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 .).

Figures

Figure 1. Anti–Factor Xa Activity and Percent Change from Baseline in Patients Receiving Rivaroxaban and Apixaban (Efficacy Population)

Shown are the values for anti–factor Xa activity (as measured by means of a validated chromogenic assay of factor Xa enzymatic activity) and the percent change from baseline in patients with acute major bleeding who received andexanet to counteract the anticoagulant effects of rivaroxaban or apixaban. Tukey box-plot values are expressed as the median (horizontal line in each box) and 25th and 75th percentiles (top and bottom of each box), with whiskers (top and bottom of each I bar) drawn to the highest data point within 1.5 times the upper quartile and to the lowest data point within 1.5 times the lower quartile. Outliers are shown as dots. The bolus of andexanet was administered during a period of 15 to 30 minutes, and the drug infusion lasted 2 hours. Subsequent time points are measured from the end of the infusion. The scales of the y axes for the two plots differ to allow proper demonstration of outliers. One patient in the efficacy population was receiving enoxaparin and is not included in these plots. The numbers below the graphs show the median values for anti–factor Xa activity, the percent change in median values from baseline, and 95% confidence intervals (CI) for this change.

Figure 2. Subgroup Analysis of Hemostatic Efficacy

Shown are the percentages of patients in the efficacy population who were adjudicated as having excellent or good hemostatic efficacy 12 hours after treatment with andexanet on the basis of prespecified criteria (Table S3 in the Supplementary Appendix). The size of the data points is proportional to the number of patients included in the subgroup analysis.

Figure 3. Thrombotic Events or Death during the 30-Day Study Period

Shown are timeline data for 18 of 67 patients in the safety population who had a thrombotic event or died after being treated with andexanet, starting with the bolus administration as baseline. Included are the patient’s age and sex, the indication for anticoagulation, and the site of the acute major bleeding event. The result of adjudication of hemostatic efficacy for patients who were included in the efficacy analysis is shown as excellent or good hemostasis (HE+) or poor or no hemostatic efficacy (HE−).