Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors

Abstract

Background: Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors.

Methods: We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin).

Results: Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage.

Conclusions: In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).

Figure 1. Anti-Factor Xa Activity in the Efficacy Population.

The median for each level of anti-factor Xa activity at each time point is marked as a horizontal line within the box. The top and bottom of the box denote the 75th and 25th percentiles, respectively, and the whiskers indicate the 90th and 10th percentiles. Outliers are shown as dots. The bolus of andexanet was delivered over 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 plots for the 134 patients who received apixaban, the 100 who received rivaroxaban, and the 16 who received enoxaparin are shown in Panels A, B, and C, respectively. (The 4 patients in the efficacy analysis who received edoxaban are not shown.) The numbers below the graphs show the median values, the percentage change in median values from baseline, and the 95% confidence intervals (CI) for this change.

Figure 2.. Hemostatic Efficacy.

Shown are the percentages of patients in the efficacy analysis who had excellent or good hemostatic efficacy at 12 hours, as assessed by the independent adjudication committee on the basis of prespecified criteria. The size of the red squares is proportional to the number of patients included in the subgroup analysis. The study hypothesis was that the rate of excellent or good hemostatic efficacy would exceed 50% (indicated by the vertical dashed line). There were five patients in the efficacy population in whom hemostatic efficacy could not be adjudicated owing to administrative reasons (see Fig. S1 in the Supplementary Appendix for details). The four patients in the efficacy population who received edoxaban are not shown for the subgroup according to drug.

Figure 3.. Receiver-Operating-Characteristic (ROC) Curves for Hemostatic Efficacy.

Shown are ROC curves for the association between anti-factor Xa activity (measured in nanograms per milliliter) and hemostatic efficacy (excellent or good vs. poor or none) in all patients who were receiving an oral factor Xa inhibitor (Panel A) and in patients with intracranial hemorrhage who were receiving an oral factor Xa inhibitor (Panel B). Patients are included in the analysis if assessment of hemostatic efficacy was available and if the level of anti-factor Xa activity was available at baseline and during andexanet treatment (at the end of administration of either the bolus or the infusion). The dashed line is a reference line indicating chance prediction. AUC denotes area under the curve.