Reversal of direct oral anticoagulants: Highlights from the Anticoagulation Forum guideline

Intended audience for the guideline

General practice, hematology, anticoagulation clinics, emergency, cardiovascular, surgical, and intensive care providers.

Authors of the guideline

The authors of the guideline are associated with the Anticoagulation Forum (acforum. org) and are recognized experts in the field. Conflicts of interest were disclosed when present.

Process used for writing the guideline

The unanimous consensus of all authors was determined for each question addressed. The authors conducted a PubMed search related to each key question by prioritizing studies involving patient-reported bleeding, thromboembolism, and mortality. In addition, they reviewed supplemental material of studies cited, US Food and Drug Administration (FDA) package inserts, and www.clinicaltrials.gov and also manually reviewed references.

Available reversal agents

Two FDA-approved target-specific reversal agents are now commercially available.

Idarucizumab is a humanized monoclonal antidabigatran antibody fragment approved for reversing dabigatran-associated bleeding.⁷

Andexanet alfa is a modified recombinant inactive form of human factor Xa that binds to and blocks the effects of factor Xa inhibitors. It is approved for reversal of apixaban and rivaroxaban in cases of bleeding.⁸ However, its use to reverse the effects of edoxaban and betrixaban is currently off-label, as larger studies are still needed to determine its efficacy and safety for this use.

Off-label use of hemostatic agents. The guideline also includes suggestions for off-label use of hemostatic agents such as activated prothrombin complex concentrate (APCC) for dabigatran-associated bleeding⁸ and 4-factor prothrombin complex concentrate (4FPCC) for direct factor Xa inhibitor-associated bleeding.^9,10

APCC contains a balanced ratio of the zymogen forms of factors II, VII, IX, and X (which are procoagulants); protein C (an anticoagulant); and tissue factor pathway inhibitor, cofactors V and VIII, and protein S.⁹ In a prospective study,¹⁰ it was associated with good hemostasis and no thromboembolic events.

4FPCC, which contains factors II, VII, IX, and X; proteins C and S; antithrombin III; and human albumin, can be considered for reversing direct factor Xa inhibitor-associated bleeding. However, in 2 studies,^11,12 4FPCC was associated with ischemic stroke and thromboembolic events. Therefore, caution is needed when using this agent.

Supportive care should be considered in all cases of bleeding associated with DOACs. This includes stopping the DOAC, applying local hemostasis, transfusing red blood cells and platelets, and volume resuscitation.

Indications for reversal agents

The guideline does not recommend routinely using reversal agents for DOAC overdose, but strongly recommends using them only in cases of the following:

• Life-threatening bleeding

• Bleeding into critical organs

• Other major bleeding not controlled with maximal support measures (stopping the anticoagulant or other medications that prolong bleeding, compression or procedures to stop the bleeding at the bleeding site, volume resuscitation, or transfusion)

• Concerns or reasonable expectation that there is a clinically relevant plasma DOAC level

• Urgent invasive procedures in DOAC-treated patients, including cardiac, vascular, and neurosurgical emergency surgeries that need to be performed to save limbs, organs, or the life of the patient.¹³

Dosage

The guideline recommends the following in cases of major bleeding or to reverse anticoagulation for urgent procedures:

If the patient is taking dabigatran, give idarucizumab 5 g intravenously. If idarucizumab is not available, the alternative is APCC 50 units/kg intravenously (off-label use).

If taking rivaroxaban in doses of 10 mg or less or if the last dose of rivaroxaban was taken 8 or more hours ago, initiate andexanet alfa in a low dose, ie, 400 mg intravenous bolus at a target rate of 30 mg/minute followed by continuous infusion at 4 mg/minute for up to 120 minutes.

If the amount or time of the last dose is unknown or if it was more than 10 mg less than 8 hours ago, initiate high-dose andexanet alfa, ie, 800 mg intravenous bolus at a rate of 30 mg/minute followed by continuous infusion at 8 mg/minute for up to 120 minutes. If andexanet alfa is not available, the recommended alternative is 4FPCC 2,000 units intravenously (Table 2).

If taking apixaban in doses of 5 mg or less or if the last dose of apixaban was taken 8 or more hours ago, initiate low-dose andexanet alfa (400 mg intravenous bolus at a target rate of 30 mg/minute followed by continuous infusion at 4 mg/minute for up to 120 minutes). If the time or amount is unknown or the last dose was more than 5 mg and less than 8 hours ago, initiate high-dose andexanet alfa (800 mg intravenous bolus at a rate of 30 mg/minute followed by continuous infusion at 8 mg/minute for up to 120 minutes) (Table 2). If andexanet alfa is not available, the recommended alternative treatment is 4FPCC 2,000 units intravenously.

If taking edoxaban or bextrixaban, give andexanet alfa 800 mg intravenous bolus followed by continuous infusion of 8 mg/minute for up to 120 minute (off-label use) or 4FPCC 2,000 units intravenously (Table 3).

Concerns

The specific reversal agents that are available for dabigatran and anti-Xa inhibitors are of clear clinical benefit, as outlined above. However, the Anticoagulation Forum guideline expresses concern over the high cost of DOAC reversal agents, which may limit their availability. In addition, there is a risk of thrombosis associated with 4FPCC and andexanet alfa. Arterial and venous thrombosis, myocardial infarction, ischemic stroke, cardiac arrest or sudden death were observed within 3 to 30 days post administration of 4FCC¹¹ and andexanet alfa⁸ (median time to the first event was 7 days).

With idarucizumab treatment, rates of thrombotic events (venous thromboembolism, ischemic stroke, myocardial infarction, and systemic embolism) were 4.8% at 30 days and 6.8% at 90 days. However, the study reported that events at 30 days may have been caused by the low level of restarting anticoagulation treatment. Thrombotic events at 90 days were likely associated with the underlying prothrombotic medical conditions rather than idarucizumab treatment.⁷

With APPC treatment, there were no thrombotic events reported.¹⁰ However, post-marketing surveillance reported thromboembolic events especially after high doses and in patients with thromboembolic risk factors.¹⁴

Therefore, the benefit of reversing anticoagulation therapy must be carefully weighed against the risk of thromboembolic events. Proper anticoagulation should be resumed once the risk of thromboembolism outweighs the risk of bleeding. The patient should be monitored for possible thromboembolic events during and after the administration of a reversal agent.

Stewardship programs

Finally, the guideline authors recommend that health systems focus on building a stewardship program to address challenging DOAC reversal cases appropriately. Most of the potential challenges can be placed into the categories of acquisition and cost, operational logistics, and appropriate utilizations. A stewardship team dedicated to developing, implementing, and maintaining system-wide processes and protocols pertaining to optimal utilization of DOAC reversal agents has been shown to be effective in overcoming these challenges.

Antifibrinolytic agents

In view of concerns about costs and side effects associated with reversal agents, some experts suggest using antifibrinolytic agents such as tranexamic acid and epsilon-aminocaproic acid for major bleeding (including life-threatening bleeding) and less serious bleeding with other comorbidities.¹⁶ The use of antifibrinolytic agents was also recommended by the 2018 European Heart Rhythm Association guideline¹³ and by UpToDate.¹⁷ The advantages of these agents are their lower cost and ready availability, with minimal risk of thrombosis.

In addition to these agents, desmopressin can be used in settings of impaired platelet function associated with uremia or antiplatelet agents.¹⁵ Dosing of desmopressin is 0.3 μg/kg subcutaneously, or intravenously in 50 mL of normal saline over 15 to 30 minutes (Table 4).¹⁷ Only 2 doses are recommended due to concerns for tachyphylaxis and hyponatremia.¹⁵

A limitation of antifibrolytic agents is the lack of good quality clinical studies. However, a multicenter randomized clinical trial is currently enrolling patients to evaluate tranexamic acid for DOAC-associated intra-cerebral hemorrhage (ClinicalTrials.gov identifier NCT02866838).

There is also promising research on ciraparantag (PER977), which is a universal antidote for direct thrombin factor Xa inhibitors and heparinoids.¹⁸