Andexanet Alfa Reverses Anticoagulant Activity of Apixaban, Rivaroxaban

The investigational drug andexanet alfa is a reversal agent designed to neutralize the anticoagulant effects of both direct and indirect factor Xa inhibitors. With an increasing number of patients receiving factor Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban, the need for reversal agents is high – particularly among those who experience bleeding or require emergency surgery.

To evaluate the safety and efficacy of andexanet alfa, Deborah M. Siegal, MD, of McMaster University in Hamilton, Canada, and colleagues conducted two parallel, randomized, double-blind, placebo-controlled studies in healthy, older patients receiving apixaban (the ANNEXA-A study) or rivaroxaban (the ANNEXA-R study). The results of the study were published in The New England Journal of Medicine.

“The ANNEXA-A and ANNEXA-R studies provide important information about the ability of andexanet alfa to reverse the anticoagulant effects of rivaroxaban and apixaban as measured by laboratory tests in healthy volunteer subjects,” Dr. Siegal told ASH Clinical News.

The study was conducted at two sites in Arizona and California between March 2014 and May 2015 and included 145 patients with a mean age of 57.9 years (range = 50-75 years). The study’s primary outcome was mean percent change in anti–factor Xa activity from baseline to nadir.

Patients received either apixaban (5 mg) twice-daily for 3.5 days or rivaroxaban (20 mg) once-daily for four days. Patients were randomized 3:1 in ANNEXA-A and 2:1 in ANNEXA-R to receive andexanet alfa or matching placebo.

Each study included two analyses of andexanet alfa. In the ANNEXA-A study, patients were treated with either:

  • 400 mg intravenous (IV) andexanet bolus administered alone at 30 mg per minute
  • 400 mg IV bolus followed by continuous 120-minute infusion at 4 mg per minute for a total of 480 mg

In the ANNEXA-A study, patients were treated with either:

  • 800 mg IV andexanet bolus administered alone at 30 mg per minute
  • 800 mg IV bolus followed by continuous 120-minute infusion at 8 mg per minute for a total of 960 mg

Safety outcomes were assessed on days 15, 36, and 43 following the administration of andexanet alfa or placebo.

Within two to five minutes following administration of andexanet alfa, anti–factor Xa activity was reduced to a greater extent and more rapidly than with placebo in both studies: 94 percent vs. 21 percent with apixaban (p<0.001) and 92 percent versus 18 percent with rivaroxaban (p<0.001). Andexanet alfa’s reversal activity persisted for two hours following bolus administration, which is consistent with the reported half-life of the drug, Dr. Siegal and co-authors noted, while anti–factor Xa activity gradually returned in those receiving placebo.

All patients except for one who received andexanet alfa had at least 80 percent reversal of anti–factor Xa activity. In contrast, none of the patients receiving placebo reached an 80 percent or greater reversal (p<0.001).

The same effects were reported for the cohort receiving andexanet alfa via a bolus plus infusion.

Following administration of bolus andexanet alfa, the mean change in thrombin generation, measured as the change in endogenous thrombin potential, was significantly greater than among patients receiving placebo in both the apixaban cohort (1323.2 nM/min vs. 88.2 nM/min, respectively; p<0.001) and the rivaroxaban cohort (1314.2 nM/min vs. 173.9 nM/min, respectively; p<0.001).

Overall, thrombin generation increased above the lower limit of the normal range within two to 10 minutes following bolus administration in all patients taking apixaban and 96 percent of patients taking rivaroxaban – compared with just 11 percent and 7 percent (p<0.001 for both), respectively, in the placebo cohorts. Similar effects were seen among those receiving andexanet alfa via a bolus plus infusion.

There were no serious adverse events associated with andexanet alfa treatment. In addition, no study participants developed antibodies to factor X or factor Xa. “These results indicate that andexanet alfa has little immunogenicity after a single IV exposure,” wrote Dr. Siegal and colleagues.

One limitation of the study is that it does not include data on the safety and efficacy of andexanet alfa in patients who require urgent reversal of factor Xa inhibitor activity due to bleeding or emergency surgery. In addition, the high frequency of coexisting conditions among patients with acute bleeding makes it difficult to determine whether complications are related to the reversal agent or to the underlying medical condition.

“Currently, there are no specific reversal agents for factor Xa inhibitors, but based on its ability to rapidly reverse factor Xa inhibitor anticoagulant effects without serious safety concerns, andexanet alfa is a promising antidote for factor Xa inhibitors,” Dr. Siegal said. “The rapid onset and offset of action of andexanet alfa and the ability to administer it as a bolus or as a bolus plus an infusion may provide flexibility with regard to the restoration of hemostasis when urgent factor Xa inhibitor reversal is required.”

The ongoing phase IIIb/IV ANNEXA-4 study is evaluating the efficacy and safety of andexanet alfa in factor Xa–treated patients with major bleeding complications, she added. “It is hoped that the availability of a rapid-acting, safe reversal agent will improve the outcomes of factor Xa–treated patients requiring urgent anticoagulant reversal for emergencies such as severe bleeding or surgery.”


Reference

Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413-2424.

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