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

Mechanism of action

  • idarucizumab is a fragment of a humanized monoclonal antibody acting like a specific reversal agent for dabigatran
  • it binds tightly to dabigatran and its acyl glucuronide metabolites and forms a complex with it, thereby immediately stopping the anticoagulant effect of dabigatran
    • dabigatran has a 300 times higher affinity for idarucizumab than for thrombin
  • does not interfere with the effects of other anticoagulants
  • does not lead to a hypercoagulable state
  • allows a bolus IV administration with rapid onset of action
  • allows fast restart of anticoagulant therapy (24h after administration)
  • several pathways contribute to the metabolism of antibodies – all  involve biodegradation of the antibody to smaller molecules, which are then reabsorbed and incorporated in the general protein synthesis
Idarucizumab (PRAXBIND) - mechanism of action

Clinial trials

  • RE-VERSE AD trial with the i.v. idarucizumab at a dose of 5 g i.v.
    • effective within minutes
    • analysis of 90 patients showed a reliable reduction of anticoagulant activity (normal coagulation in 90% of patients after 4 and 12 h)  → see here
  • there is an increasing clinical experience with PRAXBIND administration before thrombolysis and in acute ICH treatment → see here
Results of REVERESE-AD trial
REVERSE-AD trial results

Contraindications and precautions

  • 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 with pregnant women are available
  • 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 unquestionably needed
  • it has not been studied for use during labor and delivery
  • it is not known whether idarucizumab crosses into human milk
  • no data on the effects of idarucizumab on the breastfed child or milk production
  • consider benefits of breastfeeding along with the mother’s clinical need for the drug (benefits must outweigh the risk)

Idarucizumab administration

  • aseptic handling during preparation is required
  • inspect visually for particulates and discoloration before infusion
  • once the solution has been removed from the vial, the administration should begin promptly; solution in vials may be stored at room temperature (25°C [77°F]) but must be used within 6 h
  • do not mix with other drugs
  • PRAXBIND 2 x 2.5g/50 ml
    • infuse 5 g dose IV as two consecutive 2.5 g infusions or administer as bolus injections by injecting both 2.5 g vials consecutively one after another via syringe
    • a preexisting intravenous line can be used
    • flush with sterile 0.9% NS solution before infusion
    • no other infusion should be administered simultaneously via the same IV access
    • renal impairment does not impact the reversal effect of idarucizumab ⇒ no dosage adjustment is required
  • restarting antithrombotic therapy
    • patients treated with dabigatran have underlying diseases predisposing them to thromboembolic events
    • resumption of anticoagulant therapy should be considered as soon as possible to reduce the risk of thromboembolism
    • idarucizumab has no impact on the effect of other anticoagulant or antithrombotic therapies
    • dabigatran treatment can be initiated 24h after administration of idarucizumab
Idarucizumab (PRAXBIND) administration

Praxbind and intravenous thrombolysis

  • 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 the reference values  (AHA/ASA 2013 III/C)
    • normal aPTT alone is not sufficient; it does not entirely rule out elevated TT  [Kermer, 2017] [Hankey, 2014]
    • IVT can be considered in patients with normal TT or TT <60 s and normal APTT   (ESO guidelines 2021)

      • expert opinion, no sufficient 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 (indications for Praxbind include emergency procedures, which may include thrombolysis)
    • 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]
Recanalisation therapy in apatient using dabigatran

Adverse events

  • 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 disease that dabigatran is being given for
    • recurrence of bleeding (some patients may require an additional dose of idarucizumab)
    • hypersensitivity reactions (serious allergic reaction – fever, difficulty breathing due to airways spasms, hyperventilation, rash, and itching)
  • 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
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