Strategies for urgent reversal of target-specific oral anticoagulants.

Hospital Practice

ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20

Strategies for Urgent Reversal of Target-Specific Oral Anticoagulants Estella M. Davis PharmD, BCPS , Erin M. Uhlmeyer PharmD , David P. Schmidt PharmD, BCPS & Greg L. Schardt PharmD, BCPS To cite this article: Estella M. Davis PharmD, BCPS , Erin M. Uhlmeyer PharmD , David P. Schmidt PharmD, BCPS & Greg L. Schardt PharmD, BCPS (2014) Strategies for Urgent Reversal of Target-Specific Oral Anticoagulants, Hospital Practice, 42:5, 108-125 To link to this article: http://dx.doi.org/10.3810/hp.2014.12.1164

Published online: 30 Jun 2015.

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Date: 06 November 2015, At: 20:12

C L I N I C A L F E AT U R E S

Strategies for Urgent Reversal of Target-Specific Oral Anticoagulants

Downloaded by [University of Cambridge] at 20:12 06 November 2015

DOI: 10.3810/hp.2014.12.1164

Estella M. Davis, PharmD, BCPS 1,2 Erin M. Uhlmeyer, PharmD 2 David P. Schmidt, PharmD, BCPS 2,3 Greg L. Schardt, PharmD, BCPS 2,4 1 Associate Professor of Pharmacy Practice, Creighton University School of Pharmacy and Health Professions, Omaha, NE; 2Clinical Pharmacist, CHI Health-Bergan Mercy, Omaha, NE; 3System Clinical Pharmacy Coordinator, CHI Health, Omaha, NE; 4Pharmacy Manager, CHI HealthBergan Mercy, Omaha, NE

Abstract: The direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban are US Food and Drug Administration (FDA)-approved target-specific oral anticoagulants (TSOACs) that have emerged onto the market for use in some indications similar to those for warfarin; in addition, edoxaban is seeking FDA approval. Similar indications include reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation for all 3 agents, for the prevention of deep vein thrombosis that may lead to pulmonary embolism in patients undergoing hip or knee surgery for rivaroxaban and apixaban, and for the treatment and prevention of deep vein thrombosis and pulmonary embolism. As anticoagulants, they are all associated with a risk of bleeding, and, unfortunately, there are no approved antidotes for reversal of these agents. A number of small studies in human subjects and in human/animal models exposed to TSOACs have evaluated the use of activated charcoal, hemodialysis for dabigatran, or clotting factor concentrates for their ability to neutralize the anticoagulant effects or reduce drug concentrations of TSOACs. Clotting factor concentrates that have been used include prothrombin complex concentrates and recombinant factor VII. This review examines studies and case reports evaluating these strategies for expedited or emergent reversal of TSOACs. Keywords: dabigatran; rivaroxaban; apixaban; edoxaban; reversal; bleeding

Introduction/Background

Correspondence: Estella M. Davis, PharmD, BCPS, 2500 California Plaza, Omaha, NE 68178. Tel: 402-398-5646 Fax: 402-398-5928 E-mail: [email protected]

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Warfarin is an anticoagulant that has long been the mainstay for the prevention and treatment of primary and secondary thrombosis in patients with cardiovascular complications, including atrial fibrillation (AF), heart valves, deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke. Warfarin decreases the activity of vitamin K–dependent clotting factors II, VII, IX, and X, and regulatory anticoagulant proteins C and S. New oral anticoagulation medications such as dabigatran, rivaroxaban, and apixaban have emerged onto the market with US Food and Drug Administration (FDA) approval for use in some indications similar to those for warfarin, with edoxaban close behind as another new agent seeking FDA approval. Similar indications include reducing the risk of stroke and systemic embolism in patients with nonvalvular AF (for all 3 agents), preventing DVT that may lead to PE in patients undergoing hip or knee surgery (for rivaroxaban and apixaban), and treating or preventing DVT or PE.1–3 The pharmacologic targets of new oral anticoagulants differ from those of warfarin because they inhibit specific factors in the clotting cascade and are often referred to as target-specific oral anticoagulants (TSOACs). Dabigatran is a direct thrombin (factor IIa) inhibitor that binds to both free and clot-bound thrombin to prevent the

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Urgent Reversal of Target-Specific Oral Anticoagulants

conversion of fibrinogen to fibrin during the clotting cascade, to inhibit thrombin-induced platelet aggregation, and thus to prevent the development of a thrombus.1 Rivaroxaban, apixaban, and edoxaban are all direct factor Xa inhibitors that also prevent thrombin generation and development by inhibiting both free and prothrombinase-bound factor Xa.2–4 All offer advantages over vitamin K antagonist therapy due to their more rapid onset, reliable anticoagulation response, and fixed dosing regimen, as well as not requiring routine laboratory monitoring. These new oral anticoagulants received FDA approval for their efficacy and safety profiles that are superior or comparable to those of warfarin.5–7 Edoxaban is not currently FDA approved, but it is approved for use in Japan for prophylaxis of postoperative venous thromboembolism in patients undergoing major orthopedic surgery.8 The manufacturer for edoxaban submitted a New Drug Application to the FDA in January 2014 for the indications of stroke prevention in AF patients and for the treatment of DVT and PE.4,9,10 Recent postmarketing reports have shown that both dabigatran and rivaroxaban were associated with a large number of serious injury reports to the FDA and a 5-fold and 2-fold higher risk of death, respectively, than warfarin.11,12 Unfortunately, clinical trials evaluating agents for the reversal of life-threatening bleeding due to TSOACs are limited, and no specific antidote has received FDA approval for that indication. Only recently has a 4-factor prothrombin complex concentrate (PCC) received approval for immediate reversal of bleeding due to warfarin therapy.13 Reversal strategies for warfarin include withholding the medication, administration of vitamin K, or giving clotting factor substitutes such as fresh frozen plasma (FFP) or PCC.14,15 Recombinant activated factor VII (rFVIIa) is not recommended for bleeding associated with warfarin, except in the setting of life-threatening bleeding when more effective agents are not available.14,15 This review examines studies and case reports evaluating strategies for expedited or emergent reversal of TSOACs.

Materials and Methods

An electronic literature search of MEDLINE and PubMed from inception to March 2014 was conducted to identify relevant English-language clinical studies and case reports in humans or animals (if no data on a reversal strategy was available in humans) evaluating the use of proposed reversal strategies for TSOACs, including renal replacement therapies such as hemodialysis, continuous renal replacement therapies, activated charcoal, PCC, and rFVIIa.

Search terms included dabigatran, rivaroxaban, apixaban, edoxaban, reversal, hemorrhage, bleeding, life-threatening bleed, activated charcoal, hemodialysis, continuous renal replacement therapy, prothrombin complex concentrate, and recombinant factor VII. The reference lists of relevant articles, manufacturer websites, and ClinicalTrials.gov were also examined by investigators to identify further studies or case reports for inclusion.

Reversal Strategies

Warfarin is highly protein bound and takes many days to exhibit and dissipate its antithrombotic effect; therefore, the reversal strategies of activated charcoal (AC) and hemodialysis (HD) are not optimal for its removal. However, studies have evaluated the use of AC as a potential reversal strategy for TSOACs due to its rapid antithrombotic activity, and evaluated the strategy of HD with dabigatran due to its low protein binding and renal elimination. As reversal strategies, AC and HD are themselves not prohemostatic; however, administration of AC with recent ingestion of a TSOAC can prevent absorption in the intestines and prevent the drug from exerting its full anticoagulant effect. Hemodialysis can remove drugs that are renally eliminated or with low protein binding; thus, HD can remove dabigatran and reduce the amount of drug in the plasma available to exert its anticoagulant effects. Fresh frozen plasma can be used for reversal of warfarininduced bleeding. It is likely that FFP would not be a useful agent for immediate reversal of TSOACs because, unlike warfarin, it is an inactive enzyme precursor that does not inhibit the production of functional coagulation factors. The role of FFP in life-threatening bleeding caused by TSOACs would be more supportive for patients in hemorrhagic shock. Prothrombin complex concentrates and rFVIIa are hemostatic agents that have been evaluated for use in the reversal of life-threatening bleeding in patients receiving warfarin.13–15 The PCCs are concentrated pooled plasma products that typically contain 3 or 4 vitamin K–dependent procoagulant factors in higher concentrations than FFP. The PCCs are typically classified as 3-factor (3F) products that contain adequate levels of factors II, IX, X, and low factor VII levels; or 4-factor (4F) products that contain adequate levels of factors II, VII, IX, and X as well as protein C and S15 (Table 1). The majority of PCCs are unactivated, requiring activation via the coagulation cascade, and some are supplemented with heparin and antithrombin to minimize thrombotic complications when they are given. They

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Davis et al

Table 1. Composition of Prothrombin Complex Concentrates13,69 Product Activated Classification Factor

4 Factors

Factor Type

aPCC

3F-PCC

Brand Company

Feiba NFa Baxter Healthcare Corporation Yes

Bebulin Profilnine SD Kcentra Baxter Healthcare Grifols Biologics Inc. CSL Behring LLC Corporation Yes Yes Yes

Beriplex P/N Cofact Kanokad CSL Behring LLC Graha Farma LFB Group No

No

No

1.3 IU/IU 0.9 IU/IU 1.4 IU/IU 1.1 IU/IU None

24–38 IU/mL , 5 IU/mL 24–38 IU/mL 24–38 IU/mL 0.15 IU per 1 IU fIX

19–40 IU/mL 10–25 IU/mL 20–31 IU/mL 25–51 IU/mL 0.5 IU/mL

14–35 IU/mL 7–20 IU/mL 25 IU/mL 14–35 IU/mL None

14–35 IU/mL 7–20 IU/mL 25 IU/mL 14–35 IU/mL None

Available in United States Factor II Factor VII Factor IX Factor X Unfractionated heparin


3 Factors 3F-PCC

150 IU/100 fIX IU 35 IU/100 fIX IU 100 IU 100 IU/100 fIX IU None

4F-PCC

0.76–1.6 units/unit 0.4–1 unit/unit 0.8–1.24 units/unit 1–2.04 units/unit 0.016–0.08 unit/unit

4F-PCC

4F-PCC

4F-PCC

a Factor VII primarily in active form. Source: Neurocritical Care (2010)12/3: 403-413, “Prothrombin Complex Concentrates for Oral Anticoagulant Therapy-Related Intracranial Hemorrhage: A Review of the Literature” by Eric M. Bershad, Jose I. Suarez; with adaptation. With kind permission of Springer Science+Business Media. Abbreviations: fIX, factor IX; IU, international units; PCC, prothrombin complex concentrate.

are advantageous over FFP because they do not require a crossmatch, are virally inactivated, require smaller infusion volumes to achieve hemostasis, and can be infused in 15 to 30 minutes.15,16 There are many PCC products; however, only Bebulin (Baxter, Westlake Village, CA), Profilnine (Grifols Biologicals Inc., Los Angeles, CA), and Kcentra (CSL Behring LLC, Kankakee, IL) are available in the United States, and some may not be widely available.16 Recombinant activated factor VII is a hemostatic agent that forms a complex with local tissue factor to promote thrombin and ultimately fibrin production and platelet activation.15,17 It is FDA approved for the treatment of bleeding episodes or prevention of bleeding in surgical interventions or invasive procedures in patients with hemophilia A or B with inhibitors, acquired hemophilia, or congenital factor VII deficiency.17 The approved dose depends on the indication, but for the treatment or prevention of bleeding episodes in surgical interventions in patients with hemophilia A or B with inhibitors, the dose is 90 µg/kg every 2 hours; in patients with acquired hemophilia, the dose is 70 to 90 µg/kg every 2 hours; and in patients with factor VII deficiency, the dose is 15 to 30 µg/kg every 4 to 6 hours. Recombinant activated factor VII is available in 1-, 2-, 5-, and 8-mg vials given as an intravenous (IV) bolus after reconstitution. The results of common coagulation tests to measure the intensity of anticoagulation varies among TSOACs. The thrombin time (TT) is a very sensitive test to determine the presence of dabigatran at low concentrations, whereas the ecarin clotting time (ECT) test is sensitive to dabigatran at all concentrations; however, the assay is not widely available. Chromogenic antifactor Xa assays are useful for 110

monitoring coagulation with rivaroxaban and apixaban, but the assay must be calibrated for the specific factor Xa inhibitor, which may be problematic in an urgent situation. The international normalized ratio (INR) is derived from the prothrombin time (PT), and point-of-care INRs tend to be higher with dabigatran therapy than those from clinical laboratories; with factor Xa inhibitors, the assay should be calibrated for the specific agent being measured, and the differences in international sensitivity index and available assays could influence values. The activated partial thromboplastin time (aPTT) and PT are widely available, but for TSOACs the aPTT is more sensitive than the PT for direct thrombin inhibitors, whereas the PT is the more sensitive test for factor Xa inhibitors. Thrombin generation tests reflect the inhibition of thrombin (factor IIa) production by an anticoagulant, the administration of which leads to a delay before thrombin production is detected (ie, lag time), a delay in peak thrombin generation (ie, an increase in time to peak thrombin activity), and a reduction in the peak thrombin activity. The area under the curve (AUC) for the plasma thrombin concentration-time curve is diminished by anticoagulants. The endogenous thrombin potential (ETP) reflects this AUC and is often referred to as ETP-AUC.18 Further studies are being conducted with TSOACs to develop and identify optimal coagulation assays, including thromboelastography, to determine the intensity of anticoagulation with TSOACs and the impact of hemostatic reversal agents on these assays. Currently, the implication of abnormal coagulation assay results are unclear, as normal values may not indicate loss of anticoagulant effects and elevated values may occur for many reasons, making it difficult to quantify

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the degree of anticoagulation. Laboratory tests indicating when changes in anticoagulant dosing are needed or when invasive procedures or surgery are safe have not been identified.18 Providers should interpret the results in the context of patients’ clinical status. The remainder of this review examines studies evaluating the strategies of AC, HD, PCCs, or rFVIIa for expedited or emergent reversal of TSOACs in human subjects, or in animal models if human data are unavailable.


Activated Charcoal

The use of AC with dabigatran has been evaluated using only 2 in vitro models.19,20 The first model evaluated the binding of 5, 10, and 20 capsules of 150 mg dabigatran to AC in 100 mL of water to simulate situations of recent ingestion (2 to 3 hours) of large amounts of dabigatran in the stomach fluid.20 Each suspension was divided in half, and AC suspension (125 mg/mL) was added to 1 portion. Levels of dabigatran were 8.3, 15.6, and 29.6 mg/mL in the untreated suspensions in water, whereas it was undetectable in the charcoal-treated suspensions, indicating . 99.9% adsorption by AC. The second model evaluated binding of dabigatran to AC in plasma to simulate situations where it would be present in high concentrations (470 and 940 ng/mL). The sample was then split, and AC was added to half at the manufacturer’s specified concentration (125 mg/mL). Average plasma concentrations of dabigatran were 394 and 824 ng/mL from untreated plasma, respectively, compared with , 1.01 ng/mL at both concentrations in charcoal-treated plasma. These preliminary in vitro models show that dabigatran can be successfully adsorbed by AC from water or plasma. However, no studies have been conducted in vivo or in controlled trials with patients. The investigators advise that if activated charcoal is used to neutralize recent ingestion of overdose quantities of dabigatran, it should be given within 1 to 2 hours before it is absorbed within the intestine.19,20 The use of AC may be considered in cases of rivaroxaban or apixaban overdose.2,3 Use of AC was published as a case report when a 21-month-old, 12-kg child ingested two 10-mg tablets of rivaroxaban21; AC 1 g/kg was given 2 hours after ingestion. The patient’s initial INR was 2.1, increased to 3.5 at 12 hours postingestion, then decreased to 1.7 at 20 hours postingestion, and the patient remained asymptomatic with no signs of bleeding. The manufacturer of apixaban reported that AC given within 2 or 6 hours after ingestion of 20 mg of apixaban to healthy subjects, reduced the AUC by 50% or 27%, respectively.3 The plasma half-life of apixaban also decreased from 13.4 hours to 5.3 and 4.9 hours, respectively,

at 2 and 6 hours after AC administration.3 Administration of AC reduces the exposure to apixaban and lowers the AUC to facilitate elimination of apixaban, resulting in a decreased half-life.22 No studies have evaluated the use of AC with edoxaban. The product label for dabigatran does not mention AC as a recommendation for patients in the event of an overdose1; however, others’ publications1,19,23,24 have mentioned it as an option if the last dose of dabigatran was ingested within the past 2 hours to help prevent absorption, based on the data by van Ryn and colleagues.19 Activated charcoal may be considered in cases of recent acute ingestion of rivaroxaban and apixaban to limit the overall exposure and absorption of these agents.2,3

Hemodialysis

Dabigatran is a small molecule (molecular weight of 471 d) with relatively low plasma protein binding of 35% and is eliminated primarily by the kidneys (80%). Dabigatran can be removed by HD, and the manufacturer lists this method as an option in the event of an overdose.1 Approximately 49% of dabigatran can be cleared from the plasma over 4 hours using a high-flux dialyzer with a blood flow rate (QB) of 200 mL/min and dialysate flow rate (QD) of 700 mL/min, and approximately 57% of dabigatran is cleared with an increased QB rate of 300 mL/min and the same QD rate, with no appreciable increase in clearance observed at higher QB rates.1 Rivaroxaban is 92% to 95% protein bound and apixaban is 87%, and the product labeling includes the suggestion that HD would not be expected to remove them.2,3 Edoxaban has lower protein binding than the other factor Xa inhibitors, 40% to 59% protein bound; however, HD has not been evaluated as a reversal strategy with this medication, and its manufacturer suggests HD and maintaining diuresis may not be an option for removal this drug either.25 No studies were found in the literature evaluating the use of HD for emergent bleeding with rivaroxaban, apixaban, or edoxaban. Studies supporting dialysis as a method for removal of dabigatran include pharmacokinetic studies in healthy subjects26–28 and case reports in patients with bleeding or surgery requiring urgent reversal.29–35 Further case reports have examined using continuous renal replacement therapies (CRRTs) emergently as well.35–37 Three prospective studies evaluated the impact of hemodialysis on the pharmacokinetic parameters of dabigatran in subjects with end-stage renal disease (ESRD).26–28 The first open-label, controlled study examined the effects of renal impairment on the pharmacokinetics and pharmacodynamics



Davis et al

following a single dose of dabigatran in 23 stable subjects with renal function ranging from no impairment to ESRD with maintenance HD.26 Subjects received dabigatran 150 mg once if they had renal impairment or 50 mg once at the start of a 4-hour HD session if they had ESRD on maintenance HD. The study methodology did not include details on the type of dialyzer, QB, or QD rates used for dialysis. The study found an increase in dabigatran exposure in those with renal impairment, with the half-life almost doubling and the AUC 6-fold higher in ESRD subjects compared with controls. The amount of dabigatran removed from the blood by HD was determined by measuring the difference between concentrations in the blood entering the dialysis apparatus through arterial inlet and venous outlet lines to determine the extraction percentage. Based on mean concentration differences, the extraction percentage of dabigatran removed by HD was 62% at 2 hours and 68% at 4 hours. The investigators noted a limitation of their study: dabigatran was only given as a 1-time dose; thus, serum concentrations would not be predictive of patients taking it long term. Another small phase I study evaluated the elimination of various doses of dabigatran in 6 human subjects with ESRD on maintenance HD.27 This study differed from that of Stangier and colleagues26 in that subjects received dabigatran once daily over 3 days to achieve steady state. The dose regimen of dabigatran was 150 mg on day 1, 110 mg on day 2, and 75 mg on day 3. A 4-hour HD session was started 8 hours after the last dose to allow for absorption and distribution of the drug. Normal conditions were set for HD with a QB rate of 200 mL/min and QD rate of 700 mL/min, but no information was included about type of dialyzer. The average dabigatran concentration was 150 ng/mL just before HD, which decreased by 50% to 76 ng/mL after 4 hours of HD. The extraction percentage calculated from blood entering and leaving the dialyzer was 81%. The rebound after stopping HD was minor, representing a 10% increase in plasma concentration. This study confirmed that a 4-hour HD session using normal blood flow conditions eliminated approximately 50% of dabigatran, and was an efficient method for removal of dabigatran with a high dialysis extraction percentage of 81% and with a minor rebound effect. A similar phase I study in 7 ESRD study subjects who went through 2 sequential dosing and elimination periods (periods 1 and 2) separated by a 6-week washout.28 The periods consisted of dabigatran dosing on days 1 through 3, and 3 HD elimination sessions on days 1, 3, and 5. A higher HD QB rate was used for the second elimination period (period 2). The dabigatran dosing regimen and HD schedule for the 112

treatment periods were as follows: (1) on day 1, a 4-hour HD session completed (time –4 hours to 0 hour) before the first dose, and dabigatran 150 mg was given once immediately after HD (referred to as time 0 hour); (2) on day 2, no HD given and dabigatran 110 mg given once; (3) on day 3, dabigatran 75 mg given once, and then a 4-hour HD session completed 8 hours after the last dabigatran dose; and (4) on day 5, no dabigatran, with 4 hours of HD. A Polyflux dialyzer (surface area 1.4 m2) with a QB rate of 300 mL/min and QD rate of 500 mL/min was used on day 1 before the dabigatran dose. On day 3, after the 3rd dabigatran dose, a larger dialyzer was used (surface area 2.1 m2) with an increased QD rate to 700 mL/min to maximize dabigatran elimination. Also on day 3, the QB rate varied for each period and was targeted to a QB rate of 200 mL/min for period 1 or a QB rate of 400 mL/ min for period 2. The larger dialyzer (2.1 m2) with the higher QD rate of 700 mL/min was continued for use on day 5. The HD session with a QB rate of 200 mL/min (period 1) removed 49% of dabigatran from plasma volume, and 59% with a QB rate of 350 to 395 mL/min (period 2). Following HD, there was a minor redistribution of dabigatran into the plasma compartment, described as a 7.5% to 15.5% rebound in plasma concentration, which occurred maximally 4 to 8 hours after the end of HD. The study demonstrated that dabigatran plasma levels, similar to those seen that effectively treat AF, can be decreased to at least half by a 4-hour optimized HD session. Three cases reported using HD as the sole method for removal of dabigatran in a patient with emergent bleeding, and 2 cases reported using HD for urgent reversal of dabigatran before spinal and cardiac surgery.29–31 All patients were receiving dabigatran 150 mg twice daily for stroke prevention in AF. The first case was the reported use of HD in an elderly man with emergent bleeding and prolonged coagulation lab values, with an INR of 8.8, aPTT of 132.9 seconds, and TT . 22 seconds (normal 15–20), with a glomerular filtration rate , 60 mL/min upon presentation to the hospital.29 Fresh frozen plasma was initially given with minimal improvement, and then a 4-hour HD session was started using a 1.8-m2 dialyzer and QB rate of 300 mL/min (the QD rate was not specified). The plasma concentration of dabigatran just prior to HD was 1100 ng/mL and decreased to 18 ng/mL immediately after completion, thus the 4-hour HD reduced the dabigatran level by almost 99%. Twenty minutes after the HD session ended, the dabigatran concentration increased to 100 ng/mL, showing a rebound by about 4.5-fold. The extraction percentage at the timer intervals of 15, 30, 120, and 240 minutes were 97%, 96%, 49%, and 17%. After




completion of the HD session, the INR and aPTT improved and the patient was eventually discharged. In 2 other cases, HD was used to reverse the effects of dabigatran before urgent surgery.30,31 In the first case, HD was used in two 4-hour HD sessions on consecutive days in a patient with an epidural abscess and cord compression requiring spinal surgery.30 An FX100 dialyzer was used with a QB rate of 300 mL/min and QD rate of 480 mL/min. Baseline aPTT and TT were prolonged, and the dabigatran concentration was 470 ng/mL. The dabigatran concentration decreased by 47% to 250 ng/mL after the first HD session and decreased further by 37% to 160 ng/mL after the second session. By day 6, the dabigatran concentrations decreased to 10 ng/mL, and the patient was eventually discharged. In the second case, a 2.5-hour HD session was initiated in a patient admitted for cardiac transplant surgery because of an elevated preoperative TT of 90.6 seconds, although it was stopped 36 hours prior to surgery, suggesting the effects of dabigatran anticoagulation were still present.31 An Optiflux F180 dialyzer was used with a QB rate of 500 mL/h and QD rate of 800 mL/h. The TT dropped to 60 seconds after 2.5 hours of HD, and the patient was successfully prepped for cardiac surgery and successfully discharged later. Numerous cases have been reported where HD or a CRRT method in conjunction with clotting factor substitutes such as PCCs or rFVIIa for reversal of dabigatran-associated bleeding. There are cases reporting the use of HD with PCCs32,33 or rFVIIa,34,35 and a CRRT method with PCC36 or rFVIIa.35,37 Low-dose activated PCC (aPCC; FEIBA, Baxter Healthcare Corp., Westlake Village, CA) at ∼8 units/kg was used to reduce further bleeding while a dialysis catheter was placed for a 3-hour HD session in a patient presenting with severe intracranial hemorrhage (ICH) while on dabigatran.32 The initial TT was . 300 seconds and the dabigatran concentration was 312 ng/mL. Hemodialysis using a high-flux dialyzer with a QB of 350 mL/min (QD was not reported) began. Dabigatran concentrations decreased to 49, 39, and 29 ng/mL at 1 to 3 hours during HD, thus decreasing by 41%. After dialysis the dabigatran level rebounded by 49%, where it increased to 43 ng/mL 2 hours after HD, and then decreased back down to 20 ng/mL 14 hours after completion of HD. The TT also followed a similar pattern by decreasing, rebounding immediately after HD, and then decreased again. After placement of a subdural drain, the patient was transferred to an outpatient rehabilitation facility. In this case, the 3-hour HD session effectively decreased plasma dabigatran concentrations with a 49% rebound after HD ended. The authors conclude that it may be necessary to combine

intermittent HD to rapidly decrease dabigatran concentrations followed by a continuous dialysis modality to prevent drug levels from rebounding. A second case presented with an acute gastrointestinal (GI) bleed and acute kidney injury used 2 doses of 3F-PCC (Profilnine) followed by 4 sessions of emergent HD.33 Unfortunately, no specific information was provided in the case report about the dialyzer, dialysis settings, or duration of dialysis used for the sessions. The patients coagulation labs were all elevated on admission (INR 9.9, aPTT 107.4 seconds, TT . 60 seconds), decreased after the 3F-PCC doses were given (INR 2.2, aPTT 74.7 seconds), and decreased further after 4 emergent HD sessions over 5 days were given (INR 1.3, aPTT 34.8 seconds), except TT remained elevated. The patient was successfully discharged to a nursing home, requiring further HD. The use of rFVIIa with HD for emergent bleeding caused by dabigatran was reported in 1 case34 and a series of cases at 1 institution.35 One case report used rFVIIa and a 6-hour HD session to stop massive dabigatran-associated post–cardiac surgery bleeding.34 Coagulation lab values taken 1 month prior to the elective coronary artery bypass graft surgery were normal, with an elevated thrombin clotting time of 128 seconds (normal 20–30 seconds). After surgery, severe bleeding occurred, requiring supportive blood products. Due to continued bleeding, a total of 5 doses of rFVIIa were given (see the section Recombinant Activated Factor VII, below, for more details). Once bleeding decreased, the patient was transferred to the intensive care unit for a 6-hour HD session using a high flux (Polyflux 210h, Gambro Dialysatoren, Hechingen, Germany) filter with a QB rate of 320 mL/min and QD rate of 700 mL/min and bleeding decreased further. The first dabigatran concentration drawn 40 minutes postsurgery was 95 ng/mL. Immediately before HD, the concentration was 76 ng/mL, and at completion of HD it was 27 ng/mL, thus concentrations decreased by 64%. The investigators observed excellent correlation between the thrombin clotting time and dabigatran concentrations. This case supports the use of rFVIIa for reducing dabigatran-associated bleeding and a 6-hour HD session to reduce dabigatran concentrations quickly to further abate bleeding. Singh and colleagues35 reported a case series of 5 consecutive patients from March 2012 to January 2013 with estimated glomerular filtration rate , 50 mL/min receiving dabigatran who were admitted with emergent bleeding. Supportive blood products were given to all patients along with high-flux intermittent HD alone or followed by CRRT to achieve adequate hemostasis. Four of the 5 patients received rFVIIa in a range from 2 to 8 mg as a single dose



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(see the section Recombinant Activated Factor VII, below). Admission coagulation parameter ranges for the 5 patients were an aPTT of 59.7 to 133 seconds, PT of 20 to 66 seconds, INR of 1.8 to 8.4, and TT . 150. Initial dabigatran plasma concentrations ranged from 149 to 1200 ng/mL. A high-flux polysulfone dialyzer was used for all 5 patients with a QD rate of 800 mL/min; for 4 patients the QB rate was 350 mL/min, and for the fifth patient it was 400 mL/min. Two patients had just 1 HD session at 4 or 5 hours in duration, 2 patients had 2 HD sessions at 3 or 4 hours in duration, and 1 patient had an HD session at 2 hours in duration followed by continuous venovenous hemodiafiltration (CVVHDF). For these 5 patients, dabigatran concentrations decreased by 52% to 77% during HD, but rebounded to 87% from concentrations obtained at completion of HD within 2 hours. The most substantial rebound effect was seen in 1 patient in whom the dabigatran concentration increased almost 4-fold from 115 ng/mL, at the end of a 4-hour HD session, to 437 ng/mL 12 hours later; a second 4-hour HD session was initiated and the concentration decreased to 41 ng/mL. Because the TT exceeded the upper level of detection for all patients, the investigators evaluated the relationship between dabigatran plasma concentrations and corresponding aPTT results and found a significant correlation (Spearman’s correlation coefficient = 0.89; P , 0.001). They noted that the aPTT could have been affected by blood products, but the correlation suggests that an extremely elevated aPTT was indicative of supratherapeutic dabigatran concentrations. The results of these cases support the use of prolonged HD or HD followed by CRRT, but the reported greater rebound effect suggests that the steady-state volume of distribution (Vd) is greater in patients with dabigatran toxicity.35 Three studies reported using a CRRT method with either 3F-PCC36 or rFVIIa35,37 in cases of emergent bleeding due to dabigatran. However, only Singh and colleagues35 provide details on the dialysis filter and CRRT settings used to assist with removal of dabigatran. In the case series by Singh and colleagues discussed previously, in which rFVIIa was used in conjunction with HD, 1 of the 5 patients had a 2-hour HD session followed by CVVHDF due to the patient’s continued active bleeding and hemodynamic instability. The QB was set at a rate of 3000 mL/h and the QD rate was 250 mL/ min using an AN69 hemofilter (Prismaflex M100; Gambro Dialysatoren, Hechingen, Germany). The dabigatran concentration rebounded 49% from 420 ng/mL at end of the 2-hour HD session to 626 ng/mL 6 hours after completion of HD. After initiation of CVVHDF, the dabigatran concentration decreased to 416 ng/mL at 8 hours and 121 ng/mL at 30 hours. 114

The CVVHDF method attenuated the rebound effect after HD for this patient and contributed to a reduction in dabigatran concentration by 80% after 30 hours of treatment.35 The other 2 studies that reported using CRRT modes did not describe the CRRT settings or hemofilter and were in patients presenting with GI bleeds due to dabigatran; in 1 study, unactivated 3F-PCC and continuous venovenous hemodialysis (CVVHD) were used,36 and in the other rFVIIa and continuous venovenous hemofiltration (CVVHF) were used.37 In the study that used 50 units/kg of unactivated 3F-PCC, all coagulation lab results were elevated (INR 12.42, PT 147.5 seconds, aPTT . 200 seconds), the patient received multiple blood products, CVVHD started on day 3 of hospitalization with no improvement in lab results or bleeding, and the patient expired.36 The other study used 30 µg/kg of rFVIIa prior to emergent surgery in a patient with GI bleeding and cecal perforation with an elevated TT . 120 seconds.37 The CVVHD was started postoperatively and then switched to CVVHDF to try to improve the efficiency of dabigatran removal on postoperative day 2. Approximately 51 hours after the initiation of the CRRT modes, the TT dropped to 109.7 seconds. Four days after the initial surgery, the coagulation lab results improved enough for a second abdominal surgery to be performed, with a final TT of 32 seconds. The product label and small prospective studies support using HD for removal of dabigatran. No studies were found using HD for emergent bleeding with rivaroxaban, apixaban, or edoxaban, and the product labels for rivaroxaban and apixaban state that it is not expected that HD would impact their removal.2,3 The product label for dabigatran recommends 4-hour HD session using a high-flux dialyzer with a QB of 200 to 300 mL/min and QD rate of 700 mL/min, and to expect no appreciable increase in clearance observed at higher QB rates.1 In some cases from this review a higher dabigatran removal was reported, reducing concentrations by 99% after a 4-hour HD session using a QB of 300 mL/ min,29 and by 52% to 77% in a series of patients receiving 2- to 4-hour HD sessions where the QB rates were set higher, at 350 to 400 mL/min, and the QD was set at 800 mL/min.35 In 1 case, the dabigatran concentrations were reduced by 64% with a 6-hour HD session and a QB rate of 320 mL/min and a QD rate of 700 mL/min.34 The extraction percentage of dabigatran removed by HD in 1 study was 81% after 4-hour HD and 1 patient had extremely high extraction percentages reported within the first 30 minutes of a 4-hour HD session at 97%.27,29 Dabigatran has a large Vd (50–70 L), making it likely that rebound of the drug after its initial removal by HD would




occur. The product label for dabigatran states that upon cessation of HD, a redistribution effect of approximately 7% to 15% is seen, and studies reported similar rebound percentages.27,28 However, case reports in bleeding patients on chronic dabigatran reported much higher rebound effects after HD sessions at a range of 40% to 87% and even up to 4.5-fold higher.29,30,35 Singh and colleagues35 suggest that the rebound effect is probably reflective of redistribution of the drug from the peripheral (ie, adipose tissue) to the central compartment, and that steady-state Vd in dabigatran toxicity may not be reflective of that seen in stable nonbleeding patients. In the event of continued bleeding due to dabigatran, provision of supportive clotting factor agents, HD, and QB or QD rates should be optimized; increasing HD duration, giving repeated intermittent HD sessions, or switching to a CRRT method should be considered to aid in further removal of dabigatran.

Prothrombin Complex Concentrates Activated Factor PCC

There is only 1 controlled, prospective study in human subjects receiving dabigatran and rivaroxaban that has evaluated the reversal effects of aPCC.38,39 Other cases have reported using it for emergent reversal and facilitation of HD line placement in patients anticoagulated with dabigatran.32,40 There are human plasma models and animal studies evaluating the use of aPCCs for reversal of TSOACs.41–44 Activated PCC was tested along with other hemostatic agents for reversal of anticoagulation in a randomized, crossover, in vitro study using plasma of individuals administered either a single dose of dabigatran 150 mg or rivaroxaban 20 mg given once.38,39 After a 2-week washout period, subjects received the other anticoagulant. Reversal of anticoagulation was tested in vitro using the hemostatic agents of aPCC (FEIBA, Baxter Healthcare Corp., Westlake Village, CA), 4F-PCC (Kanokad, LFB Group, Paris, France), or rFVIIa (NovoSeven RT, NovoNordisk A/S, Bagsvaerd, Denmark) at various concentrations. Thrombin generation tests were evaluated to determine the effects of these agents. The final concentrations of 3F-aPCC used were 0.25, 0.5, 1, and 2 units/mL of 3F-aPCC, corresponding to 20, 40, 80, and 160 units/kg, respectively.38 By 2 hours, dabigatran significantly reduced the ETP, prolonged the lag time (LT), and delayed the time to peak thrombin activity (TTP), but it had no effect on peak concentration of thrombin. By 2 hours, rivaroxaban significantly reduced the ETP and the peak concentration of thrombin, prolonged the LT, and delayed the TTP.

For dabigatran-anticoagulated plasma, all doses of aPCC (corresponding to 20–160 units/kg) corrected to the ETPAUC, TTP, and thrombin peak close to baseline, whereas the 3 highest doses of aPCC (corresponding to 40–160 units/kg) corrected the LT. For rivaroxaban-anticoagulated plasma, aPCC doses corresponding to 20 units/kg reversed ETP-AUC to near baseline with overcorrection for all other concentrations of aPCC (corresponding to 40–160 units/kg). All doses corrected the LT and TTP and doses of 80 and 160 units/kg corrected the thrombin peak close to baseline. The authors suggested that for dabigatran-anticoagulated plasma, the minimal efficient dose for aPCC was not clearly determined, as the corresponding dose of 40 units/kg, but not 20 units/kg, corrected LT close to baseline, whereas the lowest dose of aPCC corrected all thrombin generation parameters with even an overcorrection in ETP-AUC, with a corresponding dose starting at 40 units/kg in rivaroxaban-anticoagulated plasma. The study evaluated the effect of aPCC for correction of the hemostatic defect induced by dabigatran or rivaroxaban through thrombin generation laboratory tests, but it was not designed to assess its effect on subjects anticoagulated at steady state or with active bleeding, or its impact on more readily available coagulation laboratory tests. One case report describes the use of aPCC (FEIBA) for life-threatening bleeding due to transseptal perforation that occurred during cardiac ablation in a patient on chronic dabigatran that was last taken 7 hours before the procedure.40 Transseptal perforation occurred during the ablation, requiring emergent pericardiocentesis. Two hours after the ablator crossed the septum, low-dose aPCC at 26 units/kg (3159 units) was given, with notable slowing of bleeding observed by the interventional cardiologist 5 minutes after aPCC was given, and further cessation of bleeding 15 minutes after aPCC was given. Before the procedure ended, 4.5 L of blood was removed. About 30 hours later, another lower dose of aPCC was given (1900 units). The authors noted that their case was the first to show that low-dose aPCC rapidly reversed the anticoagulant effects of dabigatran in life-threatening bleeding. They also noted that TT and dabigatran concentrations using a chromogenic ecarin test did not normalize after aPCC, suggesting that dabigatran was not directly neutralized, but its clinical effects were overridden by aPCC. This is important to note because it underscores that interpretation of laboratory coagulation test values requires consideration of each patient’s specific clinical scenario. A description of the coordinated use of aPCC before a 3-hour HD session was described in a case report discussed earlier in the HD section of this review.32 The patient was



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given a relatively low dose of aPCC at ∼8 U/kg or 530 units in an effort to reduce existing and further bleeding that may occur while placing a catheter for HD. The patient had an initial elevated TT and dabigatran concentrations, which both decreased after the HD session and the patient was successfully transferred to an outpatient rehabilitation facility. The use of aPCC (FEIBA) was evaluated in 2 studies of in vitro models using human plasma exposed to apixaban.41,42 Tissue factor, phospholipids, and calcium were used to initiate coagulation in human plasma exposed to therapeutic concentrations of warfarin, apixaban, fondaparinux, and an experimental direct thrombin inhibitor (AR-H067637).41 The permeability constant (Ks), reflecting the amount of buffer passing through the coagulum, was calculated. Warfarin increased Ks in plasma by 28% to 50%, AR-H067637 by 58% to 76%, apixaban by 36% to 53%, and fondaparinux by 72% to 91% compared with controls. Addition of aPCC 0.25- to 5-unit/mL concentrations fully reversed the effect of warfarin but only partially reversed the effects of the other anticoagulants at concentrations that increased Ks by 50% or more.41 The other in vitro study evaluated the effectiveness of aPCC (FEIBA) at 75 units/kg, 4F-PCC (Beriplex P/N, CSL Behring LLC, Marburg, Germany) at 50 units/kg, and rFVIIa at 270 µg/kg in reversing antihemostatic actions induced by apixaban (200 ng/mL) added in vitro to blood from healthy donors (n = 10).42 Effects on thrombin generation and thromboelastometry parameters were assessed. Prolongations in clotting times were corrected by the different concentrates with variable efficacies (rFVIIa . 3F-aPCC . 4F-PCC). Impairments in fibrin formation were normalized by the different concentrates. Only rFVIIa significantly restored levels of platelet deposition. The PCCs were more effective in altering thrombin generation, with rFVIIa being more effective on thromboelastometry and perfusion studies. Activated PCC can correct prolonged clotting times and affect thrombin generation altered by apixaban, but rFVIIa was more effective than both PCCs at restoring thrombin generation. More studies beyond human plasma in vitro models are needed with apixaban and PCCs to identify optimal doses, efficacy, and impact of the hemostatic agent on laboratory coagulation tests in patients taking chronic TSOACs or with active bleeding. No animal models have evaluated the effects of aPCC with apixaban, and only 2 models evaluated it with edoxaban.43,44 Two studies evaluated the use of aPCC in both in vitro models in human plasma and in vivo models in rats, to evaluate the effect on PT and bleeding time in plasma 116

exposed to edoxaban.43,44 The in vitro human plasma models used aPCC, 3F-PCC, and rFVIIa, and the in vivo rat models used either vitamin K and fresh frozen plasma or aPCC and rFVIIa. Activated PCC at concentrations of 0.15, 0.5, and 1.5 units/mL significantly decreased the prolonged PT caused by edoxaban at concentrations of 150 and 300 ng/mL in the in vitro human plasma portion of the study.43,44 Activated PCC at 50 units/kg completely reversed the PT prolonged by 1 mg/ kg/hour infusion of edoxaban, whereas aPCC at 50 to 100 units/kg reversed the prolonged PT and bleeding time in the in vivo rat model.44 The product labels of dabigatran and apixaban state that PCCs may be considered for reversal of bleeding from their anticoagulant effects, but they do not specify which PCC to use or recommend a dose, or clarify that the use of PCCs has not been evaluated in clinical trials.1,3 The product label for rivaroxaban states that the use of aPCC for reversal has not been evaluated.2 Interestingly, the 1 study in healthy human subjects38 examined the use of aPCC when subjects received either dabigatran or rivaroxaban, and found good reversal of thrombin generation tests; however, the product label of rivaroxaban states it has not been evaluated, whereas the product label of apixaban included PCCs for consideration with just 2 small in vitro studies in human plasma.43,44 Doses starting at 25 units/ kg up to 80 units/kg of aPCC, with subsequent doses based on response, could be considered for reversal of dabigatran and rivaroxaban based on the study by Marlu and colleagues38 and a case report by Dager and colleagues.40 Alternatively, lower doses such as 1 vial of aPCC (∼ 5–10 units/kg) may be considered initially for emergent procedures such as vascular line placement.32 There are no studies evaluating aPCC in human subjects with active bleeding due to rivaroxaban, and only in vitro or in vivo models in human plasma or animals exist for apixaban and edoxaban. Further investigation into the use of aPCC for reversal of anticoagulation in these populations is warranted, as the use of TSOACs will increase. There is 1 prospective observational study underway in Australia that will evaluate the use of aPCC or rFVIIa in patients receiving dabigatran or rivaroxaban for chronic conditions. Investigators plan to enroll 30 patients and evaluate the effect of the reversal agents on TT and various thromboelastogram assays.45

3-Factor PCC Unactivated

Only 1 controlled study in human subjects evaluated the use of unactivated 3-factor PCC (3F-PCC)46 for reversal of rivaroxaban, and no clinical trials in human subjects have




been conducted for reversal of dabigatran, apixaban, or edoxaban. There are 3 case reports describing its use as a reversal strategy in dabigatran-associated, life-threatening GI bleeds.33,36,47 The 3F-PCC was evaluated for reversal of rivaroxaban in an open-label, single-center, parallel-group, in vivo study of 35 healthy adults.46 The subjects were given rivaroxaban 20 mg twice daily for 4 days followed by a single 50-unit/kg dose of either 3F-PCC (Profilnine) or 4F-PCC (Beriplex) or a control. The 3F-PCC produced a smaller reduction in PT compared with 4F-PCC, but 3F-PCC more effectively reversed ETP. The explanation for the discrepant results on PT and thrombin generation was unclear, but differences in the composition of the products (heparin and factor VII in 4F-PCC) may have played a role. Clinical studies should be done to evaluate the effects of 3F-PCC in patients with active bleeding to help better define its role as a hemostatic agent for reversal. Further studies and analysis should be conducted to evaluate its impact on thrombin generation tests, common clinical coagulation tests, or determination of an optimal coagulation assay that corresponds with clinical improvement. One case described using 3F-PCC (Profilnine) 20 units/kg (2000 units) in an elderly man on dabigatran presenting with hemorrhagic shock due to GI bleeding.47 Supportive blood products were given when the initial INR was 6.79, the aPTT was 111 seconds, and liver enzymes were 30 to 60 times above baseline. After administration of 3F-PCC, the aPTT and INR decreased, HD was deferred due to coagulopathy, the patient’s clinical condition deteriorated, and he expired. Two other cases described the use of 3F-PCC (Profilnine) in situations of acute GI bleed where additional HD or CVVHD was used, as briefly discussed earlier (see section Hemodialysis).33,36 The case described by Wychowski and colleagues33 used 2 doses of 3F-PCC at 25 units/kg and then 50 units/kg, separated by 1 day, in a patient presenting with a GI bleed and acute kidney injury. The patient had elevated coagulation lab results on admission (INR 9.9, aPTT 107.4 seconds, TT . 60 seconds [reference range 22–34 seconds]). A dose of 3F-PCC 25 units/kg resulted in a reduction in INR and aPTT immediately after completion of the infusion. The next day, a second dose of 50 units/kg was administered, with the lab results showing an INR of 2.2, aPTT of 74.7 seconds, and TT . 60 seconds. The patient then underwent 4 sessions of emergent HD over the next 5 days with further reductions in INR, aPTT, and TT, and the patient was successfully discharged to a nursing home, requiring further HD.33

In the other case, described by Cano and Miyares,36 1 dose of 3F-PCC at 50 units/kg and CVVHD were prescribed in a female patient presenting with GI bleeding. Initial coagulation lab results were all elevated, and 3F-PCC 50 units/kg was given along with the other supportive blood products. After 3F-PCC administration, the lab values decreased to an aPTT of 99 seconds, PT of 35 seconds, and INR of 3.10, and CVVHD was started the next day, but it provided no further improvement in the lab results or the bleeding. Administration of rFVIIa was considered, but all therapy was withdrawn and the patient expired. The authors suggested that 3F-PCC temporarily decreased blood coagulation; earlier use of the addition of rFVIIa was considered, but the combination of rFVIIa and a PCC should be used with caution due to their thrombogenic potential.17,36 Two studies referred to in the aPCC section, earlier in this review, by Morishima and colleagues43 and Fukuda and colleagues,44 also evaluated the effect of 3F-PCC on in vitro models in human plasma exposed to edoxaban. The in vitro models used similar concentrations of 3F-PCC described previously as 0.15, 0.5, and 1.5 units/mL, which decreased the prolonged PT. The product labels of dabigatran, rivaroxaban, and apixaban state that PCCs may be considered for reversal of bleeding from their anticoagulant effects, but they do not specify which PCC to use or recommend a dose, or clarify that use of PCCs has not been evaluated in clinical trials.1–3 A starting dose of 3F-PCC at 50 units/kg could be given to reverse anticoagulation with rivaroxaban based on the study by Levi and colleagues.46 However, there are no studies in healthy subjects evaluating the use of 3F-PCC in those exposed to dabigatran or apixaban, and only 1 study in a human in vitro model for edoxaban. A case report described the successful use of 2 sequential doses of 3F-PCC at 25 units/kg and then 50 units/kg followed by multiple sessions of HD for emergent bleeding associated with dabigatran. Further studies must be conducted using 3F-PCC in human subjects or those with emergent bleeding from new TSOACs to better define its role and potential dose.

4 Factor PCC

Several small controlled studies in human subjects have evaluated the effect of 4F-PCC on the reversal of dabigatran and rivaroxaban38,48 or rivaroxaban alone.46,49 No human case reports have used 4F-PCC for emergent bleeding from TSOACs, but 1 in vitro model used human plasma exposed to apixaban42; and a few other animal studies evaluating its use with dabigatran, rivaroxaban, and edoxaban.50–52



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The effect of using a 4F-PCC was evaluated in a prospective, randomized, double-blind, placebo-controlled, crossover trial in 12 healthy males receiving either dabigatran 150 mg twice daily or rivaroxaban 20 mg twice daily for 2.5 days followed by a bolus of 4F-PCC (Cofact, Sanquin, Amsterdam, The Netherlands), at 50 units/kg, or saline.48 Dabigatran significantly increased the aPTT, ETP lag time, ECT and TT after administration, but 4F-PCC had no direct effect on these results and even slightly increased the ECT time (P = 0.08). For those subjects who received rivaroxaban, 4F-PCC immediately and completely reversed both the PT and ETP. The authors concluded that 4F-PCC at a dose of 50 units/kg reversed the laboratory effects of rivaroxaban in healthy volunteers. An in vitro study by Marlu and colleagues,38 previously mentioned in the aPCC section of this review, of plasma from 10 healthy male subjects evaluated different concentrations of reversal agents 4F-PCC (Kanokad), aPCC (FEIBA), or rFVIIa in patients taking 1-time doses of dabigatran or rivaroxaban.41 The final concentrations of 4F-PCC were 0.25, 0.5, and 1 units/mL, corresponding to 12.5, 25, or 50 units/kg of 4F-PCC. For dabigatran-anticoagulated plasma, all doses of 4F-PCC corresponding to 12.5 to 50 units/kg reversed the ETP-AUC results close to baseline, and dramatically increased thrombin generation and the thrombin peak, but had no effect on LT or TTP for those subjects receiving dabigatran.38 For rivaroxaban-anticoagulated plasma, the lower doses corresponding to 12.5 to 25 units/kg of 4F-PCC reversed ETP-AUC to near baseline with overcorrection for the concentrations corresponding to 50 units/kg. There was a dose-dependent correction of the thrombin peak starting with the lowest dose of 4F-PCC (corresponding to 12.5 units/kg), but it had no significant effect on LT or TTP. A larger study by Levi and colleagues46 in 35 healthy adults evaluated the effectiveness of giving a 50-unit/kg dose of either 4F-PCC (Beriplex) or 3F-PCC (Profilnine) to subjects receiving rivaroxaban 20 mg twice daily; this study was described previously in the 3F-PCC section of this review.46 The 4F-PCC more effectively corrected the PT compared to 3F-PCC, but 3F-PCC more effectively reversed ETP, which the authors thought was likely due to the difference of more heparin and factor VII in the 4F-PCC product. A second in vitro study of plasma and whole-blood samples from healthy volunteers exposed to rivaroxaban in increasing concentrations up to 800 µg/L administered 4F-PCC in concentrations used clinically to reverse the effects of vitamin K antagonists.49 The PT remained prolonged at all concentrations of rivaroxaban irrespective of the amount of 4F-PCC added. 118

The ETP and calibrated automated thrombography assays did not change, but the total thrombin potential normalized. The authors concluded that the response of the different thrombin generation tests is assay condition dependent, and that prospective studies are needed to clarify which assay condition and parameter best describes in vivo hemostasis in patients on rivaroxaban treated with 4F-PCC. The use of 4F-PCC (Beriplex), aPCC, and rFVIIa was described by Escolar and colleagues42 in an in vitro model using blood from 10 healthy human donors with moderately elevated concentrations of apixaban (discussed in the aPCC section of this review). The 4F-PCC was the least effective to correct clotting time prolongation compared to the other factor concentrates; 4F-PCC and aPCC were more effective than rFVIIa in improving thrombin generation. The aforementioned studies evaluated the use of 4F-PCC for correction of the hemostatic defect induced by TSOACs through thrombin generation tests and some common clinical anticoagulation laboratory tests, but further studies should be done to confirm the optimal dose of 4F-PCC for patients with active bleeding and the optimal coagulation assay that correspond with clinical improvement. Animal models have evaluated the effect of 4F-PCC on dabigatran and rivaroxaban in murine ICH models50,51 and in a rabbit model exposed to edoxaban.52 Murine models in mice exposed to incrementally large doses of dabigatran or rivaroxaban with induction of ICH found that administration of 4F-PCC (Beriplex) prevented hematoma expansion more consistently than did rFVIIa in dabigatran- or rivaroxabanassociated bleeding.50,51 One in vivo animal study in a rabbit model of acute bleeding that evaluated the use of 4F-PCC for the reversal of edoxaban found that 4F-PCC at a dose of 25 to 75 units/kg reduced the time to hemostasis and total blood loss in a dose-dependent manner.52 The product labels of dabigatran, rivaroxaban, and apixaban state that PCCs may be considered for reversal of bleeding from their anticoagulant effects, but they do not specify which PCC to use or recommend a dose, or clarify that the use of PCCs has not been evaluated in clinical trials.1–3 Four-factor PCC at doses starting with 25 to 50 units/kg could be given to reverse anticoagulation with dabigatran and rivaroxaban based on the various studies in human subjects that were reviewed in this section.38,46,48,49 However, studies in human subjects were conflicting with 1 study showing benefit in reversing ETP, AUC, thrombin generation, and thrombin peak,38 and another study showed no impact on reversing aPTT, ECT, or TT.48 An initial animal model found that similar doses of 4F-PCC could decrease bleeding time



and blood loss from edoxaban-anticoagulated blood. Further large studies in humans or case reports are needed to confirm the efficacy and optimal dose of 4F-PCC for reversal of emergent bleeding due to dabigatran or rivaroxaban, and more in vitro or in vivo studies in humans should be conducted for reversal of apixaban or edoxaban.


Recombinant Activated Factor VII (rFVIIa)

There is only 1 in vitro study of rFVIIa using blood samples from healthy male subjects administered dabigatran or rivaroxaban.38 A number of case reports have described using rFVIIa either alone53,54 or in addition to intermittent HD34,35 or continuous renal replacement therapy35,37 for reversal of emergent bleeding associated with dabigatran. There are also some in vitro models in human plasma exposed to apixaban42,55 or animal ICH models exposed to dabigatran or rivaroxaban,50,51 or animal and human in vitro models exposed to edoxaban.43,44 The only in vitro study in human subjects that examined the effect of rFVIIa in 10 healthy subjects receiving 1-time doses of dabigatran or rivaroxaban was evaluated by Marlu and colleagues38 and was discussed previously in both the aPCC and 4F-PCC sections of this review.39 The final concentrations of rFVIIa used were 0.5, 1.5, and 3 units/mL, corresponding to 30, 60, and 120 µg/kg respectively. In dabigatran-anticoagulated plasma, the highest dose of rFVIIa of 3 units/mL (corresponding to 120 µg/kg) significantly reduced the LT and TTP, but did not increase the thrombin peak above the baseline value. In rivaroxaban-anticoagulated plasma, all doses corresponding to 30 to 120 µg/kg decreased the LT and TTP, but did not increase the ETP as other hemostatic agents could. The authors suggested that rFVIIa even at the lowest dose corrected the LT and TTP in rivaroxabananticoagulated plasma, but only the highest dose corrected these parameters close to baseline in dabigatran-anticoagulated plasma. The study evaluated the effect of rFVIIa for the correction of the hemostatic defect induced by dabigatran or rivaroxaban through thrombin generation laboratory tests, but it was not designed to assess its effect on subjects anticoagulated at steady state or with active bleeding, or its impact on more readily available coagulation laboratory tests. A number of case reports have described using rFVIIa either alone53,54 or in addition to intermittent HD34,35 or CRRT35,37 for reversal of emergent bleeding associated with dabigatran (also discussed in the HD section earlier in this review). No other studies have reported using it to reverse rivaroxaban, apixaban, or edoxaban. Two case reports

describe the emergent use of rFVIIa alone or with other supportive agents in patients with life-threatening bleeds while on dabigatran.53,54 One case report was in an elderly man presenting with bone fractures and an epidural hematoma; two 1-mg units of rFVIIa were administered, with improvement in coagulation parameters.53 The other case report in which rFVIIa was used alone described administering a “weight-based dose of rFVIIa” (no specific dose was reported) in an elderly man presenting with an ICH involving both hemispheres. Unfortunately, radiologic evidence showed extensive progression of the bilateral hemorrhage and the patient expired.54 Other case reports used rFVIIa in combination with HD34,35 or a CRRT method35,37 for dabigatran-associated bleeding. One case report used 3 doses of rFVIIa at 2.4 mg/dose, followed by 2 additional doses of 7.2 mg/dose, to stop massive dabigatran-associated postcardiac surgery bleeding.34 Bleeding decreased after rFVIIa doses were administered, and the patient was transferred to the intensive care unit for HD. This case supports the use of high-dose rFVIIa in reducing dabigatran-associated bleeding, and the combination of rFVIIa followed by HD helped manage this life-threatening bleeding episode. Another case report by Singh and colleagues35 used rFVIIa in 5 of 6 patients followed by HD and/or CRRT sessions. The patients received 1-time doses of rFVIIa at doses ranging from 2 to 8 mg IV with concomitant FFP. The combined use of rFVIIa and HD or CRRT was effective in reducing dabigatran concentrations. Another case reported the successful use of 30 µg/kg rFVIIa (3000 µg) with CVVHF in an elderly patient with a GI bleed requiring hemicolectomy and multiple surgeries.37 Some in vitro models evaluated the use of rFVIIa in human plasma exposed to apixaban.42,55 One in vitro model, in which human plasma was exposed to apixaban, rivaroxaban, or dabigatran at increasing concentrations, found that rFVIIa at 5 and 50 µg/mL reversed the anticoagulant effects of apixaban at lower concentrations, showing its potential to reverse the effects of apixaban.55 Another in vitro study by Escolar and colleagues42 (described in previous sections of the review) evaluated the effects of giving rFVIIa at 270 µg/kg or other PCCs to blood exposed to apixaban. Only rFVIIa significantly restored levels of platelet deposition and corrected the clotting time compared with the other PCCs, whereas thrombin generation improved more with the PCCs compared with rFVIIa. Two animal models evaluated the effects of rFVIIa in murine models of ICH exposed to dabigatran or rivaroxaban50,51 or in vitro human plasma or in vivo rat models exposed to edoxaban.43,44 The murine models of ICH



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described by Zhou and colleagues,50,51 discussed previously in the 4F-PCC section, found that giving rFVIIa prevented hematoma expansion in rivaroxaban-exposed models, but not in those exposed to dabigatran. Two animal studies referred to in the aPCC section by Morishima and colleagues43 and Fukuda and colleagues44 evaluated the effect of rFVIIa on PT and bleeding time in plasma exposed to edoxaban in both in vitro models in human plasma and in vivo models in rats. The rFVIIa at concentrations of 100, 300, and 1000 ng/mL significantly decreased the prolonged PT caused by edoxaban in the human plasma in vitro portion of the study. Recombinant FVIIa at doses of 0.3, 1, and 3 mg/kg were studied in their in vivo model in rats exposed to an infusion of edoxaban, and the 2 highest doses decreased the prolonged bleeding time in a dose-dependent manner whereas all doses completely reversed the prolonged PT.44 The product labels of dabigatran and apixaban state that administration of rFVIIa may be considered for reversal in the event of bleeding with no specific dose suggested, but that its use has not been evaluated in clinical trials.1,3 The product label for rivaroxaban states that the use of rFVIIa for reversal has not been evaluated.2 Interestingly, the 1 study in healthy human subjects examined the use of rFVIIa when subjects received either dabigatran or rivaroxaban,38 but the product label of rivaroxaban states it has not been evaluated for reversal, whereas the product label of apixaban included rFVIIa for consideration based on only 2 small in vitro studies in human plasma.43,44 Recombinant FVIIa at a dose of 20 to 120 µg/kg could be given to reverse anticoagulation with dabigatran or rivaroxaban based on the study by Marlu and colleagues38 in humans described in this review. Case reports in patients with emergent bleeding due to dabigatran showed success using supportive blood products and rFVIIa at a dose of 1 mg or at higher doses ranging from 2 to 8 mg combined with FFP followed by HD or CRRT.34,35,37,53 In vitro models in human plasma show potential for rFVIIa to be effective in reversing the anticoagulant effects of apixaban, which the manufacturer included as a potential option but needing further clinical trial evaluation. Animal models show that rFVIIa may be effective in correcting coagulation parameters caused by TSOACs including the newer agent edoxaban. Murine models of ICH showed that 4F-PCC reduced hematoma expansion from dabigatran or rivaroxaban, but rFVIIa was only effective in preventing expansion in the rivaroxaban model. Further studies must be conducted using rFVIIa in human subjects or those with emergent bleeding from new TSOACs to more clearly define its usefulness and optimal dose. As mentioned in the aPCC 120

section of this review, there is 1 prospective observational study underway in Australia that is evaluating the use of aPCC or rFVIIa on various coagulation parameters and thromboelastogram assays in 30 patients receiving chronic dabigatran or rivaroxaban.45

Reversal Agents in Development

There are a few new agents undergoing clinical trials for reversal of TSOACs. One intriguing reversal method under investigation is a specific humanized antibody fragment (aDabi-Fab) designed to neutralize the activity of dabigatran. Initial in vitro and in vivo studies in rats found that aDabi-Fab had a very high affinity for dabigatran and structural features that mimic thrombin.56 Despite the structural similarities to thrombin, the initial rat models found that the antidote did not bind to thrombin substrates including clotting factors, convert fibrinogen to fibrin, impact thrombin-mediated feedback of coagulation resulting in elevated thrombin generation, activate platelet aggregation alone, or have an effect on the diluted TT assay. The in vitro model in rats found that clotting times that were prolonged with the addition of dabigatran were reversed in a concentration-dependent manner with aDabi-Fab. The antibody alone in the absence of dabigatran had no effect on the coagulation time. The in vivo model in rats exposed to dabigatran at steadystate levels found that the antidote completely reversed the prolonged anticoagulation activity within 1 minute of injection of aDabi-Fab, with a sustained reversal effect over the course of 25 minutes, despite continual infusion of further dabigatran.56 Three randomized, placebo-controlled, phase I studies in humans are now underway to examine the pharmacokinetics, pharmacodynamics, safety, and efficacy of aDabi-Fab, or BI 655075, as a specific reversal agent for dabigatran.57–59 The first study enrolled 145 healthy male subjects to investigate single rising doses of aDabi-Fab and explore the effective dose to reverse the anticoagulant activity of dabigatran.57,60 In part I of the study, subjects received single rising IV doses of up to 8 g aDabi-Fab. In part II, aDabi-Fab doses of 1, 2, and 4 g were administered as 5-minute IV infusions in the presence of dabigatran (220 mg twice daily for 4 days). The anticoagulant effect of dabigatran and its reversal were assessed by measuring the TT, diluted TT, aPTT, ECT, and activated clotting time. Prolongation of clotting times induced by dabigatran were reversed to baseline immediately following the 5-minute infusion of the antidote, as consistently demonstrated by all clotting assays. There was a dose-dependent reversal with increasing doses of antidote. Complete reversal




lasted for ∼30 minutes after administration of a 1-g dose of aDabi-Fab, with some return of the anticoagulation effects of dabigatran. Reversal was complete and sustained in 7 of 9 subjects administered 2 g and in all subjects administered a 4 g dose. In these subjects, TT, the most sensitive coagulation parameter, was reversed from a ratio of up to 14-fold over baseline to less than 2-fold.60 All aDabi-Fab–related adverse events were of mild intensity including headache and erythema.61 The next trial to evaluate the dabigatran-specific antidote, BI 655075, will evaluate the same pharmacokinetic, pharmacodynamic, safety, and efficacy parameters, but it will enroll 40 subjects of either sex to 3 arms stratified based on age 45 to 80 years.58 Another study will examine the effect of the dabigatran-specific antidote, BI 655075, in healthy male Japanese subjects receiving a single dose of dabigatran.59 One small phase IV study is underway examining the use of PCC or rFVIIa for reversal of dabigatran and rivaroxaban.62 A nonrandomized, crossover, single-blind trial called the Reversal of the Antithrombotic Action of New Oral Anticoagulants (REVANT) study will enroll 10 healthy subjects and examine the effect of administering PCC (the study did not specify which type) or rFVIIa after 5 days of dabigatran 150 mg twice daily or rivaroxaban 20 mg daily. The study will evaluate the reversal agents’ effects on platelet deposition and fibrin formation, thrombin generation tests, ECT, and PT. One synthetic reversal agent, PER977, is being studied in a phase I clinical trial to investigate its effectiveness, tolerability, and optimal dosing for reversal of edoxaban.63 PER977 is a small synthetic molecule that binds directly to heparins and anticoagulant drugs including factor Xa inhibitors. It has shown the potential in preclinical trials to completely reverse these agents within 30 minutes after administration.64 Participants will be randomized to a single dose of PER977 and then a second dose 1 week later or to edoxaban 60 mg followed by a single dose of PER977 3 hours later. The PT and thromboelastography reaction time will be evaluated. Another reversal agent under development is PRT4445 (or PRT064445), which has also been referred to as Andexanet or r-Antidote. It is a recombinant protein that is a modified form of factor Xa. The recombinant protein is inactive, but it retains the ability of native factor Xa to bind directly to acting factor Xa inhibitors, acting as a decoy to reverse factor Xa inhibitor-mediated anticoagulation. Therefore, it is under evaluation as an antidote for factor Xa inhibitors. Animal studies with rivaroxaban have shown that it increases INR

and corrects prolonged PT, so it may have a role in reversal of factor Xa inhibitors.65 A large, randomized, double-blind, phase II study is currently enrolling patients to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of PRT064445 to reverse the anticoagulation effects of 4 direct/indirect factor Xa inhibitors at steady-state concentrations in healthy subjects.66 Initial results from a currently ongoing phase II, doubleblind, placebo-controlled study by Crowther and colleagues67 evaluating the pharmacokinetics, safety, and reversal ability of PRT4445 on anticoagulation by rivaroxaban in healthy human subjects was recently presented. Rivaroxaban was given as an oral dose of 20 mg daily for 6 days, and then PRT4445 was given IV on day 6 at a dose of either 210 or 420 mg, 3 hours after the last dose of rivaroxaban. Immediately after completion of the 210- and 420-mg doses, anti–factor Xa activity decreased in a dose-dependent manner by 20% and 53%, respectively, and returned to placebo levels ∼2 hours after treatment. The plasma concentrations of unbound rivaroxaban decreased by 32% and 51%, respectively, after those doses of PRT4445 as well. Rivaroxabaninduced inhibition of thrombin generation and prolongation of both PT and activated coagulation time were also rapidly partially reversed by PRT4445 in a dose-dependent manner. PRT4445 was well tolerated and there were no thrombotic events or other severe adverse events. These initial results show that PRT4445 was able to dose-dependently partially reverse the anticoagulant effects of rivaroxaban pharmacodynamics markers in healthy subjects. The study will also analyze 4 more dose cohorts that can help provide more information on the optimal safe and effective dose. Therefore, PRT4445 may have potential as a universal reversal agent or antidote for all factor Xa inhibitors.67 An observational, multicenter registry, Reversal Agent Use in Patients Treated with Direct Oral Anticoagulants (RADOA), has developed a database to prospectively collect information on the use of reversal agents for patients taking vitamin K antagonists or TSOACs with severe bleeding or who require urgent intervention.68 The registry will collect information from case reports on reversal agents (including PCC, aPCC, rFVIIa, and/or HD) used for patients with severe bleeding or who require urgent reversal of anticoagulation. The anticoagulation medications included are vitamin K antagonists, rivaroxaban, apixaban, dabigatran, and edoxaban. The registry will be useful in capturing the incidence, severity, and outcome of various bleeding events due to vitamin K antagonists and TSOACs, and in evaluating the effectiveness of reversal interventions. The repository should


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be useful in identifying trends in current practice and by providing a database that institutions could query to globally compare anticoagulation reversal strategies.


Summary

Anticoagulation using TSOACs is increasing due to their effectiveness, ease of use, and their side-effect profile as compared with warfarin. Bleeding remains a side effect of anticoagulants; however, unlike with warfarin, there are currently no FDA approved agents for reversal of the anticoagulant effects of TSOACs. The TSOACs have a more rapid onset than warfarin, and prescribers should exercise caution, withhold the medications in an appropriate time frame, and monitor pertinent coagulation lab values if there is no rush for reversal. Recommended hold times for dabigatran are 1 to 5 days depending on the patients renal function1,19,38 and 1 to 2 days for rivaroxaban and apixaban,2,3,38 with potentially longer hold times for all agents in patients undergoing major surgery. There are a variety of reversal strategies that can be employed based on the urgency of anticoagulation reversal (Table 2). If there is an expedited need for reversal, AC could be used if ingestion was in the past 2 hours for dabigatran or rivaroxaban, or within 2 to 6 hours for apixaban. If there is time to obtain catheter access, HD can be initiated to enhance clearance of dabigatran. The manufacturer recommends a duration of $ 4 hours of HD to avoid rebound concentrations at settings of QB 200 to 300 mL/min or QD 700 mL/ min.1 However, some success has been reported in cases with active bleeding from dabigatran using HD sessions as short as 2 hours up to 6 hours long, QB rates up to 500 mL/ min, and QD rates as low as 480 mL/min and as high at 800 mL/min. Low dose 3F-aPCC was used to facilitate HD line placement, and low to moderate doses of 3F-PCC and rFVIIa were given with HD or CRRT methods in cases of acute bleeding due to dabigatran. In an emergent event where immediate reversal of TSOACs is needed or the patient is experiencing a lifethreatening bleed, clinical trial data are lacking, as the only published studies to date are in healthy subjects exposed to 1-time doses or a short course of the TSOAC dabigatran and rivaroxaban38,46,48 (Table 2). Starting doses of 25 to 50 units/kg of aPCC and 4F-PCC seem to be effective in reversing thrombin generation lab parameters and coagulation lab values altered by dabigatran and rivaroxaban, and 50 units/kg of 3F-PCC neutralizes some of these parameters altered by rivaroxaban. A small trial in humans found the lowest starting dose of 20 µg/kg of rFVIIa corrected thrombin generation 122

parameters altered by rivaroxaban, and only the highest dose of 120 µg/kg of rFVIIa corrected these parameters altered by dabigatran.38 There were no case reports found using concentrated clotting factors for urgent reversal of the FDAapproved TSOACs rivaroxaban or apixaban, but there were many cases of patients receiving concentrated clotting factors with active bleeding while on chronic dabigatran. The cases used doses of 8 or 26 units/kg of aPCC,32,40 20 to 50 units/kg of 3F-PCC,33,36,47 and 1 to 8 mg of rFVIIa with or without HD/ CRRT,34,35,37,53 with some success in reversing coagulation parameters, reducing dabigatran concentrations, or enabling surgical intervention. No studies were found that reported using 2 different brands or types of PCCs in combination or those agents in combination with rFVIIa. Only 1 case discussed the initial consideration of using the combination as a last resort to reverse the life-threatening bleed in their patient, but therapy was withdrawn and the authors were aware of the thrombogenic potential with coadministration of rFVIIa and PCCs.17,36 There are many in vitro or in vivo studies in human plasma or animal models that evaluated the use of the reversal strategies of AC with dabigatran, PCCs, or rFVIIa for the reversal of dabigatran, rivaroxaban, apixaban, and edoxaban. In vitro models in human plasma found that aPCC and rFVIIa can correct clotting time and thrombin generation altered by apixaban and edoxaban, and 3F-PCC can alter the PT prolonged by edoxaban. Four-factor PCC can correct clotting time and thrombin generation altered by apixaban, but not as effectively as aPCC and rFVIIa. Murine models of ICH found that 4F-PCC reduced hematoma expansion from dabigatran or rivaroxaban, but rFVIIa was only effective in preventing expansion in the rivaroxaban model. A study enrolling larger numbers of human subjects to evaluate the effectiveness of aPCC or rFVIIa for reversal of dabigatran and rivaroxaban is underway. Three-factor PCC has been studied in subjects exposed to rivaroxaban, but no controlled human study has been conducted to evaluate its effect on reversal of dabigatran. Controlled human studies are needed to validate the effectiveness seen in human or animal models of aPCC, 3F-PCC, 4F-PCC, or rFVIIa to neutralize the anticoagulant effects of apixaban or edoxaban. Studies are underway to evaluate investigational agents for reversal of the anticoagulant effects of direct thrombin inhibitors and factor Xa inhibitors. Providers should be aware of the risk of bleeding with TSOACs and consider reversal strategies discussed in this review. A registry has been created to collect information on reversal agents used for patients taking vitamin K antagonists or TSOACs, and this may be useful



Table 2. Summary of Reversal Strategies From Trials or Reports in Human Subjects or Human Plasma Models for Reversal of Target Specific Oral Anticoagulants Level of Urgency

Reversal Strategy Dabigatran


Expedited Activated charcoal (1–24 hours) Hemodialysis

Emergent (, 1 hour)

Yes, recent exposure , 2 hours8,20,23,24

Yes1 High flux dialyzer Size: 1.4–2.1 m2(28,29) HD QD rates: 480 mL/min32 700 mL/min1,27,34 800 mL/min31,37 HD QB rates: 200 mL/min1,27,28 300 mL/min1,29,30,32,34,35 400 mL/min28,35 500 mL/min31 Duration: 2 hours26 2.5 hours31 3 hours32,35 4 hours1,27–30,32,35 6 hours34 CRRT CVVHD36 CVVHDF QB rate 3000 mL/h, QD rate 250 mL/min35 CVVHF/CVVHDF34 aPCC activated Up to 25 units/kg initially with subsequent doses based on response,23,40 80 units/kg23,38 Case report 8 units/kg for catheter line placement before HD29 3F-PCC unactivated No human trial data available Case reports: Profilnine® 20 units/kg (2000 units)47 Profilnine® 50 units/kg36 Profilnine® 25 units/kg, then 50 units/kg, then 4 sessions of HD33 4F-PCC 25–50 units/kg1,38,48 rFVIIa 20–120 μg/kg1,38 Case reports: 2.4 mg/dose × 3, then 7.2 mg/dose + HD34 2–8 mg/dose + HD35 30 μg/kg (∼3 mg) + CVVHD37 1 mg/dose × 253

Rivaroxaban

Apixaban

Edoxaban

Yes, recent exposure , 2 hours2,23,24 No2

Yes, recent exposure , 2 hours3,23 No3

No data available No data available

Up to 25 units/kg initially; 0.25–5 units/mL 80 units/kg23,38 concentrations of 3F-aPCC41 75 units/kg42

0.15, 0.5, and 1.5 units/mL concentrations of 3F-aPCC43

50 units/kg23,46

No data available

0.15, 0.5, and 1.5 units/mL concentrations of 3F-aPCC43

25–50 units/kg23,38,46,48 20–120 μg/kg23,38

50 units/kg42 5 and 50 μg/mL55 270 μg/kg42

No data available 100, 300, and 1000 ng/mL concentrations of rFVIIa43

Abbreviations: aPCC, activated prothrombin complex concentrate; CRRT, continuous renal replacement therapy; CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration; CVVHF, continuous venovenous hemofiltration; 3F-PCC, 3-factor prothrombin complex concentrate; 4F-PCC, 4-factor prothrombin complex concentrate; HD, hemodialysis; rFVIIa, recombinant activated factor VII.

to identify trends in current practice, compare strategies, and evaluate outcomes.

Conclusion

There is limited information to guide clinicians on strategies to reverse bleeding due to target specific oral anticoagulants

or for those in need of an urgent procedure. Beyond withholding the medication, administration of activated charcoal, renal replacement therapy, or concentrated clotting factors including PCCs or rFVIIa may be considered based on evidence provided in this review. Despite the paucity of data, clinicians should develop anticoagulation reversal plans to


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help avoid delays in administration of reversal agents. More research is necessary to define the role of these reversal agents given alone or in combination as more clinicians adopt use of TSOACs over vitamin K antagonists.

Conflict of Interest Statement

Estella M. Davis, PharmD, BCPS, Erin M. Uhlmeyer, PharmD, David P. Schmidt, PharmD, BCPS, and Greg L. Schardt, PharmD, BCPS, have no conflicts of interest to declare.


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Management of bleeding and reversal strategies for oral anticoagulants: clinical practice considerations.

Potential antidotes for reversal of old and new oral anticoagulants.

Novel oral anticoagulants and reversal agents: Considerations for clinical development.

Reversal agents in development for the new oral anticoagulants.

The Reversal of Direct Oral Anticoagulants in Animal Models.

Reversal of the novel oral anticoagulants dabigatran, rivoraxaban, and apixaban.

Oral anticoagulants and status of antidotes for the reversal of bleeding risk.

Nonclinical Safety Assessment of PER977: A Small Molecule Reversal Agent for New Oral Anticoagulants and Heparins.

Managing bleeding and emergency reversal of newer oral anticoagulants: a review for primary care providers.

Prothrombin complex concentrates as reversal agents for new oral anticoagulants: lessons from preclinical studies with Beriplex.

Reversal of warfarin anticoagulation for urgent surgical procedures.

Reversal of direct oral anticoagulants in hemophilia treatment: ASH meeting 2015.

Direct oral anticoagulants (DOACs) versus "new" oral anticoagulants (NOACs)?

Anticoagulation reversal in the era of the non-vitamin K oral anticoagulants.

[New oral anticoagulants. Regional anaesthesia and new oral anticoagulants].

Novel oral anticoagulants: efficacy, laboratory measurement, and approaches to emergent reversal.

Novel antidotes for target specific oral anticoagulants.

Novel oral anticoagulants for atrial fibrillation.

New oral anticoagulants.

New oral anticoagulants for acute venous thromboembolism.

Cimetidine and oral anticoagulants.

Newer oral anticoagulants.

Switching between oral anticoagulants.

Letter: Oral anticoagulants.