What is the reversal strategy for Apixaban (Eliquis)?

From the Guidelines

Eliquis (apixaban) can be reversed in emergency situations using Andexxa (andexanet alfa), which is specifically designed to reverse the anticoagulant effects of factor Xa inhibitors like Eliquis. The dosing of Andexxa depends on the dose of Eliquis and when it was last taken. For patients on standard Eliquis doses, the dosing of Andexxa is as follows:

• if the last dose of apixaban was taken > 8 hours prior, a low dose of Andexxa (400 mg IV bolus followed by 4 mg/min infusion for up to 120 minutes) is administered 1
• if the last dose of apixaban was taken < 8 hours prior, or timing unknown, a high dose of Andexxa (800 mg IV bolus followed by 8 mg/min infusion for up to 120 minutes) is administered 1. Andexxa works by binding to the anticoagulant and preventing it from inhibiting factor Xa, thus restoring normal blood clotting. The efficacy and safety of Andexxa in patients taking factor Xa inhibitors with acute major bleeding has been evaluated in the ANNEXA-4 phase 3b–4 study, which demonstrated that an initial bolus and subsequent 2-h infusion of Andexxa substantially reduced anti-factor Xa activity with clinically adjudicated effective hemostasis occurring in 82% of patients 1. For life-threatening bleeding where Andexxa is unavailable, prothrombin complex concentrate (PCC) at 25-50 units/kg can be used as an alternative, though it's less effective. Activated charcoal may help if Eliquis was ingested within 2-6 hours. Hemodialysis is not effective for Eliquis removal due to its high protein binding. After reversal, patients should be monitored closely for recurrent bleeding or thrombotic events, as the reversal effect lasts only about 1-2 hours after stopping the Andexxa infusion. Some key points to consider when using Andexxa for Eliquis reversal include:
• The importance of timely administration of Andexxa to achieve effective reversal of anticoagulation 1
• The need for close monitoring of patients after Andexxa administration to prevent recurrent bleeding or thrombotic events 1
• The potential for Andexxa to be used in a variety of clinical settings, including emergency departments and intensive care units 1.

From the FDA Drug Label

The pharmacodynamic effect of apixaban tablets can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives. An agent to reverse the anti-factor Xa activity of apixaban is available

In Study 1, healthy subjects (median age: 57 years; range: 50 to 73 years) received apixaban 5 mg twice daily for three and a half days to achieve steady-state. At three hours after the last apixaban dose (~ Cmax), ANDEXXA or placebo was administered Eight subjects received placebo, and 24 received ANDEXXA, administered as a 400 mg IV bolus followed by a 4 mg per minute continuous infusion for 120 minutes (total 480 mg).

Reduction in Anti-FXa Activity In Study 1 and Study 2, the percent change from baseline in anti-FXa activity at its nadir was statistically significant (p < 0. 0001) in favor of the ANDEXXA groups compared to placebo in both Studies 1 and 2.

Eliquis Reversal:

• Andexanet alfa (ANDEXXA) is an agent that can reverse the anti-factor Xa activity of apixaban.
• The recommended dose of ANDEXXA for apixaban reversal is a 400 mg IV bolus followed by a 4 mg per minute continuous infusion for 120 minutes (total 480 mg) 2.
• The reduction in anti-FXa activity after ANDEXXA administration was statistically significant compared to placebo 2.
• Prothrombin complex concentrate (PCC), activated prothrombin complex concentrate, or recombinant factor VIIa may be considered for reversal, but have not been evaluated in clinical studies 3.

From the Research

Eliquis Reversal Agents

• Eliquis, also known as apixaban, is a direct oral anticoagulant (DOAC) that targets factor Xa and inhibits thrombin generation and clot formation 4.
• There are several agents that have been investigated for the reversal of apixaban, including prothrombin complex concentrates (PCCs) and specific reversal agents such as andexanet alfa 5, 6, 7.

Prothrombin Complex Concentrates (PCCs)

• PCCs have been shown to reverse the anticoagulant effects of apixaban in healthy subjects and in patients with major bleeding 5, 6.
• A study published in 2017 found that four-factor PCCs rapidly reversed apixaban-mediated decreases in mean endogenous thrombin potential in healthy subjects 5.
• Another study published in 2018 found that PCCs were effective in reversing apixaban's anticoagulant effects in patients with major bleeding, with 65% of patients achieving good hemostatic effectiveness 6.

Specific Reversal Agents

• Andexanet alfa is a modified FXa molecule that has been approved in the United States to reverse the anticoagulant effects of apixaban and rivaroxaban in patients with life-threatening or uncontrolled bleeding 7.
• Ciraparantag is a small-molecule inhibitor of multiple anticoagulants that has been investigated in healthy subjects, but its efficacy and safety in reversing apixaban's anticoagulant effects are still being studied 7.

Laboratory Tests

• Apixaban has little effect on prothrombin time (PT) or activated partial thromboplastin time (APTT), but it affects all parameters of thrombin generation, including lag-time, endogenous thrombin potential, and thrombin-peak 4, 8.
• The effects of apixaban on thrombin generation parameters can be used as a laboratory tool to assess the anticoagulant activity of this drug and to compare its effects with other DOACs 4.