Full Study Report of Andexnet Alfa for Bleeding Associated with Factor X Inhibitors

Study Authors: Stuart J Connolly, Mark Crowther, John W. Eikelboom, C. Michael Gibson et al for the ANNEXA-4 Investigators

N.Engl M Med 2019;380 (14): 1326-1325

Background & Purpose of the Study: Andexanet alpha is an inactive form of factor Xa which reverses the action of Factor Xa inhibitors. The purpose of the study was to determine the efficacy and safety of andexanet in patients with acute major bleeding that occurs while taking Factor Xa inhibitor. 

Methods: The study was a multicenter, prospective, open-label, single-group study which evaluated 352 patients who developed acute major bleeding within 18 hours after the administration of a factor Xa inhibitor (apixaban, rivaroxaban or edoxaban at any dose or enoxaparin at a dose of at least 1 mg/kg body weight/day.

Acute major bleeding included patients having one or more of the following features: potentially

a)  life-threatening bleeding with signs or symptoms of hemodynamic compromise (e.g poor skin perfusion, mental confusion, severe hypotension or low cardiac output that could not otherwise be explained); 

b) bleeding associated with decrease in the hemoglobin level of at least 2 g/dL (or a hemglobin level ≤8 g/dL if no baseline hemoglobin level was available) or

c) bleeding in a critical area or organ (pericardial, epidural, retroperitoneal, intrarticular, intracranial or intramuscular bleeding with compartment syndrome)

The co-primary outcomes were the percent change in anti-factor Xa activity after andexanet therapy & the percentage of patients with good or excellent hemostatic efficacy. Efficacy was assessed in the subgroup of patients with major confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng/mL (or ≥0.25 IU per mL for those receiving enoxaparin

The primary safety outcomes were mortality, thrombotic events and development of antibodies to andeanet or to native factor X and factor Xa.

Results: The mean age of the study cohort was 77 years. Intracranial bleeding occured in 64% (n=227 patients) and gastrointestinal in 26% (n=90 patients). 

The median anti-factor Xa activity decreased from 149.7 ng/mL at baseline to 11.1 ng/mL after andexanet bolus in patients who received apixaban (92% reduction; 95% CI 91 to 93)

The median anti-factor Xa activity decreased from 211.8 ng/mL at baseline to 14.2 ng/mL after andexanet bolus in patients who received rivaroxaban (92% reduction; 95% CI 88 to 94)

In 16 patients who received enoxaparin the median value for anti-factor Xa activity decreased from 0.48 IU/mL at baseline to 0.15 IU/mL at the end of the bolus administration (75% reduction; 95% CI 66 to 79).

In 82% (204 of 249 patients who could be evaluated) excellent or good hemostasis occured

Within 30 days, mortality occured in 14% (49 patients) and a thrombotic event in 10% (34 patients). 

The reduction in Factor Xa activity was not predictive of hemostatic activity but was modestly predictive in patients with intracranial hemorrhage with the area under the ROC curve of 0.64 (95% CI, 0.53 to 0.74) for the magnitude of reduction in anti-factor Xa activity from baseline to nadir during therapy.

Perspective: Given that more and more patients are on Factor Xa inhibitors, this study suggests that the safety and efficacy of andexanet is promising. The results of an ongoing randomized trial are eagerly awaited.