Background
Prospective single-arm cohort study (ANNEXA-4; no randomized control). N=352 with acute major bleeding on a factor Xa inhibitor (apixaban, rivaroxaban, edoxaban, or enoxaparin) who received andexanet alfa (Andexxa/Ondexxya), a recombinant modified inactive factor Xa decoy that binds and sequesters Xa inhibitors. FDA accelerated approval May 2018 on pharmacodynamic endpoints; ANNEXA-4 provides clinical outcomes data.
Interventions and follow up
Treatment: Andexanet alfa IV bolus (400 mg low-dose or 800 mg high-dose, weight/agent/timing-based) then 2-hour continuous infusion (4 mg/min low or 8 mg/min high)
Primary endpoint: Excellent/good hemostatic efficacy at 12 hours (adjudicated by independent committee)
Median follow-up: 30 days
Primary endpoint: Excellent/good hemostatic efficacy at 12 hours (adjudicated by independent committee)
Median follow-up: 30 days
Results
Excellent or good hemostatic efficacy at 12 hours: 82% (204/249 evaluable)
Anti-Xa activity reduction (apixaban): 92% decrease at bolus end
Anti-Xa activity reduction (rivaroxaban): 97% decrease at bolus end
Thrombotic events at 30 days: 10% (arterial + venous combined)
Death at 30 days: 14% (largely related to underlying bleeding severity)
Anti-Xa activity reduction (apixaban): 92% decrease at bolus end
Anti-Xa activity reduction (rivaroxaban): 97% decrease at bolus end
Thrombotic events at 30 days: 10% (arterial + venous combined)
Death at 30 days: 14% (largely related to underlying bleeding severity)
Adverse events
Thrombotic events: 10% within 30 days (ischemic stroke, MI, DVT, PE) attributable to reversal of anticoagulation in high-risk patients rather than andexanet itself
Infusion reactions: Urticaria, flushing in ~1%; no serious hypersensitivity
Death at 30 days: 14% (driven by ICH severity/comorbidities, not study drug)
Anti-Xa rebound: 2–3 hours after infusion end, requiring monitoring
Infusion reactions: Urticaria, flushing in ~1%; no serious hypersensitivity
Death at 30 days: 14% (driven by ICH severity/comorbidities, not study drug)
Anti-Xa rebound: 2–3 hours after infusion end, requiring monitoring
Conclusions
Andexanet alfa achieved excellent/good hemostasis in 82% of patients with major bleeding on factor Xa inhibitors, with rapid near-complete reduction in anti-Xa activity, supporting its use as a reversal agent for life-threatening or uncontrolled bleeding.
Key Limitations
Single-arm cohort with no control group, precluding causal efficacy/safety inference. Hemostatic adjudication is subjective. 10% thrombotic event rate; anti-Xa rebound after infusion. No randomized comparison vs PCC. Subsequent ANNEXA-I RCT in ICH later informed comparative data.
Clinical Context
Andexanet alfa is the targeted reversal agent for factor Xa inhibitor-associated major bleeding; ASH/ACC and society guidance support its use for life-threatening bleeds, weighing thrombotic risk and cost vs 4F-PCC. Confirmatory data from the ANNEXA-I RCT followed.