EpistemisIdarucizumab / Andexanet Alfa
ACOD Reversal Agents (e.g. *Praxbind*, *Ondexxya*).
Mechanism
Mechanism of Action
Idarucizumab and Andexanet alfa are specific reversal agents designed to immediately counteract the anticoagulant effect of DOACs in situations of severe life-threatening bleeding.
Idarucizumab (Dabigatran Antidote)
It is a humanized monoclonal antibody fragment (Fab) designed to specifically bind free or conjugated dabigatran:
- It has a binding affinity for dabigatran approximately 350 times higher than the affinity of dabigatran for thrombin itself.
- It binds extremely quickly, trapping the plasma dabigatran molecule and completely neutralizing its catalytic inhibition capacity on thrombin almost immediately.
- Does not present its own procoagulant activity.
Andexanet Alfa (Xa Inhibitor Antidote)
It is a genetically modified recombinant protein equivalent to a mimic molecule of active human Factor Xa:
- The serine residue of the active site was modified by alanine, eliminating the catalytic activity of Factor Xa (it does not induce the intrinsic cascade).
- The membrane Gla domain was removed to prevent integration into the prothrombinase complex.
- It acts as a high-affinity soluble "decoy receptor" that competitively captures Rivaroxaban or Apixaban in the plasma, releasing the patient's native endogenous Factor Xa to resume the generation of physiological thrombin.
Pharmacokinetics
Pharmacokinetics
- Idarucizumab: Intravenous administration in two consecutive rapid bolus infusions of 2.5 g (total dose 5 g). It has a reduced volume of distribution compatible with the plasma space. Biphasic clearance half-life with a terminal half-life of about 4 to 10 hours. It is excreted unchanged mainly by renal filtration in the form of inactive immune complexes. The reversal effect is evident in the aPTT in the first minutes post-infusion.
- Andexanet Alfa: Intravenous administration by initial loading bolus followed by continuous regulated intravenous infusion for 120 minutes (to avoid rebound of free tissue anticoagulant). Elimination half-life of 5 to 7 hours. Metabolic clearance and purification through the reticuloendothelial system.
Indicators and dose
Indications
- Idarucizumab: Rapid and complete reversal of the anticoagulant effects of Dabigatran in adult patients who present with life-threatening or uncontrolled bleeding, or who require emergency surgery or urgent procedures that cannot be postponed (< 8 hours).
- Andexanet Alfa: Rapid reversal of the anticoagulant effect in patients treated with Rivaroxaban or Apixaban who present life-threatening bleeding of extreme severity or uncontrolled (mainly active intracranial hemorrhage of progressive course).
Dosage and Regimens
- Idarucizumab: Fixed dose of 5 g intravenously, administered in two consecutive vials of 2.5 g/50 mL by rapid infusion of 5 to 10 minutes each or by direct intravenous injection as a rapid bolus.
- Andexanet Alfa: The dosage is adjusted individually based on the dose of oral anticoagulant previously administered and the time elapsed since the last oral intake:
| Previous DOACs | DOAC Dose Administered | Elapsed time < 8 hours (or Unknown) | Elapsed time 8 hours |
|---|---|---|---|
| Rivaroxaban | > 10 mg (or Unknown) | High Dose: IV bolus of 800 mg at 30 mg/min; followed by infusion of 8 mg/min for 120 min | Low Dose:IV bolus of 400 mg to 30 mg/min; followed by infusion of 4 mg/min for 120 min |
| Apixaban | > 5 mg (or Unknown) | High Dose: 800 mg IV bolus; followed by infusion of 8 mg/min for 120 min | Low Dose: IV bolus of 400 mg; followed by infusion of 4 mg/min for 120 min |
| Rivaroxaban / Apixaban | 10 mg / 5 mg | Low Dose: IV bolus of 400 mg; followed by infusion of 4 mg/min for 120 min | Low Dose: IV bolus of 400 mg; followed by infusion of 4 mg/min for 120 min |
Pregnancy and Breastfeeding
No analytical data on safety in pregnant women is available. Use only if there is maternal vital compromise and risk of imminent death that justifies immediate withdrawal of the anticoagulant.
Security
Contraindications
- There are no validated absolute contraindications in the context of life-saving emergencies with active uncontrolled bleeding and imminent risk of death.
- Demonstrated basic hypersensitivity to biotechnological formulations or excipients of the preparations.
Adverse Effects (ADR)
- Risk of Thromboembolic Events: Instantaneous suppression of the action of the anticoagulant immediately exposes the patient to their prothrombotic state or underlying vascular pathology (e.g., AF with stasis in the left atrial appendage or previous recurrent DVT). Rates of 3-5% of thrombotic events (such as ischemic stroke or deep vein thrombosis) have been reported in the weeks following reverter infusion. Prophylactic or precision therapeutic anticoagulation should be restarted as soon as stabilization of hemostatic hemostasis is achieved.
- Transient febrile reactions: Chills, flushing, minor headache.
Interactions
Idarucizumab and Andexanet alfa do not inhibit or induce hepatic microsomal cytochrome P450 isoenzymes, lacking metabolic interactions. Andexanet alfa may residually bind unfractionated heparin competitively, temporarily rendering intravenous heparin useless if administered shortly thereafter.
Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.
- System
- Hematology
- Cluster
- Antidotes and Reversers