Intravenous infusion

TORONTO—An antidote to factor Xa inhibitors can safely reverse the anticoagulant effect of apixaban in healthy volunteers, results of the ANNEXA-A study suggest.

The first part of this study showed that a bolus of the antidote, andexanet alfa, was effective. And none of the volunteers had serious adverse events, thrombotic events, or antibodies to factor X or Xa.

In the second part of the study, researchers tested a bolus and a 2-hour infusion of andexanet alfa.

The drug normalized coagulation parameters immediately post-bolus, and this effect was sustained during the infusion. The reversal of anti-factor Xa activity lasted 1 to 2 hours post-infusion.

As in part 1, there were no serious adverse events or thrombotic events, and none of the subjects developed antibodies to factor X or Xa.

Mark Crowther, MD, of McMaster University in Hamilton, Ontario, Canada, presented details on part 2 of ANNEXA-A at the ISTH 2015 Congress (abstract LB004). The trial was sponsored by Portola Pharmaceuticals, Inc., the company developing andexanet alfa.

The goal of the randomized, double-blind ANNEXA-A study was to evaluate the safety and efficacy of andexanet alfa in reversing apixaban-induced anticoagulation in healthy volunteers ages 50 to 75.

In part 1, 33 healthy volunteers received apixaban at 5 mg twice daily for 4 days and were then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg intravenous bolus (n=24) or to placebo (n=9). Results from this part of the study were presented at the American Heart Association 2014 Scientific Sessions.

In the second part of the study, 32 healthy volunteers received apixaban at 5 mg twice daily for 4 days and were then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg intravenous bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=24) or to placebo (n=8).

Safety

One subject in the andexanet alfa arm discontinued treatment during the infusion due to mild hives. The subject did not have any other allergic

manifestations or cardiorespiratory effects.

Six subjects had mild infusion-related reactions, 4 (16.7%) in the andexanet alfa arm and 2 (25%) in the placebo arm.

None of the subjects had an increase in D-dimer (more than 2 times the upper limit of normal) on more than 1 day.

The majority of andexanet-alfa-treated subjects had transient elevation of F1 and F2, but, in all cases, levels returned to less than or equal to 2 times the upper limit of normal by the fourth day.

Efficacy

Twenty-three subjects in the andexanet alfa arm and all 8 subjects in the placebo arm were evaluable for efficacy.

All evaluable subjects in the andexanet alfa arm had an 80% or greater reduction in anti-factor Xa activity post-infusion nadir, compared to none of the subjects on placebo (P<0.0001).

The mean percent change in anti-factor Xa activity from baseline to post-infusion nadir was 92% in the andexanet alfa arm (P<0.0001 vs placebo). And the mean percent change from baseline to post-bolus nadir was 93% (P<0.0001 vs placebo).

The mean change in free apixaban concentration from baseline to post-infusion nadir was 1.39 ng/mL in the andexanet alfa arm (P=0.0002 vs placebo).

Thrombin generation was restored to the day 1, pre-apixaban baseline range in all 23 subjects on andexanet alfa (P<0.0001). And there was no long-term effect on thrombin generation.

The researchers said andexanet alfa demonstrated rapid onset and offset of action. Furthermore, it seems that either a bolus dose alone or a bolus plus infusion can reverse apixaban’s anticoagulant activity, which could provide flexibility for bleeding patients.

Andexanet alfa is also under investigation as an antidote to rivaroxaban, edoxaban, enoxaparin, and betrixaban.

Anticoagulant antidote effective in healthy volunteers