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Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.

  • Author(s): Connolly, Stuart J;
  • Milling, Truman J;
  • Eikelboom, John W;
  • Gibson, C Michael;
  • Curnutte, John T;
  • Gold, Alex;
  • Bronson, Michele D;
  • Lu, Genmin;
  • Conley, Pamela B;
  • Verhamme, Peter;
  • Schmidt, Jeannot;
  • Middeldorp, Saskia;
  • Cohen, Alexander T;
  • Beyer-Westendorf, Jan;
  • Albaladejo, Pierre;
  • Lopez-Sendon, Jose;
  • Goodman, Shelly;
  • Leeds, Janet;
  • Wiens, Brian L;
  • Siegal, Deborah M;
  • Zotova, Elena;
  • Meeks, Brandi;
  • Nakamya, Juliet;
  • Lim, W Ting;
  • Crowther, Mark;
  • ANNEXA-4 Investigators
  • et al.
Abstract

Background

Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.

Methods

In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication.

Results

The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.

Conclusions

On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

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