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

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 .).

• Authors: Stuart J Connolly, Truman J Milling Jr, John W Eikelboom, C Michael Gibson, John T Curnutte, Alex Gold, Michele D Bronson, Genmin Lu, Pamela B Conley, Peter Verhamme, Jeannot Schmidt, Saskia Middeldorp, Alexander T Cohen, Jan Beyer-Westendorf, Pierre Albaladejo, Jose Lopez-Sendon, Shelly Goodman, Janet Leeds, Brian L Wiens, Deborah M Siegal, Elena Zotova, Brandi Meeks, Juliet Nakamya, W Ting Lim, Mark Crowther, ANNEXA-4 Investigators
• Journal: The New England journal of medicine (N Engl J Med) Vol. 375 Issue 12 Pg. 1131-41 (09 22 2016) ISSN: 1533-4406 [Electronic] United States
• PMID: 27573206 (Publication Type: Clinical Trial, Journal Article, Multicenter Study)

Chemical References

• Enoxaparin
• Factor Xa Inhibitors
• PRT064445
• Pyrazoles
• Pyridones
• Recombinant Proteins
• apixaban
• Rivaroxaban
• Factor Xa

Topics

• Acute Disease
• Aged
• Aged, 80 and over
• Cardiovascular Diseases (complications)
• Enoxaparin (adverse effects)
• Factor Xa (adverse effects, therapeutic use)
• Factor Xa Inhibitors (adverse effects, metabolism, therapeutic use)
• Female
• Gastrointestinal Hemorrhage (chemically induced, drug therapy)
• Hemorrhage (chemically induced, drug therapy)
• Humans
• Infusions, Intravenous
• Intracranial Hemorrhages (chemically induced, diagnosis, drug therapy)
• Male
• Prospective Studies
• Pyrazoles (adverse effects)
• Pyridones (adverse effects)
• Recombinant Proteins (adverse effects, therapeutic use)
• Rivaroxaban (adverse effects)
• Thrombosis (etiology)