Andexanet Alfa for FXa Inhibitor Major Bleeding

Quick Takes

  • Use of andexanet alfa was associated with a 94-95% reduction in anti-FXa activity for patients using apixaban or rivaroxaban who experience a major bleeding event.
  • Use of andexanet alfa was associated with a high degree of good or excellent hemostatic efficacy in patients with FXa inhibitor-associated major bleeding.
  • The rate of thrombotic events was modestly high (10%) after andexanet alfa administration, but did not occur once therapeutic anticoagulation resumed.

Study Questions:

What are the outcomes associated with the use of andexanet alfa for the reversal of factor Xa (FXa) inhibitor anticoagulants in patients with acute major bleeding?


The authors conducted a single-arm phase 3b/4 cohort study of patients with acute major bleeding within 18 hours of FXa inhibitor administration. Co-primary endpoints were anti-FXa activity change from baseline and assessment of excellent or good hemostatic efficacy at 12 hours. The efficacy population included patients with baseline anti-FXa activity levels above pre-defined thresholds (≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin). The efficacy population also had to have adjudicated major bleeding, defined by the modified International Society on Thrombosis and Haemostasis criteria. The safety population included all study patients. All outcomes (major bleeding, hemostatic efficacy, thrombotic events, and death) were independently adjudicated.


The study enrolled 479 patients, mean age 78 years, 54% male, 86% White. In the study population, 81% were anticoagulated for atrial fibrillation with a median time since last anticoagulant dose of 11.4 hours. Apixaban was the most used anticoagulant (51%), followed by rivaroxaban (37%), edoxaban (8%), and enoxaparin (5%). Bleeding was predominantly intracranial (69%) or gastrointestinal (23%). The median anti-FXa activity decreased from 146.9 to 10.0 ng/mL (reduction of 93%, 95% confidence interval [CI], 93-94%) among apixaban-treated patients, from 214.6 to 10.8 ng/mL (reduction of 94%; 95% CI, 93-95%) in rivaroxaban-treated patients, from 121.1 to 24.4 ng/mL (reduction of 71%; 95% CI, 65-82%) in edoxaban-treated patients, and from 121.1 to 24.4 IU/mL (reduction of 75%; 95% CI, 67-79%) for enoxaparin-treated patients. Excellent or good hemostasis was achieved in 80% (95% CI, 75-84%) of patients. Thrombotic events occurred in 10% of the safety population; in 16/50 patients with thrombotic events, these occurred while prophylactic anticoagulation was administered after the bleeding event. No thrombotic events occurred after anticoagulation was re-started.


The authors conclude that treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in patients with FXa-associated major bleeding.


The use of oral FXa inhibitors (apixaban, edoxaban, and rivaroxaban) has been associated with improved outcomes as compared to warfarin, particularly a reduction in life-threatening intracranial hemorrhage. However, strategies to manage FXa inhibitor-associated bleeding are critically important. In this final study report of the ANNEXA-4 single-arm trial of andexanet alfa, the authors report on a high degree of anti-FXa activity reversal and good or excellent hemostatic efficacy with the use of andexanet alfa. Based on prior studies, there have been some concerns about the association between andexanet alfa use and thrombosis risk. This study of >475 patients found higher rates of thrombosis (10%) as have been shown in other observational studies of FXa inhibitor-associated bleeding treated with prothrombin complex concentrates (PCC) (3.1% in a recent meta-analysis: Nederpelt CJ, et al., Crit Care Med 2021;49:e1025-36). Both the ANNEXA-4 study and the meta-analysis study included high percentages of patients with intracranial hemorrhage (69% and 88%, respectively).

An ongoing study (ANNEXA-I) will investigate the rate of thrombotic events in patients treated with either andexanet alfa or usual care (typically PCC). In the interim, andexanet alfa is an effective therapy for patients with FXa inhibitor-associated major bleeding. However, clinicians should be aware of thrombosis risk (either from an underlying thrombotic condition or potentially associated with the medication) and aim to restart therapeutic anticoagulation as soon as is clinically safe.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Geriatric Cardiology, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents

Keywords: Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Enoxaparin, Factor Xa, Factor Xa Inhibitors, Gastrointestinal Hemorrhage, Geriatrics, Hemorrhage, Hemostasis, Hemostatics, Intracranial Hemorrhage, Traumatic, Prothrombin, Rivaroxaban, Thrombosis, Vascular Diseases, Warfarin

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