Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors (ANNEXA-4)

Garrett Brown, Mercer University College of Pharmacy

Recently, the direct-acting oral anticoagulants (DOACs) were introduced to the market.  The DOACs don’t require drug level monitoring or diet restrictions, unlike warfarin.  The DOAC drugs specifically target activated factors Xa and IIa of coagulation.  Currently, the DOACs lack a reversal agent should a patient experience a serious bleeding event or require an urgent invasive procedure.  While the half-life of the direct factor Xa inhibitors is only 5-15 hours, the lack of an antidote has been stated to limit their use.  [1]


It has been observed, that prothrombin complex concentrates normalize prothrombin time. However, there are no current reversal agents to quickly reverse the anticoagulation effect of the Xa inhibitors.  Andexanet is a recombinant, modified human factor Xa decoy protein.  [1]


Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors (ANNEXA-4) [2]


Design On-going, Multicenter, Prospective, Open-label, Single group study; N= 67
Objective To evaluate the use of Andexanet in patients with acute major bleeding
Study Groups Andexanet (n= 67), apixaban (n= 31), rivaroxaban (n= 32), enoxaparin (n= 4)
Methods Patients who had received apixaban or rivaroxaban were given a bolus dose of 400 mg Andrexanet, and then they were infused with 480 mg.  For patients who had taken enoxaparin, edoxaban, or rivaroxaban 7 hours or less before the administration, a bolus dose of 800 mg was given, followed with an infusion of 960 mg. Blood samples were obtained to measure anti–factor Xa activity and the unbound fraction of the plasma level of factor Xa inhibitor during a 12-hour period. Endogenous thrombin potential was measured at baseline, at 8 hours, at 12 hours, and on day 3.  The safety population included all patients who received Andexanet, and the efficacy population included only patients in whom the baseline anti–factor Xa activity was later determined to be 75 ng per milliliter or more.
Duration April 10th, 2015 – current
Primary Outcome Measure Percent change in the anti–factor Xa activity and the rate of excellent or good hemostatic efficacy 12 hours after the Andexanet infusion
Baseline Characteristics
  Safety Population n= 67 Efficacy Population n= 47
Age, yrs (avg) 77.1 77.1
Male, n (%) 35 (52) 24(51)
White race, n (%) 54 (81) 36(77)
Time from presentation to Andrexanet bolus, hr 4.8 4.8
Rivaroxaban, n 32 26
Median Dose, mg 20 20
Time from last dose to Andexanet, hrs 12.8 12
Baseline Xa activity, ng/mL 247.4 297
Apixaban, n 31 20
Median Dose, mg 5 5
Time from last dose to Andexanet, hrs 12.1 11
Baseline Xa activity, ng/mL 137.7 174.5
Enoxaparin, n 4 1
Median Dose, mg 90 200
Time from last dose to Andexanet, hrs 10.8 13.1
Baseline Xa activity,  IU/mL 0.4 0.6
Rivaroxaban Enoxaparin Apixaban
Median Baseline Xa activity, ng/mL; IU/mL 277 0.61 IU 149.7
Xa activity post Adexanet bolus, ng/mL; IU/mL 16.8 0.15 IU 10.3
Relative decrease, % 89 N/A 93
Xa activity post 2 hr infusion Adexanet, ng/mL; IU/mL 30.6 0.19 12.5
Relative decrease % 86 N/A 92
Safety Population Efficacy Population
Excellent / Good hemostasis, n (%) 37 (55) 37 (79)
Gastrointestinal Bleeding, n (%) 33 (49) 25(53)
Intracranial bleeding, n (%) 28 (42) 20 (43)
Other bleeding, n (%) 6 (9) 2 (4)
Adverse Events Common Adverse Events: Gastrointestinal bleeding (49%), Nasal bleeding (17%)
Serious Adverse Events: Death (15%), Thromboembolic event (16%)
Percentage that Discontinued due to Adverse Events: None reported
Study Author Conclusions Andexanet rapidly reversed anti-factor Xa activity and was not associated with serious side effects.  Effective hemostasis was achieved 12 hours after an infusion of Andexanet in 79% of the patients.



The study was not controlled or blinded; however, a controlled trial with such as high risk population would not be ethical.  One limitation of the study was that it only included patients with severe bleeding events, and excluded patients with factor Xa baseline levels >75ng/mL.  A controlled study is required in order to determine if these rates are due to Adexanet therapy or due to the thrombotic state of the patient prior to administration.




  1. Levi M. Management of bleeding in patients treated with direct oral anticoagulants. Crit Care. 2016;20:249.
  2. Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016.




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