred in 0.6% to 1.4% of patients with intracranial hemorrhage (ICH) occurring at a lesser frequency. (See Major bleeding rates in VTE trials of DOACs.)

Datar and colleagues evaluated over 16,000 patients with AF receiving DOACs (n = 8,227) versus those receiving warfarin (n = 8,227). In this study, the bleeding risk was assessed by the Cunningham algorithm and bleeding occurred in 81 (0.98%) patients on DOACs versus 72 (0.87%) patients on warfarin and was not statistically significant (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.71-1.01).23

The INSigHT registry, which evaluated patients receiving DOACs for NVAF [apixaban (n = 256, 41%), dabigatran (n = 245, 39%), and rivaroxaban (n = 131, 20%)], was divided into two subcohorts based on creatinine clearance (CrCl): (1) chronic kidney disease (CKD) (CrCl 15-59 mL/min, 219) and (2) non-CKD (CrCl 60-89 mL/min, 413).24 Those with CKD were at higher ischemic and hemorrhagic risk, compared to patients without CKD. Major bleeding, as defined by the International Society for Thrombosis and Haemostasis (ISTH), occurred in 5.1% of patients with no significant differences between patients with and without CKD.24

National data show that the rate of anticoagulant prescribing is rising; specifically, use of the DOACs is increasing compared with warfarin.25,26 This increase in DOAC use makes it extremely important that critical care nurses understand when and how to effectively reverse the anticoagulant effect.

Categorizing a major bleed

There are different classification systems used to define major bleeding. (See Defining major bleeds.) ISTH criteria are used to standardize the definition of major bleeding in clinical trials for nonsurgical patients.27,28

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Classification Definition
ISTH (major bleeding)
  • hemoglobin drop of ≥2 g/dL,

  • transfusion of ≥2 units pRBCs,

  • symptomatic bleed in a critical area, or

  • fatal bleed.

TIMI (major bleeding)
  • hemoglobin drop of ≥5 g/dL,

  • intracranial hemorrhage, or

  • fatal bleed.

BARC (Type 3 bleeding) Type 3a
  • overt bleeding plus hemoglobin drop of 3 to <5 g/dL (provided hemoglobin drop is related to bleed)

  • any transfusion with overt bleeding.

Type 3b
  • overt bleeding plus hemoglobin drop ≥5 g/dL (provided hemoglobin drop is related to bleed)

  • cardiac tamponade

  • bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid)

  • bleeding requiring I.V. vasoactive agents.

Type 3c

  • intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal)

  • subcategories confirmed by autopsy or imaging or lumbar puncture

  • intraocular bleed compromising vision.

GUSTO (severe/life-threatening bleeding)
  • Hemodynamic compromise requiring treatment,

  • intracranial hemorrhage, or

  • fatal bleed.

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 blood cells; TIMI, Thrombolysis in Myocardial Infarction
Critical areas include: intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome.
Source: Bergmark BA, Kamphuisen PW, Wiviott SD, et al. Comparison of events across bleeding scales in the ENGAGE AF-TIMI 48 Trial. Circulation. 2019;140(22):1792-1801.

Interpreting the severity of a bleed is critical for appropriate management.4 A 2017 American College of Cardiology (ACC) task force developed criteria to assess if a bleed is categorized as major, where one or more conditions must be present:

  • Bleeding in a critical site, defined as intracranial, spinal, intraocular, thoracic, retroperitoneal, intra-abdominal, pericardial tamponade, airway (including posterior epistaxis), intra-articular, and intramuscular bleeds (Intraluminal gastrointestinal bleeding is not considered to be a critical site, but it may result in hemodynamic compromise.)
  • Hemodynamic instability, which includes: an increased heart rate, a systolic blood pressure (SBP) <90 mm Hg, a decrease in SBP >40 mm Hg, or orthostatic changes (SBP drop ≥20 mm Hg or a diastolic blood pressure drop ≥10 mm Hg upon standing), mean arterial pressure <65 mm Hg or signs of poor organ perfusion (for example, urine output <0.5 mL/kg/h)
  • overt bleeding with hemoglobin decreases of ≥2 g/dL or administration of ≥2 units of packed red blood cells.

Bleeding management

In 2017, the ACC published a consensus statement regarding the management of bleeding in patients on oral anticoagulation.4 This provides a useful framework to aid in decision-making regarding when to administer a reversal agent to treat bleeds associated with the use of the DOACs. For major bleeds, the document recommends stopping the DOAC, holding antiplatelet therapy if applicable, and providing supportive care including aggressive volume resuscitation, local measures to control bleeding (such as pressure or packing), correction of acidosis and hypothermia, and blood transfusion if appropriate.4 If a major bleed is considered life-threatening or located at a critical site, as defined previously, pharmacologic reversal is recommended. Timing of last ingestion of the DOAC and renal function also play a critical role in determining if a reversal agent is needed versus supportive care alone.4 Standard coagulation assays (such as INR and aPTT) are unreliable for assessing patients on DOACs. Drug-specific anti-Xa assays are not readily available and treatment should not be delayed for a pending result.

For major bleeds that do not fall into the categories previously mentioned, supportive care and surgical/procedural management of the bleed are recommended. If these measures fail, pharmacologic reversal may be considered. In nonmajor bleeds, pharmacologic reversal is generally not recommended.

Dabigatran reversal

Patients presenting with a bleed should have dabigatran and other medications that could contribute to bleeding, such as antiplatelet agents, held. If the patient ingested dabigatran within 2 to 4 hours of presentation, charcoal administration may be considered although data for its use are sparse and it should only be administered for patients with intact mental status due to risk of aspiration.4,29

Idarucizumab is the only approved reversal agent for dabigatran. It first received accelerated approval in 2015 and now has full approval.30 Idarucizumab is a humanized monoclonal antibody fragment indicated for dabigatran reversal in patients undergoing emergency surgery/urgent procedures or in the event of a life-threatening or uncontrolled bleed.31 Although only limited data support additional dosing, if reappearance of clinically relevant bleeding occurs, along with reelevation of coagulation parameters, a repeat dose may be warranted.31,32 The Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) trial was a multicenter prospective cohort study that led to the accelerated approval of idarucizumab.33 There were two groups in this trial: Group A (n = 301), which included patients with uncontrollable or life-threatening bleeding, and Group B (n = 202), which included patients who needed to undergo surgery or other invasive procedures that could not be delayed for at least 8 hours and for which normal hemostasis was required. In this trial, more than 95% of patients were receiving dabigatran for stroke prevention for AF. The median age was 78 years and 43.3% of patients had a CrCl <50 mL/min. Approximately 62% of patients in both Groups A and B had been treated with dabigatran 110 mg twice daily, which is not a therapeutic dose approved in the US. The median time since the last dose of dabigatran (reported by the patients) was 14.6 hours (Group A) and 18 hours (Group B). The primary efficacy end point was maximum percentage reversal of dTT or ECT at any point from the end of the first idarucizumab infusion until 4 hours after the end of the second infusion. The median maximum percentage dabigatran reversal was 100% (95% CI: 100,100) based on either dTT or ECT. Clinical outcomes were secondary end points, including the extent of bleeding per ISTH criteria for Group A. (See RE-VERSE AD trial data.)

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Group A (n = 301) Group B (n = 202)
Elevated baseline dTT (%) 244/301 (81.1%) 152/202 (75.2%)
Elevated baseline ECT (%) 276/301 (91.7%) 185/202 (91.6%)
Primary Endpoint (maximum percent reversal within 4 hours of 2nd infusion of idarucizumab)
Median, based on dTT or ECT 100% (95% CI, 100 to 100)
Secondary Endpoints
Cessation of bleeding within 24 hours after administration of idarucizumab 134/203(67.7%)
  1. Median time to hemostasis:

  2. 2.5 hours (95% CI, 2.2 to 3.9)

NA
Normal periprocedural hemostasis NA 184/197∗∗ (93.4%)
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 course and the extent of bleeding,
∗∗Procedure was canceled for 5 patients.

Hemostatic treatment, including whole blood and blood components, plasma derivatives, and volume expanders/prohemostatic agents was given to 201 (66.8%) patients in Group A and 79 (39.1%) patients in Group B. Specific agents included but were not limited to fresh frozen plasma (Group A, 19.3%, versus Group B, 11.9%), 3-factor prothrombin complex concentrate (3F-PCC), 4-factor PCC (4F-PCC), factor VIIa (FVIIa), or activated PCC (aPCC) (Group A, 6.6%, versus Group B, 4.0%) and tranexamic acid (Group A, 11.6%, versus Group B, 4.0%). The 30-day and 90-day mortality in Group A were 13.5% and 18.8%, respectively. In Group B, the 30-day and 90-day mortality were 12.6% and 18.9%, respectively.33

Some patients may experience a reelevation in coagulation parameters between 12 and 24 hours after treatment with idarucizumab. This is most likely due to redistribution of unbound dabigatran from the extravascular to the intravascular compartment.34 A second dose of idarucizumab should not be considered for this group unless there is a concomitant bleed.33,35 Anti-idarucizumab antibodies were found in 28 (5.6%) of the 501 patients who were assessed. Of those 28 patients, 19 tested positive for preexisting antibodies before administration, and 9 had antibodies that developed during treatment. The preexisting antibodies had no obvious effect on idarucizumab activity.33 Dabigatran is dialyzable, however it may be difficult to obtain dialysis access on a bleeding patient. The current cost of idarucizumab 2.5 g/50 mL from our institution's wholesaler is $2,226, which makes the expense of a 5 g dose $4,452. If idarucizumab is unavailable, PCC or aPCC may be considered as an off-label alternative option.4

Apixaban and rivaroxaban reversal

Patients taking apixaban or rivaroxaban presenting with a major bleed that meets criteria for pharmacologic reversal should have their FXaI held.4 Similar to dabigatran, charcoal can be administered if a patient ingested a dose of FXaI within 2 to 4 hours of presentation.4,29 There is some controversy regarding the agent of choice for pharmacologic reversal of the FXaIs. The two options currently available for reversal are:

  • coagulation factor Xa (recombinant), inactivated-zhzo, also known as andexanet alfa, the only agent that is FDA-approved for reversal of apixaban and rivaroxaban, and
  • 4F-PCC, which is used off-label for reversal of FXaIs.

Andexanet alfa. Andexanet alfa is a modified human factor Xa decoy protein that works by binding and sequestering FXaIs, causing their inactivation. The medication is administered as a bolus followed by a 2-hour infusion. The dose of andexanet depends on the DOAC taken as well as the time of last ingestion and dose of the DOAC. The half-life of andexanet is approximately 1 hour; antifactor Xa activity begins to return to baseline levels within 2 hours of infusion completion. Of note, andexanet carries a boxed warning for thromboembolic risks, ischemic risks, sudden death, and cardiac arrest.36

Andexanet received accelerated approval for reversal of rivaroxaban and apixaban in May 2018 based on the results of two studies, ANNEXA-A and ANNEXA-R, and the interim results of the ANNEXA-4 trial under the condition that a phase 4 confirmatory randomized controlled trial (RCT) be completed comparing andexanet to the standard of care, PCCs. This trial is expected to be completed by October 2022 and submitted by April 2023.37 Initially, the FDA clinical reviewer and supervisor assigned to review andexanet did not recommend approval of the drug because they had concerns over the safety and efficacy data available. However, this was overruled by the Director for the Office of Tissues and Advanced Therapies, who felt there could be a clinical benefit.38

The ANNEXA-4 trial was an open-label, single group study that included patients with acute major bleeding who had taken apixaban, rivaroxaban, edoxaban, or enoxaparin within 18 hours of presentation.39 Patients with planned surgery within 12 hours of andexanet administration, expected survival of less than 1 month, ICH + Glasgow Coma Scale score <7 or hematoma volume >60 cc, or a thrombotic event within 2 weeks of enrollment were excluded.

In patients receiving apixaban or rivaroxaban, the study found a 92% reduction in antifactor Xa levels at the end of the andexanet infusion, and among all patients, 82% were judged to have excellent or good hemostatic efficacy 12 hours after administration of andexanet. Overall, no relationship between reduction in antifactor Xa levels and hemostatic efficacy could be established. Of note, 10% of patients had a thromboembolic event and 14% of patients died within the 30-day follow-up. A postulated mechanism for an increase in thromboembolic events is that andexanet binds to tissue factor pathway inhibitor, an endogenous anticoagulant protein, possibly increasing risk of thrombosis. Criticisms of the study design of ANNEXA-4 include the exclusion of patients considered at highest risk of death, including those with expected mortality within 30 days, Glasgow Coma Scale score <7, and patients expected to need surgery within 12 hours, and the lack of a control group.40

PCCs. Like andexanet, there are no randomized placebo-controlled trials studying PCC for the reversal of FXaI-related bleeds. There have been two prospective cohort trials and a meta-analysis of 4F-PCC for reversal of FXaI-related bleeds. (See 4F-PCC for reversal of FXaI-related bleeds.) The first trial utilized 4F-PCC at a dose of approximately 25 IU/kg for apixaban- and rivaroxaban-associated major bleeds in 84 patients.41 Hemostatic effectiveness was achieved in 69.1% of patients. Thromboembolism occurred in 2.4% of patients. Death occurred in 18% of patients within the first week of the major bleed and 32% of patients within 30 days. Of the patients who expired within the first week, 86.7% had ICH. The second trial utilized 4F-PCC at a fixed dose of 2,000 IU.42 This trial found effective control of bleeding in 68% of patients overall. Excellent or good control of bleeding was seen in 76% of a subset of patients who had repeat computed tomography (n = 30) or large bleeds resulting in early death (n = 3). Thromboembolism occurred in 7.6% of patients and death occurred in 14% of patients. Of note, PCCs carry a boxed warning for arterial and venous thromboembolic complications.43

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Majeed, et al (N = 84) Schulman, et al (N = 66) Piran, et al (N = 340)
Study Characteristics
4F-PCC dose ~25 IU/kg 2,000 IU variable
Patients w/ICH 70.2% 55% 74%
Effectiveness (ISTH criteria)
Effective 69.1% 68% 69%
Effectiveness for CNS bleeds∗∗
Excellent or Good Not done 76%∗∗∗ Not done
Safety Outcomes at 30 Days
Thromboembolism 2.4% 7.6% 4%
Death 32% 14% 16%
Only 2 studies analyzed used ISTH criteria. Of the other 8 studies, 77% of patients were deemed to 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 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 et al.42
∗∗∗In an analysis of a subset of 33 patients who had repeat computed tomography (n = 30) or large CNS bleeds with early death (n = 3).
Abbreviations: CNS, central nervous system; ISTH, International Society on Thrombosis and Haemostasis; ICH, intracranial hemorrhage
Source: Reversal agents for factor Xa inhibitors. Vizient. 2018.

In addition to these prospective studies, a meta-analysis of 10 studies of patients (N = 340) treated with 4F-PCC has also been completed.44 Both retrospective and prospective studies were included in the meta-analysis. In the two studies that utilized ISTH criteria for hemostasis, 69% of patients were found to achieve effective hemostasis. In the other eight studies which used non-ISTH hemostasis criteria, 77% of patients had effective hemostasis. Four percent of patients experienced VTE, and 16% of patients died.

It is important to note that patients who would have been excluded from ANNEXA-4 were included in the 4F-PCC studies discussed above. For example, patients expected to need surgery within 12 hours and those with expected mortality within 30 days were excluded from ANNEXA-4, however that was not part of the exclusion criteria for the 4F-PCC studies. This makes it difficult, if not impossible, to compare the results of the ANNEXA-4 to the 4F-PCC trials.

Cost considerations. A recent cost comparison study was published examining andexanet versus 4F-PCC. The authors of the study calculated the cost of treatment with andexanet, considering the Medicare New Technology Add-On Payment (NTAP) reimbursement for use of andexanet, versus the cost of treatment with PCC. They found that the projected cost of andexanet, adjusted for the Medicare NTAP, would be $22,120 versus $5,670 for 4F-PCC, while the median hospital payment would be only $11,492. Further, they found that in 74% of cases the NTAP-adjusted projected andexanet cost would exceed total hospital reimbursement by a median of $7,604. The cost of 4F-PCC was found to exceed total hospital reimbursement in only 7% of cases at a median of $0.45

Choice of agent. Several professional organizations have published recommendations regarding agent of choice for reversal of the FXaIs in the setting of major bleeding. The 2018 American Society of Hematology guideline for management of VTE recommends either 4F-PCC or andexanet, both as a “conditional recommendation based on very low certainty in the evidence about effects.”46 The 2019 American Heart Association (AHA)/ACC/Heart Rhythm Society (HRS) Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation states that “andexanet alfa can be useful for the reversal of rivaroxaban and apixaban” for life-threatening bleeding.47 Later in 2019, the American College of Emergency Physicians published “Anticoagulant Reversal Strategies in the Emergency Department Setting,” which recommends reversal of oral FXaIs with andexanet as a “Tier 1” recommendation or PCC as a “Tier 2” recommendation.29 Although andexanet is only FDA-approved for reversal of apixaban and rivaroxaban, clinicians may prescribe it off-label to reverse the other oral FXaIs.

Given the lack of a head-to-head trial comparing the efficacy and safety of andexanet to 4F-PCC and the cost associated with andexanet, some clinicians challenge the addition of andexanet to hospital formularies.40 The results of the phase 4 RCT comparing andexanet to PCC, which is an FDA requirement as part of the approval of andexanet, will provide more definitive data to guide choice of agent for the reversal of FXaI.

Resumption of anticoagulation

The aforementioned 2017 ACC consensus statement for management of bleeding in patients on oral anticoagulants also provides useful guidance on when to restart anticoagulation following a bleeding event.4 It is useful to first reevaluate the indication for anticoagulation and ensure the patient still requires treatment. If not, the anticoagulant should be discontinued. If the patient does have continued need for anticoagulation, several factors should be evaluated to guide resumption of therapy. If the bleed was not at a critical site, patient is not at high risk of rebleed or at high risk of death or disability with a rebleed, and there are no immediate invasive procedures planned, anticoagulation may be restarted. Depending on the clinical status of the patient, temporary management with a parenteral anticoagulant may be warranted. Delayed resumption of anticoagulation should be considered for patients with a critical site bleed, high risk of rebleeding, or an invasive procedure planned.

Pipeline agents

Ciraparantag (PER977). Ciraparantag is a small, water-soluble, cationic, synthetic molecule that binds directly to a variety of anticoagulants, including UFH, LMWH, and select DOACs (dabigatran, rivaroxaban, apixaban, edoxaban).48-50 Ciraparantag is thought to exhibit these effects through direct, noncovalent hydrogen binding, although more recent data suggest that its mechanism in the DOACs may be due to binding and modulation of intrinsic factor IXa activity.51,52

Phase 1 and 1/2 clinical studies in humans have shown that ciraparantag completely reverses the anticoagulant effects of enoxaparin, edoxaban, rivaroxaban, and apixaban.49,50,53 This reversal was found to be sustained over a 24-hour time period for the FXaI, which offers a possible advantage over treatments such as andexanet.50,53 Of note, the presence of sodium citrate, oxalate, EDTA, or heparin, common chemicals used in blood tubes to prevent whole blood coagulation, affects the ciraparantag-anticoagulant complex, thus negating the effects of the ciraparantag in vitro. In addition, kaolin and celite-based assays, such as the anti-Xa or aPTT tests, are unusable because they bind ciraparantag, which reduces the active concentration and therefore reversal effects of ciraparantag in vitro. For these reasons, whole blood clotting time is used to study the reversal effects of ciraparantag.53 Clinical studies thus far have not identified any procoagulant effects of ciraparantag as measured by serum D-dimer, prothrombin fragment 1.2, and tissue factor pathway inhibitor concentrations.49,53

Ciraparantag is administered via slow I.V. injection.53 Commonly reported adverse reactions were minor and included facial flushing and dysgeusia, both of which resolved shortly after administration of the study drug.49,53

Factor X (FX) variants: FXaI16L and chimeric FX. FXaI16L is a human zymogen-like FX variant, which contains a single amino acid substitution compared with endogenous FX. This substitution creates an altered active binding site and prevents conversion of the molecule from zymogen to protease, thus increasing its half-life in the serum and decreasing the potential for excess activation of the clotting cascade. It is theorized that in the presence of FVa, which is activated at the site of damaged tissue, FXaI16L activity is “rescued” and restored to that of endogenous FX only near the site of injury.54 It is postulated that these properties could make FXaI16L a useful bypassing agent for treatment of bleeds associated with FXaI.

FXaI16L was studied in a phase 1 trial to characterize its pharmacokinetic and pharmacodynamic properties. Forty-nine healthy male volunteers were administered doses ranging from 0.1-5 mcg/kg FXaI16L or placebo. Plasma concentrations peaked within 2 to 5 minutes postdose and were undetectable within 40 minutes. Dose-dependent decreases in aPTT were noted 2 to 5 minutes postdose and returned to baseline within 2 hours. Increased D-dimer levels were observed at higher doses of FXaI16L 2 to 4 hours postdose and returned to baseline within 24 to 48 hours. PT/INR and Factor V (FV) activity were not altered following administration of FXaI16L. No serious adverse events were reported, although nasopharyngitis and oropharyngeal pain were reported by several volunteers. No neutralizing antibody production was observed in any of the volunteers.55

Various chimeric FX molecules have been synthesized by using FX variants found in the venom and liver of Elapid snakes. One molecule, FX-C, has specifically been found to restore thrombin generation in plasma spiked with apixaban and edoxaban, respectively, without inducing in vitro hypercoaguability, indicating its potential as a bypassing agent to reverse FXaI anticoagulation. Further in-vivo studies are needed to further elucidate the potential therapeutic application of these molecules.56

Nursing considerations

Administration. Idarucizumab is the reversal agent for dabigatran and it is given intravenously. Prior to administration, the I.V. line should be flushed with normal saline. Dosing is typically as a bolus I.V. injection or as an I.V. infusion. Individual institutions should have a standardized method of administration, to avoid confusion.

I.V. administration of andexanet requires use of a 0.22 micron, low protein binding, in-line filter. Dosing is as an I.V. bolus followed by an I.V. infusion, which should be started within 2 minutes of the bolus dose. The rate depends on the dosing regimen.36

Administration of 4F-PCC should occur through a dedicated I.V. line. It is important that blood is not allowed to enter the infusion line as fibrin clot may form.43

Monitoring. Hypersensitivity reactions. Any of the reversal agents can cause hypersensitivity reactions. Signs and symptoms of these reactions may include rash, hives, flushing, angioedema, bronchospasm, wheezing, tachypnea, hypotension, and nausea or vomiting. If a serious reaction occurs during administration, the infusion should be discontinued, the prescribing clinician should be notified immediately, and the reaction should be treated appropriately. Patients with hereditary fructose intolerance who have received idarucizumab may due at an increased risk of adverse reactions (such as hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure, or death) due to the sorbitol content.31

Thromboembolic events. Patients who take anticoagulants are at a higher thrombotic risk because of their underlying indication for anticoagulation. Following reversal of any anticoagulant, the risk of thrombosis increases. It is important for critical care nurses to be aware of the signs and symptoms of thromboembolic events (such as deep vein thrombosis, pulmonary embolism, acute coronary syndrome, and ischemic stroke) and to continually monitor patients for these events following reversal of anticoagulation. (See Signs and symptoms of thromboembolic events.)

-
DVT PE ACS Stroke
  • Extremity swelling

  • Extremity pain/tenderness

  • Redness of the skin

  • Dyspnea

  • Tachycardia

  • Chest pain/discomfort

  • Hemoptysis

  • Hypotension

  • Lightheadedness

  • Syncope

  • Dyspnea

  • Chest pain/pressure

  • Pain or discomfort in one or both arms, jaw, neck, back, or stomach

  • Dizziness or lightheadedness

  • Nausea

  • Sweating

  • Sudden numbness or weakness in the face, arm, or leg, especially on one side of the body

  • Sudden confusion, trouble speaking, or difficulty understanding speech

  • Sudden trouble seeing in one or both eyes

  • Sudden trouble walking, dizziness, loss of balance, or lack of coordination

  • Sudden severe headache with no known cause

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

-
DOAC DOAC half-life Reversal agent administration concerns
Direct thrombin inhibitor
Dabigatran (Pradaxa) 12-17 hours Idarucizumab (Praxbind)
• Flush line with normal saline prior to infusion
• Administer through dedicated line
Factor Xa inhibitors
Apixaban (Eliquis) 12 hours Andexanet alfa (Andexxa)∗∗
• Administer with 0.22 micron in-line filter
Betrixaban (Bevyxxa) 19-27 hours • Start infusion within 2 minutes of bolus dose completion
Edoxaban (Savaysa) 10-14 hours 4F-PCC (Kcentra)
• Administer through dedicated line
Rivaroxaban (Xarelto) 5-13 hours • Blood should not be allowed to enter the infusion line as fibrin clot may form.
Half-life—may be prolonged in patients with renal impairment
∗∗Andexanet alfa is off-label for the reversal of betrixaban and edoxaban
4F-PCC is off-label for all FXaIs

Conclusion

In conclusion, as DOAC utilization continues to rise, knowledge of emergent reversal strategies is paramount. Understanding when and how to use pharmacologic reversal is critical to successful management of the bleeding patient. (See DOAC reversal summary.)

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        Keywords:

        andexanet alfa; direct oral anticoagulant (DOAC); idarucizumab; prothrombin complex concentrate (PCC); reversal

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