Andexanet alfa reverses the anticoagulation activity of edoxaban and rivaroxaban. Andexanet alfa dose-dependently reduces plasma concentration of rivaroxaban and edoxaban, respectively. Chromogenic FXa assay was performed to determine the anti-FXa activity of rivaroxaban or edoxaban in plasma treated with antidotes. (A-B) Andexanet alfa reduced plasma concentration of edoxaban; no change in plasma concentration of edoxaban was observed with PER977. At 200 µg/mL andexanet, the plasma concentration of edoxaban decreased by ∼99%. Andexanet alfa reduced plasma concentration of rivaroxaban; no change in plasma concentration of edoxaban was observed with PER977. At 200 µg/mL andexanet, the plasma concentration of rivaroxaban decreased by ∼99%. Results are expressed as the mean ± SE of 6 measurements from 2 independent experiments (n = 2). TEG assay was performed in noncitrated human blood. Andexanet alfa neutralized the anticoagulation activity of edoxaban. However, PER977 did not neutralize the anticoagulation activity of edoxaban. (C-D) 100 µg/mL andexanet alfa normalized the augmented clotting time induced by edoxaban and rivaroxaban. However, 50 µg/mL PER977 did not show edoxaban and rivaroxaban anticoagulation reversal activity. Data are median with interquartile ranges (n = 6 donors). Black horizontal lines represent median, and error bars represent interquartile range. Asterisks indicate significant differences in comparison with the edoxaban control. Mann-Whitney (unpaired, 2-tailed) U tests were performed to determine significance, with P < .05 indicating a statistically significant change (*P = .026 for the edoxaban control vs andexanet alfa–treated groups; *P = .041 for the rivaroxaban control vs andexanet alfa–treated groups).