Current Strategies for the Management of Bleeding Associated with Direct Oral Anticoagulants and a Review of Investigational Reversal Agents

The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–17, 2019 Ó 2019 Published by Elsevier Inc. 0736-4679/$ - see front matter

https://doi.org/10.1016/j.jemermed.2019.10.011

Clinical Review CURRENT STRATEGIES FOR THE MANAGEMENT OF BLEEDING ASSOCIATED WITH DIRECT ORAL ANTICOAGULANTS AND A REVIEW OF INVESTIGATIONAL REVERSAL AGENTS Colin G. Kaide, MD, FACEP, FAAEM, UHM* and Michael P. Gulseth, PHARMD† *Department of Emergency Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio and †Anticoagulation Services, Sanford University of South Dakota Medical Center, Sioux Falls, South Dakota Corresponding Address: Colin G. Kaide, MD, FACEP, FAAEM, UHM, Department of Emergency Medicine, Wexner Medical Center at the Ohio State University, 760 Prior Hall, 376 W. 10th Ave., Columbus, OH 43210

, Abstract—Background: The management of lifethreatening bleeding in patients who are receiving direct oral anticoagulants (DOACs) is a serious medical concern. Objective: This review provides a concise, balanced overview of the current and future approaches for reversing the anticoagulation effects of DOACs, particularly factor Xa (FXa) inhibitors. Discussion: The anticoagulant activity of the direct thrombin inhibitor dabigatran can be reversed by idarucizumab, but until recently, options for the management of major bleeding in patients who were receiving FXa inhibitors were limited to nonspecific strategies, including supplementation of clotting factors with prothrombin complex concentrates (PCCs) or activated PCCs for attenuating anticoagulation effects. They appear as a treatment option in many hospital guidelines despite the lack of approval by the U.S. Food and Drug Administration and the lack of rigorous medical evidence supporting their use in this setting. The development of specific reversal agents may provide improved strategies for the management of bleeding. Andexanet alfa is a modified FXa molecule approved in the United States to reverse the anticoagulant effects of FXa inhibitors (rivaroxaban and apixaban) in patients with life-threatening or uncontrolled bleeding. Ciraparantag is a small-molecule inhibitor of multiple anticoagulants that has been investigated in healthy subjects. Conclusion: The current guidelines for management of DOAC-associated bleeding are being updated to reflect

that the reversal agent for rivaroxaban and apixaban is now available. For other FXa inhibitors, in the absence of a reversal agent, nonspecific strategies that include PCCs are recommended. The population of patients anticoagulated with DOACs is growing, and we hope that specific reversal agents will improve the approach to management of major bleeding in this population. Ó 2019 Published by Elsevier Inc. , Keywords—bleeding; DOAC; FXa; reversal of anticoagulation

INTRODUCTION Direct factor Xa (FXa) inhibitors (rivaroxaban [Xarelto, Janssen], apixaban [Eliquis, Bristol-Myers Squibb and Pfizer], edoxaban [Savaysa, Daiichi-Sankyo], and betrixaban [Bevyxxa, Portola Pharmaceuticals]) and the thrombin inhibitor (dabigatran [Pradaxa, Boehringer Ingelheim]) are classified as direct oral anticoagulants (DOACs), in contrast to indirect FXa inhibitors (enoxaparin [Lovenox, Sanofi], dalteparin [Fragmin, Pfizer], and fondaparinux [Arixtra, GlaxoSmithKline]). This group of agents was formally known as novel oral anticoagulants or non–vitamin K oral anticoagulants; however, the term DOAC more accurately describes how these agents work and is now the preferred term. DOACs have been adopted for the prevention and treatment of

Reprints are not available from the authors.

RECEIVED: 10 May 2019; FINAL SUBMISSION RECEIVED: 30 September 2019; ACCEPTED: 13 October 2019 1

2

multiple thromboembolic disorders, including the prevention of stroke in patients with nonvalvular atrial fibrillation, acute treatment and secondary long-term prevention of deep vein thrombosis and pulmonary embolism, for patients at risk of venous thrombosis after orthopedic surgery or after the acute hospitalization of medically ill patients, and for extended prophylaxis of venous thromboembolism (VTE) in hospitalized acutely ill medical patients (1–4). The use of these agents is increasing because they offer several clinical and pharmacologic advantages over vitamin K antagonists (VKAs) (5,6). However, like other anticoagulants, their use is associated with a risk of acute major bleeding, including the potential for lifethreatening intracranial hemorrhage (ICH) (7). Data from clinical trials and real-world prospective analyses in DOAC-treated patients have shown yearly major bleed rates of #4% (Table 1) (8–14,17–20). It is estimated that >80,000 serious DOAC bleeds occurred in 2015 in the United States alone, and mortality related to acute major bleeding is substantial, particularly for patients with ICHs (#48%); therefore, specific strategies are necessary for managing DOACassociated bleeding to improve patient care and outcomes (7,10,12,21–23). Until recently, the only specific DOAC reversal agent was idarucizumab (Praxbind, Boehringer Ingelheim) for dabigatran reversal. Andexanet alfa (Andexxa, Portola Pharmaceuticals) is now approved in the United States as a reversal agent for rivaroxaban and apixaban. Before the approval of andexanet alfa, strategies for the management of bleeding in patients receiving these FXa inhibitors have included the use of nonspecific supplementation of clotting factors with nonactivated clotting factors (prothrombin complex concentrates [PCCs]) or activated PCCs (aPCCs), such as factor VIII inhibitor bypassing activity (FEIBA, Shire). This approach is potentially suboptimal for a variety of reasons. While PCCs were originally developed for the treatment of patients with hemophilia B, the main indication for PCCs in contemporary practice is to replace the coagulation factor deficiency induced by VKAs (e.g., warfarin) (Figure 1) (24–27). In the United States, a 4factor PCC (Kcentra [Beriplex in Europe], CSL Behring) was specifically developed and approved to reverse the effects of VKAs. Robust clinical evidence of efficacy to manage FXa inhibitor–associated bleeding is lacking, and there are currently no phase III clinical trials in patients with acute major bleeding. In addition, optimal dosing strategies are not known (28–31). To conduct a literature review on strategies used to reverse the anticoagulation effects of DOACs, we searched PubMed using the following terms: anticoagulation reversal, DOAC, warfarin, PCCs, rivaroxaban,

C. G. Kaide and M. P. Gulseth

apixaban, edoxaban, betrixaban, dabigatran, idarucizumab, andexanet alfa, ciraparantag, trauma, head injury bleed, intracranial hemorrhage, and gastrointestinal hemorrhage; we then reviewed the results to identify relevant English-language articles. We also gathered current guidelines and subsequently screened the bibliographies of the guidelines and relevant articles from our PubMed search to identify additional references. Following an overview of the mechanistic strategies for anticoagulation, this review discusses DOACs and approaches for reversing the anticoagulation effects of these agents, particularly for direct FXa inhibitors. We summarize the current evidence and recommendations for the use of PCCs to attenuate the anticoagulation effects of FXa inhibitors and associated bleeding. We then present the most recent evidence on the specific reversal agents idarucizumab and andexanet alfa for the treatment of direct thrombin inhibitor– and FXa inhibitor–associated acute major bleeding, respectively, while balancing that discussion with potential advantages of strategies, including PCCs. We also include a summary of evidence demonstrating the effectiveness of an investigational reversal agent, ciraparantag. DISCUSSION Mechanistic Strategies for Anticoagulation The formation of a thrombus (blood clot) is a rapid process and is the final step in a cascading series of enzymatic reactions that may be initiated by trauma and/or endothelial cell surface disruption (Figure 1) (24,32). The interaction of tissue factor (TF) with FVIIa subsequently leads to the activation of FX and formation of FXa. The interaction of FXa with FVa leads to activation of prothrombin and formation of thrombin, which in turn converts fibrinogen into fibrin. The dependence of coagulation on this variety of interacting components offers several targets for therapeutic intervention. The synthesis of several components of the coagulation pathway, including factors II, VII, IX, and X, are dependent on vitamin K (25). Warfarin interferes with the oxidation/ reduction cycle of vitamin K and thereby reduces production of vitamin K–dependent factors (Figure 1) (24). Newer approaches to anticoagulation involve agents that bind directly to the activated key coagulation factors (FXa or FIIa/thrombin) to inhibit their activity (25). Anticoagulant therapy is indicated for a variety of patients who are at risk of thrombotic events and for VTE prevention and treatment; however, any anticoagulation therapy is associated with an increased risk of bleeding (25), and methods to reverse anticoagulation and restore hemostasis are required.

Management of DOAC-Associated Bleeding

3

Table 1. Examples of Annual Bleeding Rates Associated with Factor Xa Inhibitors in Clinical Trials Evaluating Stroke Prophylaxis in Patients with Nonvalvular Atrial Fibrillation Intracranial Hemorrhage

Gastrointestinal Bleeding

3.6% vs 3.4%; p = 0.58 2.75% vs 3.43%; p < 0.001 1.61% vs 3.43%; p < 0.001 2.13% vs 3.09%; p < 0.001 1.4% vs 1.2%; p = 0.57

0.5% vs 0.7%; p = 0.02 0.39% vs 0.85%; p < 0.001 0.26% vs 0.85%; p < 0.001 0.33% vs 0.80%; p < 0.001 0.4% vs 0.4%; p = 0.69

3.2% vs 2.2%†; p < 0.001 1.51% vs 1.23%; p = 0.03 0.82% vs 1.23%; p < 0.001 0.76% vs 0.86%; p = 0.37 0.4% vs 0.04%; p = 0.71

Analysis Period

Major Bleeding‡

Intracranial Hemorrhage

Gastrointestinal Bleeding

1/1/2011–12/31/2014

3.3%

0.3%

1.9%

10/1/2011–12/31/2013 10/1/2010–6/30/2015

3.4% 2.33% vs 4.46%; p < 0.001 2.37% vs 3.03%; p < 0.01 4.04% vs 3.64%; p = 0.60 3.0%

0.21% 0.29% vs 1.06%; p < 0.001 0.28% vs 0.79%; p < 0.001 0.44% vs 0.79%; p < 0.001 0.5%

1.49% 1.78% vs 3.04%; p < 0.001 1.97% vs 1.95%; p = 0.78 3.26% vs 2.53%; p = 0.03 1.1%

Clinical Trials

Follow-Up

Major Bleeding*

ROCKET-AF, rivaroxaban vs warfarin (8)

Median, 707 days

ENGAGE AF-TIMI 48, edoxaban high dose vs warfarin (9) ENGAGE AF-TIMI 48, edoxaban low dose vs warfarin (9) ARISTOTLE, apixaban vs warfarin (10)

Median, 2.8 y

AVERROES, apixaban vs aspirin (11)

Mean, 1.1 y

Real-world Retrospective Analyses Truven MarketScan, rivaroxaban or apixaban (12) DRESDEN, rivaroxaban (13) OLDW, apixaban vs warfarin (14)

Median, 1.8 y

OLDW, dabigatran vs warfarin (14) OLDW, rivaroxaban vs warfarin (14) RIETE, patients with acute VTE (15,16)

3/2001–12/2009

OLDW = OptumLabs Data Warehouse. All rates are in percent per year, except where indicated. Because of differences in trial designs and patient populations, no direct comparisons between agents can be made. * Definition of major bleeding based on the International Society on Thrombosis and Haemostasis criteria, except for the ROCKET-AF trial, which also included permanent disability. † Proportion of patients with gastrointestinal bleeds. ‡ Definition of major bleeding varied across studies.

Warfarin

Vitamin K reductase Idarucizumab Oxidized vitamin K

Ciraparantag (reversal agent)

Reduced vitamin K

Vitamin K dependent carboxylase Precursor clotting factors II, VIII, IX, and X

FFP/PCC supplements functional clotting factors

Functional clotting factors II, VIII, IX, and X

Rivaroxaban, Apixaban, Edoxaban, Betrixaban

Andexanet alfa (reversal agent)

IIa, VIIa, IXa, and Xa Activation

Functional clotting levels reduced by warfarin therapy

Dabigatran

TFPI Note: Activated clotting factors produced from FFP/PCC would be inhibited by DOACs; when a PCC is used for reversal, the intent is to overwhelm the pharmacologic activity with clotting factors.

Figure 1. Anticoagulation pathway and reversal strategies. Adapted from Gulseth (24). DOAC = direct oral anticoagulant; FFP = fresh frozen plasma; PCC = prothrombin complex concentrate; TFPI = tissue factor pathway inhibitor.

4

Bleeding Risk Associated with Factor Xa Inhibitors Therapy with DOACs has been associated with the effective treatment and prevention of VTE and stroke prevention, but like all anticoagulants, their use is associated with a risk of major bleeding, including gastrointestinal bleeds and ICHs (7). Data from clinical trials and realworld prospective analyses in patients who are treated with DOACs have consistently shown annual major bleed rates of 2–4% (Table 1) (8–14,17–20). In 2015, approximately 2.9 million patients received FXa inhibitors and approximately 84,886 (3.4%) were hospitalized for major bleeding based on Marketscan data (12). Data from the ongoing Computerized Registry of Patients with Venous Thromboembolism (RIETE) in patients receiving anticoagulant therapy revealed that 3.0% of patients experienced major bleeding within 3 months (80% of the study cohort) or longer after a VTE event; bleeding was fatal in 25% of those patients, indicating major bleeding as a strong predictor of mortality (15,16). Major bleeding is associated with an increased risk of mortality—overall mortality rates caused by any bleeds during 30 days postdischarge range from 20–48%, as reported in clinical trials and real-world prospective analyses (10,23,26,33). Among those, mortality rates related to ICH bleeds are especially high (#45% within 30 days of the event) compared with mortality rates related to non-ICH bleeds (#14% within 30 days of the event) (10,23,26). Patients who experience DOAC-associated bleeding are also at increased risk of developing subsequent thrombotic events, and patients who experience ICH are at even higher risk (10,34–36). In a clinical trial, after a major bleed in patients who were taking apixaban or warfarin, patients who experienced an ICH bleed or a non-ICH major bleed were at a 22-fold and 13-fold increased risk, respectively, to develop thrombotic events (ischemic stroke or myocardial infarction) within 30 days of the bleeding event compared with patients who experienced no bleeding (10). Major bleeding events often led to changes or interruptions in antithrombotic therapy, which may have contributed to the increased risk of thrombotic events in these patients.

C. G. Kaide and M. P. Gulseth

currently no approved reversal agents for the other direct FXa inhibitors, edoxaban and betrixaban. While theoretically andexanet alfa should be able to reverse bleeding from other anti-FXa agents, such as edoxaban and betrixaban, at this time robust data were not available to allow for approval by the U.S. Food and Drug Administration (FDA) for these indications; studies are ongoing for these other agents. The antithrombotic effects of the oldergeneration anticoagulants unfractionated heparin and warfarin can be completely or partially reversed by protamine sulfate and vitamin K plus fresh frozen plasma (FFP) or PCC, respectively (49). Antifibrinolytic agents (e.g., tranexamic acid and ε-aminocaproic acid) have been considered adjunctive therapies for the reversal of bleeding; however, they have not been studied in patients who are taking DOACs (50). PCCs have been developed to contain highly concentrated coagulation factors (II, IX, and X in 3-factor PCCs or II, VII, IX, and X in 4-factor PCCs; 3-factor PCCs may contain low levels of FVII) to specifically replenish coagulation factors that are missing in hemophilia or warfarintreated patients in order to support clot formation (51). These 3- and 4-factor PCCs reverse the anticoagulant effects of warfarin by replenishing VKA-depleted clotting factors (similar to FFP) or treat hemophilia-associated bleeds by specifically supplying missing coagulation factors and therefore are not specific FXa inhibitor reversal agents per se (52–55). In cases of major bleeding where approved reversal agents are not available, PCCs are often used off label in an attempt to restore hemostasis as a nonspecific strategy (Figure 1) (24). The goal of PCCs for nonspecific reversal of anticoagulation from FXa inhibitors is to overload the system with upstream factors and ‘‘overwhelm’’ inhibition of direct thrombin or FXa. Because circulating anti-Xa or anti-II agents are still present in the blood, some of the additional factors provided by PCCs may be inhibited in the same way as native factors X and II, thereby limiting their effectiveness. In addition to andexanet alfa, another specific reversal agent for FXa inhibitors is currently under clinical development. Ciraparantag (PER977, Perosphere) is a novel small molecule that is currently in phase II trials and is being developed as a reversal agent for multiple anticoagulants (including FXa and FIIa inhibitors) (25).

Reversal of Anticoagulation Effects Anticoagulants and Measures of Coagulation The currently available agents for use in the treatment of major bleeding associated with anticoagulants are listed in Table 2. There are 2 specific agents approved for reversal of a DOAC: idarucizumab is approved for reversal of the direct thrombin inhibitor dabigatran and andexanet alfa is approved for reversal of the direct FXa inhibitors apixaban and rivaroxaban. There are

In practice, patients being considered for reversal should be assessed with appropriate clinical and novel coagulation assays to help determine if the medication is present and likely physiologically contributing to the overall patient situation. For FXa inhibitors, elevated prothrombin time (PT) can detect the presence of certain FXa

Name Warfarin

U.S. Trade Name Coumadin

Direct oral anticoagulants Betrixaban Bevyxxa Rivaroxaban Xarelto

Mechanism of Action

Reversal Agent

Vitamin K antagonist

Vitamin K, PCC, and FFP

Direct FXa inhibitor Direct FXa inhibitor

None Andexanet alfa

Reversal Agent Recommended Dose Vitamin K: 1–10 mg oral dose or slow IV infusion (25–50 mL normal saline over 15–30 min) (37) PCC: 25–50 units/kg, depending on INR (37) FFP: 10–15 mL/kg (37)

Low dose: 400 mg IV bolus followed by a 4 mg/mL infusion for #120 min (41) High dose: 800 mg IV bolus followed by an 8 mg/mL infusion for #120 min (41) Low dose: 400 mg IV bolus followed by a 4 mg/mL infusion for up to 120 mins (41)† 50 units/kg (37)

Estimated Cost of Reversal Agent

Year of U.S. Approval

Vitamin K: $57–114 for 5–10 mg tablet; $39.50–395.00 for 1–10 mg injectable solution (38) 4-factor PCC (Kcentra): $2540 (25 units/kg) to $5080 (50 units/kg) for an 80-kg patient (39) FFP: $45.32 per unit (225–300 mL) (40)

1954

— Low dose: $24,750* High dose: $49,500*

2017 2011

Low dose: $24,750*†

2012

4-factor PCC (Kcentra): $2540 (25 units/kg) to $5080 (50 units/kg) for an 80-kg patient (39) $3600 for 5 g dose (43,44)

2015

Apixaban

Eliquis

Direct FXa inhibitor

Andexanet alfa

Edoxaban

Savaysa

Direct FXa inhibitor

PCC

Dabigatran

Pradaxa

Direct thrombin inhibitor

Idarucizumab

5 g (2 vials, each 2.5 g) IV infusion or bolus (42)

Indirect FXa and thrombin inhibitor

Protamine‡

Slow infusion of 1 mg per 100 USP heparin units, not to exceed 50 mg (45)

$1.20–60.90 for 1–50 mg injectable solution (46)

1939

Indirect FXa inhibitor and thrombin inhibitor (more FXa inhibition than thrombin inhibition) Indirect FXa inhibitor and thrombin inhibitor (more FXa inhibition than thrombin inhibition)

Protamine (partial reversal)§

$0.60–60.90 for 0.5–50 mg injectable solution (46)

1993

$0.60–60.90 for 0.5–50 mg injectable solution (46)

1994

Indirect FXa inhibitor

None

1 mg per 1 mg of enoxaparin if last dose administered #8 h; 0.5 mg per 1 mg of enoxaparin if last dose administered >8 h (47) Slow infusion of 1 mg per 100 antiXa IU of dalteparain; second infusion of 0.5 mg per 100 antiXa IU of dalteparin if aPTT remains prolonged after 2–4 h (48) —

—

2001

Unfractionated heparin Heparin sodium Heparin sodium Low molecular weight heparins Enoxaparin Lovenox

Dalteparin

Fragmin

Fondaparinux

Arixtra

Protamine (partial reversal)k

Management of DOAC-Associated Bleeding

Table 2. Anticoagulants and Approved Reversal Agents

2010

5

aPTT = activated partial thromboplastin time; FFP = fresh frozen plasma; FXa = factor Xa; INR = international normalized ratio; IV = intravenous; PCC = prothrombin complex concentrate. * New Technology Add-on Payment (NTAP) available since October 1, 2018; the maximum NTAP is $14,062.50 or 50% of the wholesale acquisition cost of the low dose. NTAP is expected to remain in effect for a period of 2–3 years until the cost of andexanet alfa is included in the recalibration of the diagnosis-related group payment rates. † High dose is only needed if apixaban dose >5 mg. ‡ Based on heparin sodium label (Pfizer). § Based on enoxaparin label. k Based on dalteparin label.

6

inhibitors but does not measure the degree of anticoagulation in the same manner as with warfarin (e.g., a patient with an international normalized ratio of 1.6 may be fully anticoagulated). PT is most sensitive for rivaroxaban, but is less sensitive for apixaban and edoxaban (56). Elevated PT therefore can help detect the presence of FXa inhibitors, but the degree to which it is useful varies by agent (for example, a normal PT in a patient taking rivaroxaban is less likely to have clinically significant rivaroxaban levels compared with a normal PT in patients taking apixaban or edoxaban). Measuring anti-FXa activity levels is the most specific and direct measurement of the activity of FXa inhibitors. The biggest limitation of anti-FXa activity levels is the lack of commercially available tests in the United States correlated for FXa-inhibiting DOACs; however, DOAC-calibrated assays are available for research and are available for use at some larger institutions. Activated partial thromboplastin time (aPTT) demonstrates low sensitivity for FXa inhibitors but is more sensitive for the FII inhibitor dabigatran (56). Measuring an ecarin clotting time, chromogenic ecarin assay, or dilute thrombin time are considered the best measures to quantify the amount of dabigatran present. However, the biggest limitation is the lack of commercially available tests in the United States. Dabigatran-calibrated assays are available for research and are available for use at some larger institutions. While a normal aPTT cannot completely rule out therapeutic dabigatran levels, if elevated, it can help confirm the presence of dabigatran in plasma. Thrombin time (not dilute thrombin time), a commonly available laboratory measurement, if normal or measurable (below the maximum limit), likely assures low levels of dabigatran (Tables 3 and 4) (27,64). The effects of PCCs on these parameters may be variable among FXa inhibitors, inconsistent, or reflect a delayed onset of action limiting the utility of retesting after treatment (29– 31). However, if idarucizumab is used for dabigatran, appropriate testing may be beneficial to detect possible plasma rebound out of the tissues (24). There is also growing interest in the use of thromboelastography in trauma patients to measure the physical properties (e.g., viscoelasticity) of different phases of clot formation and fibrinolysis in whole blood (63,66). Because thromboelastography encompasses interactions between clotting factors, fibrinogen, and platelets, it contributes to the overall understanding of a patient’s coagulation and can provide insights on the need for transfusion of blood products when used alongside standard coagulation tests. Nonspecific Supplementation of Coagulation Factors PCCs and aPCCs. In the United States, 3 types of PCC products are currently available for the urgent reversal

C. G. Kaide and M. P. Gulseth

of warfarin: 3- and 4-factor PCC and aPCC (56). The 3-factor PCCs currently available in the United States are Bebulin (Baxter) and Profilnine (Grifols). The only 4-factor PCC currently available in the United States is Kcentra and the only aPCC is FEIBA. The mechanism of action by which PCCs and aPCCs (which are composed of concentrated coagulation replacement factors) may affect anticoagulation activity of FXa inhibitors is nonspecific and based on ‘‘overwhelming’’ the anticoagulation effect (Figure 1). The estimated costs of administering Kcentra in an 80-kg patient range from $2540 (25 units/kg) to $5080 (50 units/kg) (39). PCCs or aPCCs carry a potential risk for prothrombotic effects, although the extent of this risk is unknown and likely varies in different situations (56). Because of the presence of activated clotting factors, FEIBA is theoretically more thrombogenic than nonactivated PCCs (67). The label for the 4-factor PCC (Kcentra) and aPCC (FEIBA) include a black box warning for arterial and venous thromboembolic complications and 3-factor PCCs (Bebulin and Profilnine) include warnings for thromboembotic events (53–55,68). It is recommended that PCCs be used with caution, particularly in patients who are predisposed to acute arterial thrombosis or other coagulopathic states (69–72). Although PCCs have been linked to thrombotic outcomes in some situations, when 4-factor PCC was tested vs. FFP for warfarin reversal, no excess thrombotic outcomes were found. However, when used to reverse DOAC therapy, it is unclear whether raising clotting factor levels to supraphysiologic levels could cause excess clotting events (55). The potential for PCCs or aPCCs to reduce blood loss in patients who are actively bleeding while on an FXa inhibitor has never been studied in clinical trials (73). Limited data are available from studies in healthy volunteers in which pharmacodynamic markers of anticoagulation were primarily used to assess the effect of these agents. Moreover, most observations about the use of PCCs in DOAC-associated bleeding come from case reports or case series (56,74). Several reports indicate that PCCs have been used successfully in this setting (56). No prospective clinical trials have been performed to evaluate the efficacy of PCCs and aPCCs in bleeding patients who are receiving FXa inhibitors. PCCs and anticoagulant effects in healthy subjects. .Randomized, placebo-controlled studies are limited to data on the use of PCCs in healthy volunteers anticoagulated with rivaroxaban, apixaban, edoxaban, or dabigatran, based on assessments of coagulation parameters, including PT, clotting time, thrombin time, endogenous thrombin potential (ETP), or anti-FXa activity (27–31,75–78). Because PCCs are not specific FXa inhibitor reversal agents, the studies did not demonstrate direct effect of PCCs on

Management of DOAC-Associated Bleeding

7

Table 3. Measures of Coagulation Measure

Description

Prothrombin time (PT)

PT measures the amount of time necessary to generate fibrin after activation of factor VII and is an evaluation of the function of the extrinsic and common pathways (factors VII, V, X, prothrombin, and fibrinogen) (57) aPTT measures the time necessary to generate fibrin from the initiation of the intrinsic pathway and is sensitive to reduced levels of integral components of the intrinsic and common pathways (factors XII, IX, XI and VIII, X, V, prothrombin, and fibrinogen) (57) TT measures the time necessary for the reaction of fibrinogen to fibrin in the presence of thrombin. It determines whether an abnormality is caused by either a decrease in normal fibrinogen or an inhibitor to its activation (57) ECT is a meizothrombin generation test that quantifies direct thrombin inhibitors. Ecarin activates prothrombin through proteolytic cleavage, which produces meizothrombin, an intermediate with proteolytic activity that can induce clot formation (58) The ECA is comparable to the ECT, with the addition of prothrombin. Detection of direct thrombin inhibitors is based on cleavage of a chromogenic substrate into paranitroalanine by generation of meizothrombin (59) ETP is a measure of the capacity of a given plasma sample to generate thrombin and provides a method for quantifying the effect of multiple, interacting factors in the coagulation pathway (60). ETP can be used to evaluate both hypo- and hypercoagulability (61) Chromogenic anti-FXa assays can detect the activity of unfractionated and low molecular weight heparins and direct and indirect anti–factor Xa inhibitor. This technique has been used to measure the extent of anticoagulation in patients receiving direct anti–factor Xa inhibitors (62) TEG measures the viscoelastic properties of the whole blood as it clots. It is not a substitute for traditional coagulation measures but can provide information on the dynamics of clot development, stabilization, and dissolution (63)

Activated partial thromboplastin time (aPTT)

Thrombin time (TT) Ecarin clotting time (ECT)

Ecarin chromogenic assay (ECA) Endogenous thrombin potential (ETP)

Anti-FXa activity

Thrombelastography (TEG)

reversing anti-FXa levels. In 1 study in healthy subjects taking rivaroxaban, 50 international units (IU) per kilogram of the 4-factor PCC Kcentra failed to immediately and completely reverse PT (31,79). In another study in healthy subjects, 50 IU/kg 4-factor PCC (Cofact, Sanquin) reversed anticoagulation effects of rivaroxaban as assessed by PT and ETP (78). In the same study, the anticoagulation

effects of dabigatran (assessed by clotting time, PT, and thrombin time) were not reversed by PCC (78). In contrast, in another study in healthy subjects who received apixaban, 37.5 IU/kg or 25 IU/kg PCC (Cofact) restored PT prolongation induced by apixaban after 15 min, but neither PCC dose achieved an immediate ETP increase to preapixaban levels, possibly indicating only a partial reversal of

Table 4. Laboratory Guidelines for Direct Oral Anticoagulant–Related Bleeding (12,64) Laboratory Test

Baseline

Serum creatinine Ionized calcium Complete blood cell count PT* Anti-FXa activity*† aPTT‡ ECT/ECA/dTT‡ Arterial or venous pH

U U U U U U U U

Fibrinogen

U

2 h After Reversal

Every 6 h  24 h

U U

U U

U U U

U U U

U

U

Other Recommendations

During resuscitation, a goal of pH > 7.25 should be attempted to facilitate the effectiveness of reversal agents Levels should not be reduced as a result of FXa inhibitors; however, if fibrinogen is low, it should be addressed

aPTT = activated partial thromboplastin time; DOAC = direct oral anticoagulant; dTT = diluted thrombin time; ECA = ecarin chromogenic assay; ECT = ecarin clotting time; FXa = factor Xa; PT = prothrombin time. * For FXa inhibitor–related bleeding. † Chromogenic anti–FXa kits are approved by the U.S. Food and Drug Administration to measure the anticoagulant effect of unfractionated heparin, low molecular weight heparin, or pentasaccharide (65). Anti-FXa kits for research purposes are available for rivaroxaban, apixaban, edoxaban, and dabigatran with calibrators for each inhibitor. Except for dabigatran, repeated testing is of limited utility because of variable effects. ‡ For dabigatran-related bleeding.

8

C. G. Kaide and M. P. Gulseth

a conclusive difference between the 2 groups. Taken together, these observations suggest that PCCs might normalize coagulation parameters in healthy subjects, but the results are somewhat inconsistent (79).

the anticoagulant effect of apixaban (29). Similar results were observed in yet another study, where 4-factor PCCs (50 IU/kg Cofact or Kcentra) returned ETP to preapixaban baseline levels 4 h after PCC infusion (27). In a study in healthy subjects anticoagulated with edoxaban, administration of PCC (Bebulin; 25 or 50 IU/kg) did not accelerate the return of PT to baseline levels, but substantially accelerated ETP return to baseline over a time frame of several hours (30). Finally, in a study of healthy subjects from whom punch biopsy specimens has been obtained, a 4factor PCC (Kcentra) was found to at least partially reverse bleeding duration and ETP, but not PT, with most significant reversal at 50 IU/kg. However, it is important to note that the 95% confidence intervals for reduction in bleeding duration or bleeding volume after the administration of 50 IU/kg PCC overlapped with those after the administration of placebo, suggesting that there was not

A

Specific Reversal Agents: Approved Agents Idarucizumab. Idarucizumab has been approved in the United States and the European Union for reversal of the anticoagulant effects of dabigatran for emergency surgery/urgent procedures or in patients with lifethreatening or uncontrolled bleeding (80). It is a monoclonal antibody that binds dabigatran with high affinity; dabigatran is preferentially bound by idarucizumab over thrombin (Figure 2A) (81). Idarucizumab binds dabigatran with approximately 350 times the affinity with which thrombin binds dabigatran (80). Therefore,

B Catalytically inactive FXa inhibitor

No membranebinding domain

FXa inhibitor Membranebinding domain

A419

S419 Catalytically active

Gla

S S

S S

Factor Xa

1

2 FXa inhibitors block enzymatic activity of FXa

Andexanet Alfa 3

Andexanet alfa directly binds and sequesters unbound FXa inhibitors with high affinity

With Andexanet Alfa

Without Andexanet Alfa

a

AnXa

C

Absence of GLA domain prevents assembly into prothrombinase complex on platelet surface

FIIa FIIa

FXa Inhibitors

DOAC

Xa

An

Xa

DOAC

FXa FVa

Factor Xa or lla

Factor Xa or lla

Anticoagulation: Factor Xa or IIa activity inhibited by DOAC

Reversal: Factor Xa or IIa activity restored when ciraparantag binds DOAC

Thrombin

An

Ciraparantag

FXa FIIa FII

Prothrombin

FVa

FXa FIIa FII

Prothrombin

4

FVa

Platelet Surface

FIIa FII

Prothrombin

Restoration of FXa activity and normal thrombin generation

Figure 2. Structure and mechanism of action of reversal agents. (A) Mechanism of action of idarucizumab. Idarucizumab is a monoclonal antibody that binds dabigatran with high affinity preferentially over thrombin, and readily displaces dabigatran, allowing fibrin formation to occur normally (81). (B) Structure and mechanism of action of andexanet alfa. The prothrombinase complex, which consists of FXa and its cofactor FVa, assembles on a membrane surface, where it converts prothrombin (FII) to thrombin (FIIa). Andexanet alfa binds the FXa inhibitors and does not compete with FXa for incorporation into the prothrombinase complex because it lacks the membrane-binding g-carboxyglutamic acid domain. By binding and sequestering FXa inhibitors, andexanet alfa reverses FXa inhibition and restores that capacity of prothrombinase to generate thrombin and to effect hemostasis (82, 83). Top portion reprinted with permission from Dobesh et al. (82). Bottom portion based on (83). (C) Proposed mechanism of action of ciraparantag. Ciraparantag binds to the anticoagulant via noncovalent hydrogen bonds and blocks access to key binding domains on FXa and thrombin, reversing the anticoagulant effect (84). AnXa = andexanet alfa; DOAC = direct oral anticoagulant; FII = factor II; FIIa = factor IIa; FVa = factor Va; FXa = factor Xa.

Management of DOAC-Associated Bleeding

idarucizumab readily displaces dabigatran, allowing fibrin formation to occur normally (80). The results from 503 patients treated with dabigatran enrolled in the single-arm, noncomparative Reversal Effects of Idarucizumab in Patients on Active Dabigatran (REVERSE-AD) prospective study who experienced either life-threatening bleeding or those who required immediate surgery for which hemostasis was required showed that idarucizumab rapidly reversed the anticoagulant effect of dabigatran in 100% of patients (85). Reversal of the anticoagulant effect was assessed via the dilute thrombin time or ecarin clotting time at any point from the end of the first idarucizumab infusion to 4 h after the second infusion. Among patients who underwent surgery, normal hemostasis was reported in 93.4%. At 90 days, thrombotic events occurred in 6.3% of patients who experienced life-threatening bleeding and in 7.4% of patients who required immediate surgery. Only 9 of 503 patients (1.8%) received >5 g of idarucizumab (85). The decision to administer an additional dose of idarucizumab should be made on a case-by-case basis. In the United States, the wholesale cost of a 5-g dose of idarucizumab is approximately $3600 (43,44). Andexanet alfa. Andexanet alfa (coagulation factor Xa [recombinant], inactivated-zhzo [FDA label name]) has been approved in the United States for the reversal of the anticoagulant effects of rivaroxaban and apixaban in patients with life-threatening or uncontrolled bleeding (86). However, it is not approved for reversal of anticoagulation for emergent/urgent invasive procedures. It is a recombinant, modified human FXa decoy protein that has been developed for reversal of direct and indirect FXa inhibitors and binds FXa inhibitors with high affinity. Andexanet alfa lacks a membrane-binding g-carboxyglutamic acid (GLA) domain and is catalytically inactive because of a modification of the serine residue in the protease catalytic triad (Figure 2B) (82,83,86). As a result, andexanet alfa can bind and sequester FXa inhibitors blocking their activity but is no longer capable of assembly into the prothrombinase complex to generate thrombin. Because of its similarity to FXa, andexanet alfa also binds and sequesters tissue factor pathway inhibitor (TFPI) with high affinity. TFPI is a natural anticoagulant and regulates the initiation phase of the tissue factor pathway. Binding of TFPI by andexanet alfa may be related to transient elevations in markers of coagulation activation (prothrombin fragment 1+2 and D-dimer) and could provide a mechanism to cause hypercoagulability (87,88). Andexanet alfa and anticoagulant effects in healthy subjects. In phase II and III studies in healthy volunteers, administration of andexanet alfa rapidly reversed

9

parameters that measure direct FXa inhibition, with dose-dependent reversal of anti-FXa activity, reduction in unbound (pharmacologically active) plasma levels of direct FXa inhibitors, and restoration of thrombin generation (89–94). In phase III studies, the efficacy and safety of andexanet alfa for the reversal of apixaban- and rivaroxaban-induced anticoagulation was assessed in older healthy volunteers (93). Andexanet alfa was administered either as a bolus or as a bolus plus a 2-h infusion. For both treatment regimens, compared with placebo, anti-FXa activity was significantly reduced by 92–94% among those anticoagulated with rivaroxaban (27 participants) or apixaban (24 participants), respectively. The onset of these effects was rapid (within 2–5 min after administration), sustained during the 2-h infusion of andexanet alfa, and persisted for 1–2 h after completion of the infusion (consistent with pharmacodynamic halflife of andexanet alfa) (93). Finally, treatment with andexanet alfa rapidly restored thrombin generation (to above the lower limit of the normal range) that had been suppressed by treatment with apixaban or rivaroxaban. For both regimens, within 2–10 min of administration of andexanet alfa, normal thrombin generation was restored in 100% of subjects in the apixaban study and in 96% of subjects in the rivaroxaban study, and the effects were sustained throughout the 2-h infusion. Thrombin generation remained within normal limits for the duration of the observation (#22 h). Andexanet alfa was well tolerated in the phase II and III studies of healthy subjects, and there were no serious or severe adverse events (89–94). Transient elevations in prothrombin fragments 1+2 and D-dimer were observed that generally returned to the normal range within 24–72 h. However, no thrombotic events were reported in healthy subjects. No subjects developed antibodies to FX or FXa, and no neutralizing antibodies against andexanet alfa were detected (93). All adverse events related to administration alfa were non-serious and mild. In the phase III study (145 participants), 1 subject with a history of hives experienced erythematous hives during infusion of andexanet alfa. The condition resolved after a single dose of diphenhydramine, and no other infusion reactions were observed. Andexanet alfa and hemostatic efficacy in bleeding patients. The efficacy and safety of andexanet alfa were confirmed in a single-arm, noncomparative phase IIIb/ IV study in patients with acute major bleeding (ANNEXA-4). The full study report of data from 352 patients with primarily intracranial (64%; 56% spontaneous, 44% traumatic) or gastrointestinal (26%) bleeding showed that andexanet alfa rapidly reduced anti-FXa activity with effective hemostasis as adjudicated by an independent committee based on established criteria (95). Briefly,

10

for gastrointestinal bleeding, hemostasis was considered effective if there was a <10% (excellent) or $10% to #20% (good) decrease in both corrected hemoglobin/hematocrit at the 12-h post–andexanet infusion time point, compared with baseline (95). For ICH, criteria for effective hemostasis included serial computed tomography or magnetic resonance imaging scans that were reviewed by an independent core laboratory. For intracerebral hematoma, hemostasis was considered excellent if there was #20% increase from baseline in hematoma volume, or good if there was >20% to #35% increase from baseline in hematoma volume, at 1 or 12 h postinfusion. The assessment of effective hemostasis for subarachnoid and subdural bleeding events was similar, except that the maximal hematoma thickness was used. After administration of the andexanet alfa bolus, the median anti-FXa activity decreased by 92% for both the 100 patients treated with rivaroxaban and the 134 patients treated with apixaban; these levels were sustained during the 2-h infusion of the study drug (95). Twelve hours after andexanet alfa infusion, clinical hemostasis was adjudicated as excellent or good in 204 of 249 patients (82%). Among patients with intracranial or gastrointestinal bleeding, 135 of 168 patients (80%) and 51 of 60 patients (85%), respectively, achieved excellent or good hemostasis. It is possible that maintenance of reversal of coagulation parameters (e.g., anti-FXa activity) for 2 h accounted for the hemostatic efficacy because blood clots are formed rapidly and, therefore, rapid reversal of anticoagulation could be sufficient to generate a stable clot in a bleeding patient. However, the optimal infusion duration is unclear, particularly in patients needing urgent invasive procedures, for whom the ANNEXA-4 study was not designed to evaluate. In emergency settings, variable pharmacokinetic and pharmacodynamic factors, along with patients’ potential comorbid conditions, introduce additional difficulty for determining optimal infusion length (93). It is possible that longer (or shorter) infusions could be needed in these situations, but more studies are needed. If longer infusions are needed, and the medication is priced at a premium based on a 2-h infusion, it is possible that hospital formularies will carefully consider the role of PCC vs andexanet alfa for reversal. The wholesale price of the bolus plus a 2-h infusion of andexanet alfa is $24,750 for the low dose, which most patients receive, and $49,500 for the high dose. Andexanet alfa received a New Technology Add-on Payment (NTAP) that has been available since October 1, 2018; the maximum NTAP is $14,062.50 or 50% of the wholesale acquisition cost of the low dose. NTAP is expected to remain in effect for a period of 2–3 years, until the cost of andexanet alfa is included in the recalibration of the diagnosis-related group payment rates. The agent comes in 100-mg vials (or 200-mg vials pending FDA

C. G. Kaide and M. P. Gulseth

approval) and doses of 400–800 mg and 480–960 mg are required for the initial intravenous bolus and follow-on infusion, respectively, and therefore it will almost certainly take longer to prepare than a dose of PCC. It is much more expensive than current PCCs on the market (approximate drug costs for 4-factor PCC range from $2540–$5080 [39]), and off-label infusions longer than 2 h may be cost prohibitive. The full study report of ANNEXA-4 indicated that 34 of 352 patients (10%) had a thrombotic event by 30 days (95). Only 8 patients had resumed therapeutic anticoagulation before the thrombotic event, and in total 220 of 352 patients (62%) had resumed anticoagulation within 30 days. Most thrombotic events most likely occurred after andexanet alfa was cleared; however, it is still possible that the inhibition of TFPI causes some hypercoagulability— 11 patients had a thrombotic event within 5 days after andexanet alfa treatment, and the remainder occurred between 6 and 30 days after treatment (93,95). The agent carries a black box warning regarding possible thrombotic risk. While it is still not clear if andexanet alfa has thrombotic risk, the administration was not associated with other serious side effects. There were 2 patients with infusion reactions that were considered mild to moderate in severity, and no antibodies to FXa or FX, and no neutralizing antibodies to andexanet alfa developed. In summary, the full analysis of this study in patients receiving a FXa inhibitor and presenting with acute major bleeding demonstrated the clinical efficacy and safety of andexanet alfa in patients requiring urgent anticoagulant reversal. Specific Reversal Agents: Investigational Agents Ciraparantag. Ciraparantag is a small molecule (512 Da) that is reported to bind directly to unfractionated heparin and low molecular weight heparin, as well as to dabigatran, rivaroxaban, apixaban, and edoxaban, preventing target site inhibition of the activity of either thrombin or FXa (Figure 2C) (84). It reportedly does not bind to coagulation factors or other plasma proteins (25,49). Therefore, ciraparantag may potentially function as a universal reversal agent for several classes of anticoagulants. However, available data on ciraparantag are limited, and its mechanism of action is not clearly documented. The proposed mechanism of action of ciraparantag is that it binds to the anticoagulant via noncovalent hydrogen bonds, thus blocking access to key binding domains on FXa and thrombin; however, the precise details of the binding properties of ciraparantag remain unclear (96). Ciraparantag has only been studied in healthy volunteers anticoagulated with edoxaban or enoxaparin. Ciraparantag and anticoagulant effects in healthy subjects. Ciraparantag does not appear to reverse specific biomarkers of FXa inhibitor–mediated anticoagulation

Management of DOAC-Associated Bleeding

11

(anti-FXa levels and unbound levels of FXa inhibitor) (97,98). The effect of ciraparantag on whole blood clotting time has been studied in healthy volunteers receiving edoxaban or enoxaparin (84,97,99,100). In 1 study, healthy volunteers received edoxaban followed by varying doses of ciraparantag or placebo. Edoxaban increased whole blood clotting time by 37% over baseline and, within #10 min, ciraparantag 100 mg and 300 mg reduced whole blood clotting time to within 10% of baseline, and the effect persisted for 24 h (97,100). Similar findings are evident from a phase I/II study with enoxaparin and ciraparantag. The whole blood clotting time returned to 5–10% of baseline within 5 min after ciraparantag injection, and this effect was sustained over 24 h (49). To date, published studies of ciraparantag have relied on measurement of whole blood clotting time but have not measured specific biomarkers of FXa inhibitor–mediated anticoagulation (98). The clinical utility of using whole blood clotting time to measure response is not currently known (101–103). A new phase II study for reversal of rivaroxaban anticoagulation by ciraparantag has been initiated, with the primary efficacy endpoint measuring anticoagulant reversal also assessed by whole blood clotting time (104). GUIDELINES ON MANAGEMENT OF BLEEDING ASSOCIATED WITH FXA INHIBITORS Treatment Recommendations Several academic societies have published guidelines that discuss management of FXa inhibitor–associated bleeding. Among these groups there is almost universal agreement that reversal of anticoagulation should be restricted to severe/life-threatening bleeding or therapeutically treated patients in need of an emergency invasive procedure (69,70,73,81,105–109). The current

prescribing information for rivaroxaban and apixaban recommends the use of a specific agent (i.e., andexanet alfa) to reverse anti-FXa activity, while the prescribing information for betrixaban and edoxaban provides limited direction for reversal of anticoagulation in FXa inhibitor–associated bleeding management (Table 5) (69,70,73,81,105). It is important to note that, unlike many drugs that have been approved by the FDA, the efficacy and safety of andexanet alfa has not yet been assessed in a randomized controlled trial and it is premature to consider andexanet alfa the standard of care. With the approval of andexanet alfa, the manufacturer has agreed to conduct another randomized clinical trial (ANNEXA-I) assessing the effectiveness vs usual care in reversing FXa inhibitors. Comprehensive evidence-based recommendations and guidelines on strategies for the management of acute major bleeding associated with DOACs are expected to be updated in lieu of the recent approval of the specific reversal agent for rivaroxaban and apixaban. The American College of Cardiology has recently updated their guidelines and developed a ManageAnticoag application, and the American College of Chest Physicians provided the description of andexanet alfa in their revised guidelines for antithrombotic therapy for atrial fibrillation (41,110,111). Updated guidelines from the Emergency Medicine Cardiac Research and Education Group recommend andexanet alfa for the reversal of the anticoagulation effects of all FXa inhibitors, including edoxaban and betrixaban, because the mechanism of action of andexanet alfa suggests that it may be equally effective in these agents (108). Similarly, recent guidelines from the Anticoagulation Forum recommend andexanet alfa for rivaroxaban- and apixaban-associated bleeding and either the use of andexanet alfa or 4-factor PCCs for edoxaban- and betrixaban-associated bleeding (107). The American Society of Hematology recommends the

Table 5. Guidance from Direct Oral Factor Xa Inhibitor Prescribing Information Name

Guidance

Rivaroxaban (Xarelto)

An agent to reverse the anti-FXa activity of rivaroxaban is available. The use of procoagulant agents, such as PCC, aPCC, or rFVIIa, may be considered but has not been evaluated in clinical studies An agent to reverse the anti-FXa activity of apixaban is available. Use of procoagulant reversal agents, such as PCC, aPCC, or rFVIIa, may be considered but has not been evaluated in clinical studies A specific reversal agent for edoxaban is not available. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity A specific reversal agent is not available. There is no experience with hemodialysis in individuals receiving betrixaban. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity

Apixaban (Eliquis) Edoxaban (Savaysa) Betrixaban (Bevyxxa)

Specific Reversal Agent Andexanet alfa Andexanet alfa None None

aPCC = activated prothrombin complex concentrate; FXa = factor Xa; PCC = prothrombin complex concentrate; rFVIIa = recombinant factor VIIa.

12

C. G. Kaide and M. P. Gulseth

use of either andexanet alfa or 4-factor PCCs for management of life-threatening bleeding in patients with VTE receiving FXa inhibitors and does not state a preference for one treatment over the other (109). Current guidelines from the Neurocritical Care Society, the European Heart Rhythm Association, the Thrombosis and Hemostasis Society of North America, the European Society of Cardiology Working Groups on Cardiovascular Pharmacotherapy and Thrombosis, and the American College of Emergency Physicians all discuss the use of PCCs for FXa inhibitor–associated bleeding in the absence of a specific reversal agent; however, they acknowledge the limited clinical evidence in this setting (70,73,81,105,106). No randomized comparisons have been conducted comparing specific reversal agents vs aPCC or PCC. These trials could help discern whether increasing the level of blood clotting factors to supraphysiologic levels via PCCs vs reversal of anticoa-

gulation with specific reversal agents is the optimal reversal strategy. In the case of life-threatening/emergency situations, general supportive measures, first-line specific reversal strategies, and second-line strategies in the absence of reversal agents are recommended (Figure 3). Existing reversal strategies involve 1) using a specific antidote for the DOAC (e.g., idarucizumab for dabigatran and andexanet alfa for rivaroxaban or apixaban) and 2) nonspecific reversal of anticoagulant activity (this may include PCCs or aPCC) (41,81). For the administration of PCCs, current guidelines recommend weighing the potential prothrombotic effects of PCCs against the potential benefits (73). The need for DOAC reversal agents is perhaps most essential in cases of emergent and immediate bleeding. These are situations where decision-making is more complex and often more consequential. DOAC reversal

Necessity of reversal? • Bleeding with hemodynamic instability • Not possible to postpone surgery or handle bleeding for ≥1 half-life of the OAC • Life-threatening bleeding due to bleeding site (e.g., intracranial bleeding)

No Moderate/severe bleeding/urgent surgery

General measures • Stop DOAC • Mechanical compression • Support measures – Hemodynamic support – Volume replacement – Blood transfusion • Specific interventions (e.g., surgical hemostasis) • Maintain diuresis • Reevaluate indication for antithrombotic therapy

Yes Life-threatening bleeding/emergency surgery

General measures • Intensive care setting • Hemodynamic support

First-line therapy if specific antidote is available • Intensive care setting • Use 5 mg idarucizumab for dabigatran • Use low- or high-dose andexanet alfa for rivaroxaban or apixaban (andexanet alfa should not be used in surgery patients because it has not been investigated in this population) • Use 4F-PCC for VKA (warfarin) Therapies if reversal agent is not available or inappropriate • If idarucizumab is not available, administer 4F-PCC or aPCC 50 units/kg IV • If andexanet alfa is not available, or surgery is planned, for rivaroxaban or apixaban, administer 4F-PCC 50 units/kg IV or aPCC 50 units/kg IV • If 4F-PCC is not available for VKA (warfarin), use plasma 10–15 mL/kg • Use 4F-PCC 50 units/kg IV for edoxaban • If 4F-PCC is not available for edoxaban, administer aPCC 50 units/kg IV

Figure 3. Recommendation for anticoagulation reversal (American College of Cardiology and European Society of Cardiology). Reversal treatment intervention begins with a determination of the necessity of reversal. In the case of life-threatening/ emergency situations, general support measures and reversal strategies are initiated and the availability of specific reversal agents is assessed. If reversal agents are available for dabigatran, rivaroxaban, apixaban, or warfarin (VKA), these are considered first-line therapies. If reversal agents are not available, other therapies should be considered as listed. Adapted from Niessner et al., Tomaselli et al., and the American College of Cardiology guidance for anticoagulation reversal (37,41,81). 4F-PCC = 4-factor prothrombin complex concentrate; aPCC = activated prothrombin complex concentrate; DOAC = direct oral anticoagulant; IV = intravenous; OAC = oral anticoagulant; VKA = vitamin K antagonist.

Management of DOAC-Associated Bleeding

approaches in these settings should assess patients’ history with vascular disease, individual thrombotic risk, and the nature of patient’s response to supportive care (24). Clear, standardized guidelines and protocols should be in place for managing DOAC-associated bleeding before it happens. Position Statements About PCCs The current guidelines suggest that PCCs and aPCCs should not be used in all circumstances because their risk–benefit profile in this setting is poorly understood. On the basis of anecdotal experience and limited evidence from the peer-reviewed literature, members participating in the 2012 Thrombosis and Hemostasis Summit of North America could not reach consensus concerning the use of 3-factor or 4-factor PCCs to stop critical bleeding or reverse the anticoagulant effects of DOACs (105). Recommendations from the Neurocritical Care Society indicate that the administration of agents to correct anti-FXa–associated coagulopathy is advisable, and that 4-factor PCCs or aPCCs may be preferred over rFVIIa because of more consistent evidence of reversal of coagulation parameters and lower risk of thromboembolism (rFVIIa has been associated with a relatively high thrombosis rate [12.8–24%]) (70). However, the committee stated that the available data are not sufficient to support the efficacy of available hemostatic agents for the reversal of oral FXa inhibitor–induced anticoagulation (70). Guidelines resulting from the 2016 Anticoagulation Forum suggest that clinicians should consider the use of nonspecific reversal strategies in patients who are refractory to standard therapies, but only until specific reversal agents are available (69). For direct FXa inhibitors, inactivated 4-factor PCC (50 U/kg) was suggested rather than aPCCs because aPCCs may pose a greater risk of thrombosis; FFP and rFVIIa were not recommended (69). Further, the European Heart Rhythm Association states that the ability of PCCs or aPCCs to reduce blood loss and improve outcome has yet to be recognized, and that the administration of PCCs or aPCCs may be considered in a patient with lifethreatening bleeding only if immediate hemostatic support is required (73). A report from the Anticoagulation Education Task Force suggested considering PCCs or aPCCs to restore hemostasis in DOAC-treated patients with lifethreatening bleeding but noted that idarucizumab is the preferred reversal agent for dabigatran (112), and a paper from the Thrombolysis in Myocardial Infarction Study Group concluded that in patients with serious bleeding, specific reversal agents (if available) should be used preferentially over nonspecific agents (113). In late 2017, a scientific statement from the American Heart Association and the report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways provided

13

guidelines on the management of bleeding in patients on DOACs (37,114). Both reports agreed that in the absence of specific antidotes PCCs may be considered. Similarly, a 2017 policy statement from the American College of Emergency Physicians recommended that dabigatrantreated patients with life-threatening bleeding be given idarucizumab, or PCCs if the antidote is not available. PCCs were also recommended for the reversal of anticoagulation in the presence of FXa inhibitors if no FDAapproved reversal agents were available (106). It is worthy to note that these guidelines were drafted before andexanet alfa was approved and the price of therapy was known. CONCLUSIONS Given the rapid and wide adoption of oral FXa inhibitors and the projected increase in their use within the large patient population at risk for thrombotic complications, clinicians are increasingly likely to encounter patients with acute major bleeding caused by anticoagulation therapy. Consequently, there has been concern among physicians regarding the management of acute major bleeding and restoration of coagulation before emergency surgery or invasive procedures. There is also a need for further research and improved evidence-based treatment guidelines, because current guidelines for FXa inhibitor– associated uncontrolled bleeding are based on expert opinion rather than clinical trial data and specific reversal strategies have not been compared with nonspecific strategies (81). Andexanet alfa is the first agent approved for the reversal of the FXa inhibitors rivaroxaban and apixaban but is not approved for facilitating emergency procedures. The investigational reversal agent ciraparantag is being investigated for reversal of direct and indirect FXa inhibition. These reversal agents may improve the quality of care and management of acute major bleeding in patients needing urgent reversal of anticoagulation. Additional studies, including randomized controlled trials in trauma populations, are needed before specific reversal agents can be considered standard of care. Acknowledgments—Dr. Kaide participates in educational activities for Portola Pharmaceuticals, Inc. Financial support for medical editorial assistance was provided by Portola Pharmaceuticals, Inc., United States. We thank Sarah Jablonski Schandle, PHD, of Accuverus, Inc., and Kimberly Fuller, PHD, of SciFluent Communications for their medical editorial assistance.

REFERENCES 1. Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med 2015; 128:1300–5.e1302.

14 2. Instititute for Safe Medical Practices. QuarterWatch. Available at: http://www.ismp.org/quarterwatch/pdfs/2015Q4.pdf. Accessed March 23, 2019. 3. Baker D, Wilsmore B, Narasimhan S. Adoption of direct oral anticoagulants for stroke prevention in atrial fibrillation. Intern Med J 2016;46:792–7. 4. Chi G, Goldhaber SZ, Kittelson JM, et al. Effect of extendedduration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis. J Thromb Haemost 2017;15:1913–22. 5. Bauer KA. Pros and cons of new oral anticoagulants. Hematology Am Soc Hematol Educ Program 2013;2013:464–70. 6. Dempfle CE. Direct oral anticoagulants–pharmacology, drug interactions, and side effects. Semin Hematol 2014;51:89–97. 7. Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014;124:2450–8. 8. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883–91. 9. Giugliano RP, Ruff CT, Wiviott SD, et al. Mortality in patients with atrial fibrillation randomized to edoxaban or warfarin: insights from the ENGAGE AF-TIMI 48 trial. Am J Med 2016; 129:850–7.e852. 10. Held C, Hylek EM, Alexander JH, et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J 2015;36:1264–72. 11. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–17. 12. Deitelzweig S, Neuman WR, Lingohr-Smith M, Menges B, Lin J. Incremental economic burden associated with major bleeding among atrial fibrillation patients treated with factor Xa inhibitors. J Med Econ 2017;20:1217–23. 13. Beyer-Westendorf J, Forster K, Pannach S, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014;124:955–62. 14. Yao X, Abraham NS, Sangaralingham LR, et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc 2016;5. 15. Nieto JA, Solano R, Ruiz-Ribo MD, et al. Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism: findings from the RIETE registry. J Thromb Haemost 2010;8: 1216–22. 16. Prandoni P, Trujillo-Santos J, Sanchez-Cantalejo E, et al. Major bleeding as a predictor of mortality in patients with venous thromboembolism: findings from the RIETE Registry. J Thromb Haemost 2010;8:2575–7. 17. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011;365:2167–77. 18. Cohen AT, Spiro TE, Buller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368:513–23. 19. Hull RD, Schellong SM, Tapson VF, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010;153:8–18. 20. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 2016;375:534–44. 21. Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015;13:2012–20. 22. Gomez-Outes A, Lecumberri R, Suarez-Gea ML, TerleiraFernandez AI, Monreal M, Vargas-Castrillon E. Case fatality rates of recurrent thromboembolism and bleeding in patients receiving direct oral anticoagulants for the initial and extended treatment

C. G. Kaide and M. P. Gulseth

23.

24. 25. 26.

27.

28.

29.

30.

31.

32. 33. 34. 35.

36.

37.

38. 39.

40.

of venous thromboembolism: a systematic review. J Cardiovasc Pharmacol Ther 2015;20:490–500. Hankey GJ, Stevens SR, Piccini JP, et al. Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. Stroke 2014; 45:1304–12. Gulseth MP. Overview of direct oral anticoagulant therapy reversal. Am J Health Syst Pharm 2016;73(10 suppl 2):S5–13. Milling TJ Jr, Kaatz S. Preclinical and clinical data for factor Xa and ‘‘universal’’ reversal agents. Am J Med 2016;129(suppl 11): S80–8. Milling TJ Jr, Clark CL, Feronti C, et al. Management of factor Xa inhibitor-associated life-threatening major hemorrhage: a retrospective multi-center analysis. Am J Emerg Med 2018;36: 396–402. Song Y, Wang Z, Perlstein I, et al. Reversal of apixaban anticoagulation by four-factor prothrombin complex concentrates in healthy subjects: a randomized three-period crossover study. J Thromb Haemost 2017;15:2125–37. Barco S, Whitney Cheung Y, Coppens M, Hutten BA, Meijers JC, Middeldorp S. In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate. Br J Haematol 2016;172:255–61. Cheung YW, Barco S, Hutten BA, Meijers JC, Middeldorp S, Coppens M. In vivo increase in thrombin generation by fourfactor prothrombin complex concentrate in apixaban-treated healthy volunteers. J Thromb Haemost 2015;13:1799–805. Brown KS, Wickremasingha P, Parasrampuria DA, et al. The impact of a three-factor prothrombin complex concentrate on the anticoagulatory effects of the factor Xa inhibitor edoxaban. Thromb Res 2015;136:825–31. Levi M, Moore KT, Castillejos CF, et al. Comparison of threefactor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost 2014;12:1428–36. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008;359:938–49. Piccini JP, Garg J, Patel MR, et al. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J 2014;35:1873–80. Milling TJ Jr, Frontera JA. Exploring indications for the use of direct oral anticoagulants and the associated risks of major bleeding. Am J Manag Care 2017;23(4 suppl):S67–80. Sengupta N, Feuerstein JD, Patwardhan VR, et al. The risks of thromboembolism vs. recurrent gastrointestinal bleeding after interruption of systemic anticoagulation in hospitalized inpatients with gastrointestinal bleeding: a prospective study. Am J Gastroenterol 2015;110:328–35. Nielsen PB, Larsen TB, Skjoth F, Gorst-Rasmussen A, Rasmussen LH, Lip GY. Restarting anticoagulant treatment after intracranial hemorrhage in patients with atrial fibrillation and the impact on recurrent stroke, mortality, and bleeding: a nationwide cohort study. Circulation 2015;132:517–25. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC Expert Consensus Decision Pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2017;70:3042–67. Phytonadione. Avaiable at: https://www.drugs.com/price-guide/ phytonadione. Accessed October 28, 2019. UPMC System Pharmacy and Therapeutics Committee Formulary Review. Prothrombin complex concentrate (human) (Kcentra CSL Behring LLC)). 2013. Available at: http://emcrit.org/wpcontent/uploads/2013/2012/Kcentra_2014FPCC_SPT.pdf. Accessed October 28, 2019. Shander A, Ozawa S, Hofmann A. Activity-based costs of plasma transfusions in medical and surgical inpatients at a US hospital. Vox Sang 2016;111:55–61.

Management of DOAC-Associated Bleeding 41. American College of Cardiology. ManageAnticoag App. Available at: https://www.acc.org/tools-and-practice-support/mobileresources/features/manageanticoag. Accessed October 24, 2018. 42. Praxbind (idarucizumab) injection, for intravenous use [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2018. 43. Jarrett JB, Gimbar RP. Idarucizumab (Praxbind) for dabigatran (Pradaxa) anticoagulant reversal. Am Fam Physician 2017;95: 798–800. 44. Praxbind. Available at: http://www.drugs.com/price-guide/ praxbind. Accessed October 28, 2019. 45. Heparin sodium injection, USP [package insert]. New York, NY: Pfizer, Inc.; 2019. 46. Protamine. Available at: https://www.drugs.com/price-guide/ protamine. Accessed October 28, 2019. 47. Lovenox (enoxaparin sodium injection) for subcutaneous and intravenous use [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC.; 2018. 48. Fragmin (dalteparin sodium) injection, for subcutaneous use [package insert]. New York, NY: Pfizer, Inc.; 2019. 49. Ansell JE. Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. J Thromb Thrombolysis 2016;41:248–52. 50. Shih AW, Crowther MA. Reversal of direct oral anticoagulants: a practical approach. Hematology Am Soc Hematol Educ Program 2016;2016:612–9. 51. Christos S, Naples R. Anticoagulation reversal and treatment strategies in major bleeding: update 2016. West J Emerg Med 2016; 17:264–70. 52. Babilonia K, Trujillo T. The role of prothrombin complex concentrates in reversal of target specific anticoagulants. Thromb J 2014; 12:8. 53. Profilnine SD [package insert]. Los Angeles, CA: Grifols Biologicals Inc.; 2010. 54. Bebulin [package insert]. Westlake Village, CA: Baxalta US Inc.; 2015. 55. Kcentra [package insert]. Kankakee, IL: CSL Behring LLC; 2013. 56. Dager W, Hellwig T. Current knowledge on assessing the effects of and managing bleeding and urgent procedures with direct oral anticoagulants. Am J Health Syst Pharm 2016;73(10 suppl 2):S14–26. 57. Raber M. Coagulation tests. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston: Butterworths; 1990. 58. Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb 2003; 33:173–83. 59. Curvers J, van de Kerkhof D, Stroobants AK, van den Dool EJ, Scharnhorst V. Measuring direct thrombin inhibitors with routine and dedicated coagulation assays: which assay is helpful? Am J Clin Pathol 2012;138:551–8. 60. Hemker HC, Beguin S. Thrombin generation in plasma: its assessment via the endogenous thrombin potential. Thromb Haemost 1995;74:134–8. 61. Chantarangkul V, Clerici M, Bressi C, Tripodi A. Standardization of the endogenous thrombin potential measurement: how to minimize the effect of residual platelets in stored plasma. Br J Haematol 2004;124:355–7. 62. Ikeda K, Tachibana H. Clinical implication of monitoring rivaroxaban and apixaban by using anti-factor Xa assay in patients with non-valvular atrial fibrillation. J Arrhythm 2016;32:42–50. 63. da Luz LT, Nascimento B, Rizoli S. Thrombelastography (TEG(R)): practical considerations on its clinical use in trauma resuscitation. Scand J Trauma Resusc Emerg Med 2013;21:29. 64. The Ohio State University, Wexner Medical Center. Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa): factor Xa inhibitors—reversal treatment for bleeding. 2nd ed. Available at:. https://evidencebasedpractice.osumc.edu/Documents/Guidelines/ Rivaroxaban.pdf. Accessed May 8, 2019. 65. Gosselin RC, Francart SJ, Hawes EM, Moll S, Dager WE, Adcock DM. Heparin-calibrated chromogenic anti-Xa activity

15

66. 67. 68. 69.

70.

71.

72.

73.

74. 75.

76. 77.

78.

79. 80. 81.

82.

83. 84.

measurements in patients receiving rivaroxaban: can this test be used to quantify drug level? Ann Pharmacother 2015;49:777–83. Scarpelini S, Rhind SG, Nascimento B, et al. Normal range values for thromboelastography in healthy adult volunteers. Braz J Med Biol Res 2009;42:1210–7. Awad NI, Cocchio C. Activated prothrombin complex concentrates for the reversal of anticoagulant-associated coagulopathy. P T 2013;38:696–701. FEIBA [package insert]. Westlake Village, CA: Baxalta US Inc.; 2017. Burnett AE, Mahan CE, Vazquez SR, Oertel LB, Garcia DA, Ansell J. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis 2016;41:206–32. Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2016;24:6–46. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 suppl):e152S–84. Dentali F, Marchesi C, Giorgi Pierfranceschi M, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 2011;106:429–38. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of nonvitamin K antagonist anticoagulants in patients with nonvalvular atrial fibrillation. Europace 2015;17:1467–507. Grottke O, Aisenberg J, Bernstein R, et al. Efficacy of prothrombin complex concentrates for the emergency reversal of dabigatraninduced anticoagulation. Crit Care 2016;20:115. Nagalla S, Thomson L, Oppong Y, Bachman B, Chervoneva I, Kraft WK. Reversibility of apixaban anticoagulation with a fourfactor prothrombin complex concentrate in healthy volunteers. Clin Transl Sci 2016;9:176–80. Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 2015;131:82–90. Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217–24. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate:a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9. Dzik WH. Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal. J Thromb Haemost 2015; 13(suppl 1):S187–94. Pollack CV Jr. Evidence supporting idarucizumab for the reversal of dabigatran. Am J Emerg Med 2016;34:33–8. Niessner A, Tamargo J, Morais J, et al. Reversal strategies for nonvitamin K antagonist oral anticoagulants: a critical appraisal of available evidence and recommendations for clinical management-a joint position paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy and European Society of Cardiology Working Group on Thrombosis. Eur Heart J 2017;38:1710–6. Dobesh PP, Bhatt SH, Trujillo TC, Glaubius K. Antidotes for reversal of direct oral anticoagulants. Pharmacol Ther 2019; https://doi.org/10.1016/j.pharmthera.2019.107405. [Epub ahead of print]. Yeh CH, Fredenburgh JC, Weitz JI. The real decoy: an antidote for factor Xa-directed anticoagulants. Circ Res 2013;113:954–7. Laulicht B, Bakhru S, Jiang X, et al. Antidote for new oral anticoagulants: mechanism of action and binding specificity of PER977. J Thromb Haemost 2013;11:75.

16 85. Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017; 377:431–41. 86. Andexxa (coagulation factor Xa (recombinant), inactivated-zhzo), lyophilized powder for solution for intravenous injection [package insert]. South San Francisco, CA: Portola Pharmaceuticals, Inc.; 2018. 87. Lu G, Lin J, Curnutte JT, Conley PB. Andexanet alfa, a universal antidote under development for factor Xa inhibitors, reverses rivaroxaban-induced inhibition of thrombin generation initiated by the intrinsic coagulation pathway independent of TFPI [abstract]. Presented at the American Society of Hematology 58th Annual Meeting, San Diego, CA, December 3–6, 2016. 88. Lu G, Lin J, Coffey G, Curnutte JT, Conley PB. Interaction of andexanet alfa, a universal antidote to fXA inhibitors, with tissue factor pathway inhibitor enhances reversal of fXA inhibitor-induced anticoagulation [abstract]. J Thromb Haemost 2015;13:634–5. 89. Crowther M, Kitt M, Lorenz T, et al. A phase 2 randomized, double-blind, placebo-controlled trial of PRT064445, a novel, universal antidote for direct and indirect factor Xa inhibitors [abstract]. J Thromb Haemost 2013;11:30. 90. Crowther M, Levy G, Lu G, et al. Reversal of enoxaparin-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for direct and indirect fXa inhibitors-a phase 2 randomized, double-blind, placebo-controlled trial [abstract]. J Thromb Haemost 2014;12:7. 91. Crowther M, Levy GG, Lu G, et al. A phase 2 randomized, doubleblind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors [poster]. Blood 2014;124:4269. 92. Crowther M, Vandana M, Kitt M, et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for FXa inhibitors [poster]. Blood 2013;122:3636. 93. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015;373: 2413–24. 94. Siegal D, Lu G, Leeds JM, et al. Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa. Blood Adv 2017;1:1827–38. 95. Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019;380:1326–35. 96. Kalathoukaren MT, Creagh AL, Lu G, et al. Comparing mechanisms of action of novel anticoagulant reversal agents through studies on binding partners and on clot formation and clot structure [abstract]. J Thromb Haemost 2016;14:31. 97. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014;371:2141–2. 98. Hollenbach S, Lu G, DeGuzman F, et al. Andexanet-alfa and PER977 (arapazine) correct blood loss in a rabbit liver laceration model - only andexanet reverses markers of FXa-mediated anticoagulation [abstract]. Circulation 2014;130:A14657. 99. Ansell JE, Laulicht BE, Bakhru SH, Hoffman M, Steiner SS, Costin JC. Ciraparantag safely and completely reverses the antico-

C. G. Kaide and M. P. Gulseth

100. 101. 102.

103.

104.

105. 106. 107. 108.

109.

110.

111. 112.

113. 114.

agulant effects of low molecular weight heparin. Thromb Res 2016;146:113–8. Ansell JE, Bakhru SH, Laulicht BE, et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost 2017;117:238–45. Ojito JW, Hannan RL, Burgos MM, et al. Comparison of point-ofcare activated clotting time systems utilized in a single pediatric institution. J Extra Corpor Technol 2012;44:15–20. Doherty TM, Shavelle RM, French WJ. Reproducibility and variability of activated clotting time measurements in the cardiac catheterization laboratory. Catheter Cardiovasc Interv 2005;65:33–7. Anderson L, Quasim I, Steven M, et al. Interoperator and intraoperator variability of whole blood coagulation assays: a comparison of thromboelastography and rotational thromboelastometry. J Cardiothorac Vasc Anesth 2014;28:1550–7. ClinicalTrials.gov. Phase 2 placebo-controlled, single-site, singleblind study of rivaroxaban reversal by ciraparantag as measured by WBCT. Available at: https://www.clinicaltrials.gov/ct2/show/ NCT03172910. Accessed November 28, 2018. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012;87(suppl 1):S141–5. Reversal of non-vitamin K antagonist oral anticoagulants (NOACs) in the presence of major life-threatening bleeding. Ann Emerg Med 2017;70:944–5. Cuker A, Burnett A, Triller D, et al. Reversal of direct oral anticoagulants: guidance from the Anticoagulation Forum. Am J Hematol 2019;94:697–709. Gibler WB, Racadio JM, Hirsch AL, Roat TW. Management of severe bleeding in patients treated with oral anticoagulants: proceedings monograph from the Emergency Medicine Cardiac Research and Education Group-International Multidisciplinary Severe Bleeding Consensus Panel October 20, 2018. Crit Pathw Cardiol 2019;18:143–66. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv 2018;2:3257–91. American College of Cardiology. Guidance for Anticoagulation Reversal. Available at: https://www.acc.org//media/NonClinical/Images/Tools%20and%20Practice%20Support/Mobile% 20Resources/ManageAnticoag/B18120_ManageAnticoag_App_ Fact_Sheet.pdf. Accessed October 24, 2018. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018;154:1121–201. Ageno W, Buller HR, Falanga A, et al. Managing reversal of direct oral anticoagulants in emergency situations. Anticoagulation Education Task Force White Paper. Thromb Haemost 2016;116: 1003–10. Ruff CT, Giugliano RP, Antman EM. Management of bleeding with non-vitamin K antagonist oral anticoagulants in the era of specific reversal agents. Circulation 2016;134:248–61. Raval AN, Cigarroa JE, Chung MK, et al. Management of patients on non-vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation 2017;135: e604–33.

Management of DOAC-Associated Bleeding

ARTICLE SUMMARY 1. Why is this topic important? Given the rapid and wide adoption of direct oral anticoagulants (DOACs), including factor Xa (FXa) inhibitors, it is essential for emergency physicians to understand the supporting evidence and guidelines for managing major bleeding in patients anticoagulated with these agents and to be informed of novel reversal agents that may change current management strategies. 2. What does this review attempt to show? This review summarizes and evaluates the current standards for management of acute major bleeding in patients anticoagulated with DOACs and assesses clinical evidence for nonspecific strategies as well as novel investigational reversal agents. 3. What are the key findings? Currently, revised guidelines recommend considering specific reversal agents (idarucizumab for reversal of the direct thrombin inhibitor dabigatran, and andexanet alfa for reversal of the direct FXa inhibitors apixaban and rivaroxaban), as first-line therapies in patients with lifethreatening bleeding. In the absence of reversal agents, second-line therapies with prothrombin complex concentrates or activated prothrombin complex concentrates are recommended as nonspecific options to supplement clotting factors in anticoagulated, bleeding patients until specific reversal agents are available. Note that these recommendations were drafted before andexanet alfa was approved and before pricing was known. 4. How is patient care impacted? This evaluation of current and investigational strategies for management of major bleeding in patients anticoagulated with DOACs provides concise information on how emergency care and outcomes in bleeding patients may be improved.

17