Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis

Crit Care. 2022 Jun 16;26(1):180. doi: 10.1186/s13054-022-04043-8.


Background: Andexanet alfa is approved (FDA "accelerated approval"; EMA "conditional approval") as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH).

Methods: This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression.

Results: The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16-6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13-0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC.

Conclusions: In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.

Keywords: Andexanet alfa; Direct factor Xa inhibitor reversal; Four-factor prothrombin complex concentrate; Intracranial hemorrhage.

MeSH terms

  • Adult
  • Aged
  • Anticoagulants
  • Blood Coagulation Factors / pharmacology
  • Blood Coagulation Factors / therapeutic use
  • Factor Xa / therapeutic use
  • Factor Xa Inhibitors / adverse effects
  • Hemorrhage
  • Hemostatics*
  • Humans
  • Intracranial Hemorrhages / chemically induced
  • Intracranial Hemorrhages / drug therapy
  • Propensity Score
  • Prospective Studies
  • Pyrazoles
  • Pyridones
  • Recombinant Proteins / therapeutic use
  • Retrospective Studies
  • Rivaroxaban / adverse effects
  • Thrombosis*


  • Anticoagulants
  • Blood Coagulation Factors
  • Factor Xa Inhibitors
  • Hemostatics
  • PRT064445
  • Pyrazoles
  • Pyridones
  • Recombinant Proteins
  • prothrombin complex concentrates
  • apixaban
  • Rivaroxaban
  • Factor Xa

Associated data