Antidote reverses effects of apixaban, rivaroxaban in healthy subjects
An investigational antidote to factor Xa inhibitors has proven succesful in reversing the effects of apixaban and rivaroxaban in a pair of phase 3 studies of healthy
volunteers.
In the ANNEXA-R and ANNEXA-A studies, researchers evaluated the safety and efficacy of the antidote, andexanet alfa, in volunteers receiving rivaroxaban and apixaban, respectively.
In both studies, andexanet alfa met all efficacy endpoints.
There were no serious or severe adverse events and no thrombotic events in either study.
“The findings of [these studies] are an advance towards resolving major bleeding complications effectively within minutes,” said Deborah Siegal, MD, of McMaster University in Hamilton, Ontario, Canada.
Dr Siegal and her colleagues reported the findings in NEJM. The studies were funded by Portola Pharmaceuticals, the company developing andexanet alfa.
The randomized, double-blind, placebo-controlled ANNEXA-R and ANNEXA-A studies were conducted to evaluate the safety and efficacy of andexanet alfa in reversing the anticoagulant effect of rivaroxaban and apixaban, respectively, in healthy volunteers ages 50 to 68.
The primary endpoint was reduction in anti-factor Xa levels. Secondary endpoints included reduction in plasma levels of unbound rivaroxaban or apixaban and restoration of the endogenous thrombin potential, a measure of thrombin generation.
ANNEXA-R efficacy
In part 1 of this study, 41 healthy volunteers received rivaroxaban at 20 mg once daily for 4 days. They were then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg intravenous (IV) bolus (n=27) or placebo (n=14).
Within 2 to 5 minutes of bolus completion, andexanet alfa significantly reduced the anti-factor Xa activity of rivaroxaban compared with placebo—92% and 18%, respectively (P<0.001).
And andexanet alfa significantly reduced the level of unbound rivaroxaban in the plasma compared with placebo—23.4 ng/mL and 4.2 ng/mL, respectively (P<0.001).
Thrombin generation was fully restored in 96% of subjects who received andexanet alfa and 7% of placebo-treated subjects (P<0.001).
In part 2 of the study, 39 healthy volunteers received rivaroxaban at 20 mg once daily for 4 days. They were then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes (n=26) or placebo (n=13).
Andexanet alfa significantly reduced anti-factor Xa activity compared with placebo—97% and 45%, respectively (P<0.001). And reversal persisted in andexanet alfa-treated subjects for 1 to 2 hours after the infusion was complete.
The reduction in unbound rivaroxaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of unbound rivaroxaban compared with placebo—30.3 ng/mL and 12.1 ng/mL, respectively (P<0.001).
Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 0% of placebo-treated subjects (P<0.001).
ANNEXA-A efficacy
In part 1 of this study, 33 subjects received apixaban at 5 mg twice daily for 3.5 days. They were then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus (n=24) or placebo (n=9).
Within 2 to 5 minutes of bolus completion, andexanet alfa reduced the anti-factor Xa activity of apixaban compared with placebo—94% and 21%, respectively (P<0.001).
Andexanet alfa significantly reduced the level of unbound apixaban in the plasma compared with placebo—9.3 ng/mL and 1.9 ng/mL, respectively (P<0.001).
Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 11% of placebo-treated subjects (P<0.001).
In part 2, 31 healthy volunteers received apixaban at 5 mg twice daily for 4 days. They were then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=24) or placebo (n=8).
