Rapid reversal of rivaroxaban and apixaban with andexanet alfa in life/limb threatening bleeding

1. Andexanet alfa (Ondexxya©) is licensed and indicated for rapid reversal of Apixaban
and Rivaroxaban presenting with life/limb-threatening bleeding.

2. Definition of life/limb-threatening bleeding:

• Intracranial (CT or MRI documented).
• Retroperitoneal (CT or MRI documented).
• Intra-ocular (excludes conjunctival).
• Spontaneous muscle haematoma associated with compartment syndrome.
• Pericardial.
• Non-traumatic intra-articular.
• Any invasive procedure to stop bleeding.
• Active bleeding from any orifice plus BP≤90mmHg systolic, or oliguria or ≥20g/l fall in Hb.
• Major trauma and BP≤90mm Hg systolic.

3. The decision to use Andexanet alfa should be made by the patient’s consultant/consultant on call; following full documented cautious consideration of the risks (including a 10% risk of serious thrombotic events – MI, CVA, DVT/PE) v benefits for the patient and clinical outcome. 

• For patients with haemorrhagic stroke, the senior decision maker is the Stroke Consultant, as for stroke thrombolysis. If the Borders Stroke Consultant is not available, the on call stroke team in NHS Lothian are the next point of contact for a clinical decision on use in stroke patients.

4. Dose regime and administration in adults (≥ 18 years old) who have taken either drug in
the last 48 hours:

• Patients who have taken apixaban ≤5mg or rivaroxaban ≤10mg, or who had apixaban
  >5mg or rivaroxaban >10mg more than 8 hours previously, should be given low dose
  andexanet alfa 400mg intravenous (IV) bolus (30mg/minute) then 480mg as an IV
  infusion over two hours (4mg/minute).
• Patients who had apixaban >5mg or rivaroxaban >10mg within the preceding 8 hours
  or at an unknown time, should be given high dose andexanet alfa 800mg IV bolus
  (30mg/minute) then 960mg as an IV infusion over two hours (8mg/minute).
• Andexanet alfa should be prepared following the guidance on the Medusa IV
  Monograph. It is important to note that andexanet alfa must be given using an infusion
  pump via an in-line 0.2 or 0.22 micron low-protein filter (Medex filters available in
  ED)

5. Monitoring for efficacy is clinical.

2 citrate coagulation tubes should be sent (taxied to RIE and NOT to BGH lab - the anti Xa levels done on apixaban are different from the levels for LMWH monitoring) requesting PT, APTT, and fibrinogen along with a request for anti Xa levels, pre and 30 mins post-andexanet alfa. A significant reduction in Xa is not always seen and this does not suggest a lack of clinical efficacy.

6. Contraindications and cautions

• Previous life-threatening reaction to andexanet alfa.
• There is a significant risk of thrombotic event from andexanet and/or from reversing rivaroxaban or apixaban in prothrombotic patients, this should be considered.
• The safety and efficacy of andexanet alfa is not established for children below age of 18, or in pregnancy or lactation.
• Andexanet alfa should not be used for reversal of anticoagulation for any other anticoagulants.
• Andexanet alfa should not be used for reversal of anticoagulation with apixaban or rivaroxaban for routine surgery.
• Patients with GCS <7 should not receive andexanet alfa.
• Patients with haemorrhage volume > 60cc (4.8 cm diameter).
• Where there is poor prognosis for other reasons (life expectancy < 1 month).

7. Management of bleeding which does not fulfil the licensed criteria (as in 2.) should be individualised and the following treatments considered:

• Consider activated charcoal to reduce absorption of apixaban/rivaroxaban in the case of overdose.
• Consider the severity and location of the haemorrhage.
• Consider the use of appropriate symptomatic treatment including mechanical compression for severe epistaxis, surgical haemostasis with bleeding control procedures, fluid replacement and haemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets to control bleeding.
• If these interventions do not control bleeding, a specific pro-coagulant reversal agent such as PCC or recombinant factor VIIa (r-FVIIa) could be considered.

8. Restarting anticoagulation:

When clinically stable with adequate haemostasis, anticoagulation can be re-commenced at 24 hours. Clinical review of the risk:benefit of and the timing of re-starting anticoagulation should be carried out by the clinical team in charge of the patient with input from haematology colleagues.