16. Anticoagulant reversal

Key Points

 

• Reversal of anticoagulation is dependent on the type of anticoagulant and indication for reversal (ie. bleeding versus surgical procedure versus supratherapeutic drug levels).
• Parenteral anticoagulants have a short half-life and in many scenarios stopping the medication infusion is all that is necessary for reversal.
• Vitamin K antagonists can be reversed by Vitamin K, plasma, or prothrombin complex concentrate.
• The direct oral anticoagulants, dabigatran, rivaroxaban, and apixaban all have specific reversal agents that can be used; however, in centers where these medications are not available prothrombin complex concentrates could be considered particularly for the reversal of the factor-Xa inhibitors.

Introduction

Use of anticoagulation for stroke prevention in patients with atrial fibrillation and the treatment and prevention of venous thromboembolic events continues to rise. In this chapter, the reversal of oral, parenteral and subcutaneous anticoagulants will be discussed with a focus on recommendations found in the Antithrombotic Therapy and Prevention of Thrombosis: American College of Chest Physicians Evidence-Based Clinical Practice (ACCP) Guidelines and the American Society of Hematology (ASH) guidelines for management of venous thromboembolism  [1-3].
  

Reversal of Parenteral and Subcutaneously Administered Anticoagulants

There are two primary classes of FDA-approved parenteral anticoagulants:

1. Medications that act as cofactors with antithrombin III to inactivate factor Xa and/or thrombin (unfractionated heparin)
2. Medications that directly target and inactivate thrombin (argatroban and bivalirudin).

Subcutaneously administered medications include low molecular weight heparins (LMWH, ie. enoxaparin and dalteparin) and fondaparinux, a synthetic anticoagulant that indirectly inhibits factor Xa. If the need for anticoagulant reversal is non-urgent (ie. no bleeding, no need for urgent procedure) then the infusion or injection can be held. Below, methodology for urgent/ emergent reversal of parenteral and subcutaneous anticoagulants is described. 

 

 

Reversal of Oral Anticoagulants

Millions of patients are treated with oral anticoagulant therapy. Though historically, the vitamin K antagonist, warfarin, was the oral anticoagulant of choice, the direct oral anticoagulants (DOACs) have gained popularity. Current FDA-approved DOACs include dabigatran, a direct thrombin inhibitor and the FXa inhibitors rivaroxaban, apixaban, and edoxaban [4].  

 

Vitamin K Antagonists

Non-urgent Reversal

In the absence of bleeding, reversal may be necessary for an elective procedure. For pre-operative INR reversal, warfarin should be discontinued five days prior to the procedure [6]. If surgery needs to be performed prior to 5 days, then Vitamin K can be considered. For patients at high risk of thrombosis, peri-procedural anticoagulation using bridging therapy may need to be utilized [6].
In the absence of bleeding VKA reversal also needs to be considered for supratherapeutic INR levels. The risk of bleeding increases significantly when the INR exceeds 4.5 [7]. For patients receiving VKA with INRs > 4.5 and <10 without clinically relevant bleeding, temporary cessation of VKA alone without the addition of vitamin K is recommended. However, if INR is >10 without bleeding, low dose vitamin K is recommended [1, 2].

VKA Reversal in the Setting of Clinically Relevant and Major Bleeding

In cases of clinically relevant bleeding with INR > 4.5, in addition to cessation of VKA, administration of vitamin K is recommended [1] and in emergency situations, parenteral vitamin K (10 mg) instead of oral vitamin K is recommended given more rapid onset. In addition to cessation of VKA and administration of vitamin K, for life-threatening bleeding,  providers should also consider the use of FFP or  PCC [8].

Importantly, even when using FFP or PCC vitamin K is necessary to prevent rebound effects of anticoagulation due to the short half-life of FFP and PCC. Of note, both the ACCP and ASH guidelines recommend the use of 4F-PCC rather than FFP for VKA-associated major bleeding [1, 2]. However, 4F-PCC may not be available at all centers therefore 3F-PCC and FFP are alternative options.
 

Direct oral anticoagulants

Though offering more ease of use and favorable safety when compared to vitamin K antagonists, until the advent of specific antidotes, lack of specific reversal agents has been one of the disadvantages for considering a DOAC. The specific and nonspecific options for reversal of DOACs are discussed below (Table 1).

 

Non-Urgent Surgical Procedures and Non-major Bleeding

For the purposes of elective or non-urgent surgical procedures, all DOACs can be discontinued for days preceding the surgery. The number of days that the DOAC should be stopped varies with each medication and takes into account the metabolism and excretion of the DOAC as well as patient-specific factors such as renal function. For non-major bleeding, along with supportive care, the DOAC should be discontinued.

If urgent reversal is necessary then the medications (with the exception of andexanet alfa for surgical reversal) discussed below are potential options.

Specific Reversal Agents

Reversal of Dabigatran

Idarucizumab, a humanized monoclonal antibody was approved in 2015 by the FDA for reversal of dabigatran in situations of life-threatening bleeding or emergency surgery.  Idaruizumab binds to dabigatran and the active glucuronide metabolites of dabigatran the complexes are cleared by the kidneys [4]. In the REVERSE-AD trial, parenteral administration of idarucizumab reversed the anticoagulant effect of dabigatran by 100%. Administration of idarucizumab allowed surgery to be performed in 97.5% of patients and periprocedural hemostasis was normal in 93.4% of these patients, mildly abnormal in 5.1% of patient, and moderately abnormal in 1.5% of patients. In addition, in those patients requiring reversal due to bleeding, median time to cessation of bleeding was 2.5 hours. The rates of thrombotic events were consistent with rates reported after hospitalization for uncontrolled bleeding or major surgical procedures. The patients enrolled in the study were elderly and had several co-morbid conditions and deaths in the study were thought to be secondary to the index event or to a coexisting condition [9].  

 

Reversal of Oral Factor Xa Inhibitors

In 2018, andexanet alfa, a recombinant modified Factor Xa molecule that binds and sequesters factor Xa (FXa) inhibitors, was approved for the reversal of apixaban and rivaroxaban in settings of life-threatening bleeding based on results for the ANNEXA-4 trial which demonstrated substantial reduction in anti-factor Xa activity in patients with acute major bleeding associated with FXa inhibitors as well as effective hemostasis in 82% of patients [10]. 10% and 14% of patients had at least one thrombotic event or died within 30 days of receiving the reversal agent. Reversal of FXa inhibitors for emergent surgical procedures is not an approved indication for andexanet alfa and in these scenarios the use of PCC could be considered.

 

Nonspecific reversal agents for DOACs

Prior to the approval of specific reversal agents, PCC had been the primary pharmacologic option for the reversal of DOACs, however the efficacy of PCC for reversal of DOACs is still uncertain. 3F-and 4F-PCC as well as activated PCC (aPCC) and recombinant activated VII  have been used for reversal of DOACS [11] although more robust data is available for the use of 4F-PCC for the reversal of FXa inhibitors.

The safety and efficacy of 4F-PCC was assessed in a meta-analysis of 10 case series with 340 patients who received 4F-PCC for direct FXa inhibitor-related major bleeding. In the 2 studies that used International Society of Thrombosis and Hemostasis criteria for clinical outcomes, the proportion of patients with effective management of major bleeding was 0.69 ( 95% confidence interval, 0.61-0.76) and in the eight remaining studies not using ISTH criteria the proportion of patients with effective management of major bleeding was 0.77 (95% CI, 0.63-0.92). The overall conclusion of the study was that due to the lower level of evidence it is difficult to determine whether 4F-PCC in addition to cessation of FXa inhibitors is more effective than cessation of FXa inhibitors alone in patients with FXa inhibitor-related major bleeding. Although this study did not have strong enough data to definitely support the use of 4F- PCC in direct oral FXa inhibitor-related major bleeding, in those patients where andexanet alfa is not available or in patients with less severe clinical bleeding, 4F-PCC is certainly a viable pharmacologic option to consider[12, 13].  

 

Use of Activated Charcoal and Hemodialysis for Reversal of DOACs

In centers where andexanet alfa, idarucizumab or 4F-PCC are not available, consideration could be made to administer activated charcoal if rivaroxaban, apixaban, or dabigatran have been ingested in the last two hours. Hemodialysis is another method for reversal of the DOAC but can only be used for the reversal of dabigatran; hemodialysis has the ability to remove up to 68% of dabigatran [14]. Apixaban and rivaroxaban are not dialyzed because they are highly protein-bound [3]. In addition, edoxaban is approximately 50% bound to proteins and hemodialysis is not an effective method for edoxaban removal [15]. 
 

Conclusions

Options for reversal of anticoagulation are dependent on indication for reversal and type of anticoagulant.  For non-clinically significant bleeding or elective procedures, reversal may simply take place by turning off the infusion for parenteral anticoagulants or not administering the next dose of subcutaneous or oral anticoagulant. However, for clinically relevant bleeding and urgent procedures, nonspecific and specific reversal agents should be considered. 

 

 

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