Andexanet Alfa


Article Author:
Mirembe Reed
Prasanna Tadi


Article Editor:
Diala Nicolas


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Abigail Frank
Jon Sivoravong


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Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
5/15/2019 5:06:05 PM

Indications

Andexanet alfa is a recombinant modified factor XA protein approved by the FDA in May 2018 for the reversal of apixaban and rivaroxaban in patients with life-threatening or uncontrolled bleeding.[1].

Factor XA inhibitors have been shown to be as effective as warfarin with a better safety profile in terms of bleeding. They are also convenient in that less routine blood monitoring is required than with the use of warfarin. However, emergency room visits and hospital admissions for bleeding due to factor XA inhibitors have risen with increasing use of these agents. Andexanet alfa is the first FDA approved reversal agent for factor XA inhibitors. It is not currently approved for the reversal of edoxaban, fondaparinux, or low-molecular-weight heparins due to lack of sufficient data in patients on these agents.

Andexanet alfa was approved as breakthrough therapy and as an orphan drug based on the results of two phase 3 trials, annexa-A and annexa-R. These trials evaluated the efficacy and safety of andexanet alfa in reversing of apixaban and rivaroxaban, respectively, in healthy volunteers. The FDA also considered the interim results of an on-going trial, ANNEXA-4, which analyzed reversal of apixaban, rivaroxaban, edoxaban or enoxaparin in patients presenting with acute major bleeding within 18 hours of the last dose of a factor XA inhibitor. [1]

Mechanism of Action

Andexanet alfa acts as a decoy and sequesters rivaroxaban or apixaban, inhibiting them from binding to natural factor XA. The increase in available factor XA reduces anticoagulant action which can be measured by anti-factor XA activity, thrombin generation, or unbound factor XA inhibitor plasma concentration from baseline. In clinical trials, the median decline in anti-factor XA activity for apixaban or rivaroxaban was 88% or higher. Binding of andexanet alfa to factor XA inhibitors is dose-dependent. There is a rapid decrease in anti-FXa activity after the bolus has been given. This decrease in anti-FXa activity is sustained during the infusion. After the infusion, anti-XA activity increases and peaks 4 hours after the infusion. After the peak, anti-FXa activity decreases at a rate similar to that of the clearance of FXa inhibitors. In ANNEXA-A, andexanet alfa restored thrombin generation in 100% healthy volunteers who were on apixaban therapy. Thrombin generation was restored in 96% of healthy volunteers on rivaroxaban therapy who received andexanet alfa in ANNEXA-R. 

Andexanet alfa also binds tissue factor inhibitor pathway (TPFI), a peptide that inhibits factor XA. Binding TPFI reduces its activity, thus increasing the formation of thrombin. Tissue factor pathway inhibition is sustained for at least 22 hours after andexanet alfa therapy. 

The volume of distribution is almost equivalent to blood volume at 5 liters, clearance is about 4.3 liters per hour, and the half-life is 5 to 7 hours. [2]

Administration

Andexanet alfa is available as a lyophilized powder in 100 mg, single-use vials with no preservatives. Vials should be refrigerated at 2 to 8 degrees C. Reconstitute each 100 mg vial with 10 mL of sterile water for injection to make a concentration of 10 mg/mL. Dissolution takes approximately 3 to 5 minutes. The reconstituted drug is stable for 8 hours at room temperature and for 24 hours at 2 to 8 degrees C in the vial. The reconstituted solution can also be transferred to polyolefin or polyvinyl intravenous bags where it is stable for 8 hours at room temperature or for 16 hours at 2 to 8 degrees C.

Two dosing regimens (low and high) are based on which factor XA inhibitor is to be reversed, when it was last taken, and the dose that was given.

  • The low dose protocol includes a bolus of 400 mg given at a rate of 30 mg/min followed by an infusion of 4 mg/min for up to 2 hours.
  • The high dose protocol is 800 mg administered at 30 mg/min and then an infusion at 8 mg/min for up to 2 hours.
  • If the last dose of rivaroxaban was 10 mg or less and drug administration was less than 8 hours ago or unknown, give the low dose.
  • If the last dose of rivaroxaban was more than 10 mg or of an unknown amount and drug administration was less than 8 hours ago or unknown, give the high dose.
  • If the last dose of apixaban was 5 mg or less and drug administration was less than 8 hours ago or unknown, give the low dose.
  • If the last dose of apixaban was more than 5 mg or unknown and drug administration was less than 8 hours ago or unknown, give the high dose.
  • If the last dose of either drug was given 8 or more hours ago, give the low dose. [3]

Andexanet alfa should be given intravenously, using a 0.2 or 0.22-micron in-line filter. Administering more than one dose has not been tested.

Adverse Effects

Adverse effects include deep vein thrombosis, arterial thrombosis, pulmonary embolism, ischemic stroke, acute myocardial infarction, and death. Other effects include cardiogenic shock, heart failure exacerbations, urinary tract infections, pneumonia, acute respiratory failure, and infusion-related reactions.

In a 2018 interim report of the ANNEXA-4 clinical trial, 6 of 227 (2.6%) had experienced thrombosis within 3 days and 24 patients (11%) within 30 days. Twenty-seven of 227 (12%) patients died at 30 days. One hundred thirty-nine of 227 (61%) received andexanet alfa for intracranial hemorrhage, and 16 of these 139 patients (12%) died within 30 days. The mean age of patients in this trial was 77 years, and 78% of them had atrial fibrillation. [4]

It is important to re-initiate anticoagulation therapy as soon as it is clinically appropriate to reduce the risk of thrombosis after andexanet alfa therapy. Thrombosis may occur even after re-initiation of anticoagulation.

Contraindications

There is no clinical trial data on the use of andexanet alfa in pregnancy, labor, delivery or lactation. Safety has not been tested in patients who have experienced thrombosis or disseminated intravascular coagulation within 14 days before bleeding that requires treatment with andexanet alfa. It has also not been tested in patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within 7 days before bleeding requiring andexanet alfa treatment. [5]

Monitoring

Drug effects can be measured by anti-XA activity, free fraction of apixaban or rivaroxaban, and thrombin generation. Anti-Xa activity returns to placebo levels about 2 hours after a bolus or infusion, but tissue factor pathway inhibitors persist for about 22 hours after the drug is given.[6]

Increase in tissue-factor-initiated thrombin generation is maintained during the infusion and persists for about 22 hours. Monitor patients for signs and symptoms of thrombosis.[5]

Enhancing Healthcare Team Outcomes

Reversal of apixaban or rivaroxaban with andexanet alfa in patients who are bleeding requires coordination with a multidisciplinary team. Licensed independent practitioners should contact pharmacy and nursing immediately to coordinate the process of drug preparation and administration. Nurses play a vital role in monitoring for signs and symptoms of thrombosis. Inform patients that thrombotic events may occur within 30 days after andexanet alfa treatment. 


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Andexanet Alfa - Questions

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A 59-year-old male patient in the hospital on rivaroxaban therapy after hip replacement surgery. He has a history of pulmonary embolism. While he was on the floor, his systolic blood pressure fell to 84 mm Hg and hemoglobin/hematocrit fell from 12 g/dL and 35% to 9 g/dL and 29%. He was transfused with four units of packed red blood cells, received 2 liters of normal saline and prothrombin complex concentrates therapy. He was transferred to the intensive care unit on norepinephrine 0.5 mcg/kg/min and normal saline at 100 ml/hr. Two days later, hemoglobin/hematocrit are now 11 g/dL/32%. Norepinephrine and sodium chloride have been weaned, and mean arterial pressure (MAP) is sustained at greater than 65. Which of the following would be appropriate about the need for further use of a reversal agent in this patient today?



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A 62-year-old man with a medical history of hypertension and pulmonary embolism. He takes amlodipine 5 mg a day and apixaban 5 mg BID. He presents to the emergency department with a chief complaint of a severe headache. He last took his medications 5 hours ago at 8 am. CT scan reveals intracranial hemorrhage. Apixaban therapy is held, and a decision is made to treat with andexanet alfa. What is the recommended dose of andexanet alfa for this patient?



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A 65-year-old man with heart failure with reduced ejection fraction (EF) of 20%, hypertension, and atrial fibrillation. Home medications include amiodarone 200 mg a day, carvedilol 25 mg twice a day, lisinopril 10 mg a day, and dabigatran 75 mg twice a day. He presents to the emergency department after a fall. Head CT reveals an intracranial hemorrhage. An order is written for andexanet alfa. What would be the next course of action?



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A 78-year-old female with a past medical history of deep vein thrombosis seven weeks ago, hypertension, atrial fibrillation, and diabetes mellitus. She was taking rivaroxaban 20 mg once a day until two weeks days ago when she was admitted and transferred to the intensive care unit for a gastrointestinal bleed. She received andexanet alfa for reversal. She is now hemodynamically stable and has been discharged from the hospital. Is the patient still a candidate for anticoagulation for deep vein thrombosis and atrial fibrillation?



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A 53-year-old woman who has a past medical history of atrial fibrillation who is brought to the emergency department with dizziness, light-headedness, and blood in her stool. She has been taking rivaroxaban 20 mg once a day for approximately one year. She received her last dose of rivaroxaban approximately 14 hours ago. Her hemoglobin is 6.7 g/dL, and blood pressure is 78/49 mmHg. She is given fluid boluses with normal saline, is transfused with two units of packed red blood cells and started on a norepinephrine infusion. The provider decides to use andexanet alfa. Which of the following is an appropriate order for andexanet alfa for this patient?



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Andexanet Alfa - References

References

Heo YA, Andexanet Alfa: First Global Approval. Drugs. 2018 Jun 20     [PubMed]
Connolly SJ,Milling TJ Jr,Eikelboom JW,Gibson CM,Curnutte JT,Gold A,Bronson MD,Lu G,Conley PB,Verhamme P,Schmidt J,Middeldorp S,Cohen AT,Beyer-Westendorf J,Albaladejo P,Lopez-Sendon J,Goodman S,Leeds J,Wiens BL,Siegal DM,Zotova E,Meeks B,Nakamya J,Lim WT,Crowther M, Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. The New England journal of medicine. 2016 Sep 22     [PubMed]
Andexxa--an antidote for apixaban and rivaroxaban. The Medical letter on drugs and therapeutics. 2018 Jun 18     [PubMed]
Siegal DM,Curnutte JT,Connolly SJ,Lu G,Conley PB,Wiens BL,Mathur VS,Castillo J,Bronson MD,Leeds JM,Mar FA,Gold A,Crowther MA, Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. The New England journal of medicine. 2015 Dec 17     [PubMed]
Rose DK,Bar B, Direct Oral Anticoagulant Agents: Pharmacologic Profile, Indications, Coagulation Monitoring, and Reversal Agents. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2018 May 9     [PubMed]
Tummala R,Kavtaradze A,Gupta A,Ghosh RK, Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. International journal of cardiology. 2016 Jul 1     [PubMed]

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