BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, 
but there are no specific agents for the reversal of the effects of these drugs. 
Andexanet is designed to reverse the anticoagulant effects of factor Xa 
inhibitors.
METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 
mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized 
placebo-controlled study was conducted to evaluate andexanet administered as a 
bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean 
percent change in anti-factor Xa activity, which is a measure of factor Xa 
inhibition by the anticoagulant.
RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was 
reduced by 94% among those who received an andexanet bolus (24 participants), as 
compared with 21% among those who received placebo (9 participants) (P<0.001), 
and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 
1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% 
versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the 
rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% 
among those who received an andexanet bolus (27 participants), as compared with 
18% among those who received placebo (14 participants) (P<0.001), and unbound 
rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng 
per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 
7% of the participants (P<0.001). These effects were sustained when andexanet 
was administered as a bolus plus an infusion. In a subgroup of participants, 
transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were 
observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic 
events were reported.
CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and 
rivaroxaban in older healthy participants within minutes after administration 
and for the duration of infusion, without evidence of clinical toxic effects. 
(Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R 
ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).