ADD-ONS / ANTICOAGULANT THERAPY

Idarucizumab (PRAXBIND)

Created 10/11/2021, last revision 25/04/2023

the use of idarucizumab as an antidote (to reverse the anticoagulant effects of dabigatran) was approved by the FDA in October 2015 [Cassels, 2015]
it has a 300 times greater affinity for thrombin than dabigatran
indicated in adult patients treated with dabigatran (PRADAXA) in situations where the anticoagulant effects need to be rapidly reversed:
- urgent surgery/urgent procedures (including intravenous thrombolysis)
- life-threatening/uncontrolled bleeding (including ICH)
virtually no contraindications (except allergy) or relevant drug interactions, no serious AEs

Mechanism of action

idarucizumab is a fragment of a humanized monoclonal antibody that acts as a specific reversal agent for dabigatran
it binds tightly to dabigatran and its acyl glucuronide metabolites and forms a complex with it, thereby immediately halting the anticoagulant effect of dabigatran
- dabigatran has a 300-fold higher affinity for idarucizumab than for thrombin
no interference with other anticoagulants and no secondary hypercoagulable state
administered as an IV bolus with rapid onset of action
allows rapid resumption of anticoagulant therapy (24h after administration)

several pathways contribute to antibody metabolism – all involve the biodegradation of antibodies into smaller molecules, which are then reabsorbed and incorporated into the general protein synthesis

RE-VERSE AD trial with idarucizumab at a dose of 5g IV
- effective within minutes
- analysis of 90 patients showed a reliable reduction of anticoagulant activity (normal coagulation in 90% of patients at 4 and 12 hours) → see here
there is growing clinical experience with PRAXBIND administration prior to thrombolysis and in the acute treatment of ICH → see here

allergy to idarucizumab or ingredients
patients with hereditary fructose intolerance may be at risk of adverse reactions (such as low blood sugar, low phosphate, metabolic acidosis, increase in uric acid, and acute liver failure)

no adequate and well-controlled studies on pregnant women
it is not known whether idarucizumab can cause fetal harm when administered to a pregnant woman ⇒ should be given to a pregnant woman only if absolutely necessary
no data for use during labor and delivery

it is not known whether idarucizumab passes into human milk
no data on the effects of idarucizumab on nursing infants or on milk production
the benefits of breastfeeding should be weighed against the mother’s clinical need for the drug (the benefits must outweigh the risks)

aseptic handling is required during the preparation
visually inspect for particulates and discoloration before infusion
once the solution is removed from the vial, the administration should begin immediately; vials may be stored at room temperature (25°C /77°F) but must be used within 6h
do not mix with other medication

PRAXBIND 2 x 2.5g/50 ml
- administer 5g dose IV as two consecutive 2.5 g infusions or bolus injections
- an existing intravenous line may be used; flush with sterile 0.9% NS solution prior to infusion
- no other infusion should be administered simultaneously via the same IV access
- renal impairment does not affect the reversal effect of idarucizumab ⇒ no dose adjustment is required

resuming antithrombotic therapy
- patients treated with dabigatran have underlying conditions predisposing them to thromboembolic events
- resumption of anticoagulant therapy should be considered ASAP to reduce this risk
- idarucizumab does not interfere with other anticoagulant or antithrombotic therapies
- dabigatran treatment can be started 24h after idarucizumab administration

intravenous thrombolysis (IVT) in patients with acute ischemic stroke is possible with dabigatran therapy if aPTT + TT, ECT, or HEMOCLOT values do not exceed the upper limits of normal (AHA/ASA 2013 III/C)
- normal aPTT alone is not sufficient; it does not completely rule out an elevated TT [Kermer, 2017] [Hankey, 2014]
- IVT may be considered in patients with normal TT or TT <60 s and normal APTT (ESO guidelines 2021)
  - expert opinion, insufficient evidence to make an evidence-based recommendation
- Hemoclot – a dabigatran level < 50 ng/ml > 6h after the last dose of the drug indicates the absence of anticoagulant activity
administration of thrombolysis after prior neutralization of the effect of dabigatran with the antidote PRAXBIND is possible (IVT is an emergency procedure)
- according to expert consensus, the combination of idarucizumab and IVT is suggested for patients with acute ischemic stroke of <4.5 h duration (ESO guidelines 2021) [Diener, 2017]
- according to registry data, administration of the antidote PRAXBIND in patients with acute stroke followed by thrombolysis is effective, safe, and easy to perform [Kermer, 2017]

common side effects
- hypokalemia (7%)
- delirium (7%)
- constipation (7%)
- fever (6%)
- pneumonia (6%)
- headache (5%)
serious side effects:
- blood clots – patients are exposed to increased thrombotic risk of the underlying condition for which dabigatran is being given
- recurrent bleeding (some patients may require an additional dose of idarucizumab)
- hypersensitivity reactions (severe allergic reaction – fever, difficulty breathing due to airway spasms, hyperventilation, rash, and itching)
patients with hereditary fructose intolerance may be at risk for adverse effects such as low blood glucose, low phosphate, metabolic acidosis, increased uric acid, and acute liver failure