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Andexanet Alfa

Editor: Diala Nicolas Updated: 8/8/2023 2:03:31 AM


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

Factor Xa inhibitors have demonstrated effectiveness 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 the increasing use of these agents. Andexanet alfa is the first FDA-approved reversal agent for factor Xa inhibitors. It does not currently have approval for the reversal of edoxaban, fondaparinux, or low-molecular-weight heparins due to a lack of sufficient data in patients on these agents.[2]

Andexanet alfa received approval as a 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 apixaban and rivaroxaban, respectively, in healthy volunteers. The FDA also considered the interim results of an ongoing trial, ANNEXA-4, which analyzed reversal of apixaban, rivaroxaban, edoxaban, or enoxaparin in patients presenting with major acute bleeding within 18 hours of the last dose of a factor Xa inhibitor.[1]

Mechanism of Action

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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. The binding of andexanet alfa to factor Xa inhibitors is dose-dependent. There is a rapid decrease in anti-factor Xa activity after giving the bolus. This decrease in anti-factor Xa activity remains throughout the infusion. At the initiation of the infusion, anti-factor Xa activity increases and peaks 4 hours later. After the peak, anti-factor Xa activity decreases at a rate similar to that of the clearance of factor Xa inhibitors. In ANNEXA-A, andexanet alfa restored thrombin generation in 100% healthy volunteers who were on apixaban therapy. Thrombin generation returns 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 remains 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.[3]


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 24 hours at 2 to 8 degrees C in the vial. The reconstituted solution is also transferrable to polyolefin or polyvinyl intravenous bags, where it is stable for 8 hours at room temperature or 16 hours at 2 to 8 degrees C.

Two dosing regimens (low and high) have their basis on which factor Xa inhibitor requires reversal, when the patient received their last dose, and the size of the dose.

  • 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 patient received the last dose of either drug 8 or more hours ago, give the low dose.[4]

Andexanet alfa administration should be intravenous, 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 three 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.[5]

It is crucial to re-initiate anticoagulation therapy as soon as clinically appropriate to reduce the risk of thrombosis after andexanet alfa therapy. Thrombosis may occur even after the re-initiation of anticoagulation.[6]


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


Drug effects are measurable by anti-Xa activity, free fraction of apixaban or rivaroxaban, and thrombin generation. Anti-Xa activity returns to placebo concentrations about 2 hours after a bolus or infusion, but tissue factor pathway inhibitors persist for about 22 hours after giving the drug.[8]

An 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.[7][9][7]

Enhancing Healthcare Team Outcomes

Reversal of apixaban or rivaroxaban with andexanet alfa in patients with anticoagulation therapy-induced bleeding requires coordination with an interprofessional team. Licensed independent practitioners should contact the 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.

When clinicians prescribe or order factor Xa inhibitors, they should work collaboratively with the pharmacy staff to ensure proper dosing, the absence of drug interactions, and the availability of andexanet alfa.[10] Nursing should be thoroughly familiar with the dosing of both the Xa inhibitor and andexanet alfa, so they can administer anticoagulation effectively as well as react promptly when a reversal is necessary. These examples of interprofessional team coordination will lead to better patient outcomes with fewer adverse events. [Level 5]



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Jaspers T, Shudofsky K, Huisman MV, Meijer K, Khorsand N. A meta-analysis of andexanet alfa and prothrombin complex concentrate in the treatment of factor Xa inhibitor-related major bleeding. Research and practice in thrombosis and haemostasis. 2021 May:5(4):e12518. doi: 10.1002/rth2.12518. Epub 2021 May 24     [PubMed PMID: 34084991]

Level 1 (high-level) evidence


. Andexxa--an antidote for apixaban and rivaroxaban. The Medical letter on drugs and therapeutics. 2018 Jun 18:60(1549):99-101     [PubMed PMID: 29913471]

Level 3 (low-level) evidence


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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, ANNEXA-4 Investigators. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. The New England journal of medicine. 2016 Sep 22:375(12):1131-41. doi: 10.1056/NEJMoa1607887. Epub 2016 Aug 30     [PubMed PMID: 27573206]


Sewell JH, Williams L, McKnight E, Nguyen A, Sarac M. What is the role of andexanet alfa in the reversal of anticoagulant effects? JAAPA : official journal of the American Academy of Physician Assistants. 2021 Jan 1:34(1):8-9. doi: 10.1097/01.JAA.0000723956.47623.90. Epub     [PubMed PMID: 33332828]


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 Aug:27(8):2049-2058. doi: 10.1016/j.jstrokecerebrovasdis.2018.04.004. Epub 2018 May 9     [PubMed PMID: 29753603]


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Procopio GL, Jain RP, Tompkins DM, Perez JM, Bicking K. Impact of a pharmacist driven anticoagulation reversal program at a large academic medical center. Journal of thrombosis and thrombolysis. 2022 Jan:53(1):158-166. doi: 10.1007/s11239-021-02491-7. Epub 2021 Jun 7     [PubMed PMID: 34097227]