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

Abstract

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.

Multicenter experience with andexanet alfa for refractory pericardial bleeding during catheter ablation of atrial fibrillation

“…To date, the only FDA‐approved indication for PCC is reversal of vitamin K antagonists in acute major bleeding 8 . In a propensity score‐weighted analysis of two cohorts who received andexanet or PCC for reversal of apixaban or rivaroxaban in intracranial hemorrhage, andexanet was associated with greater hemostasis and reduced mortality compared to PCC 9 …”

Direct Oral Anticoagulants: Laboratory Challenges and Antidotes

“…Indirect comparisons and observational data suggest better outcomes from using specific antidotes. 58 59 These hypothesis-generating observations are currently being tested in the ANNEXA-I study—a randomized trial in DOAC-related ICH which compares andexanet alfa directly against standard of care including PCC.…”

Management of bleeding in patients on direct oral anticoagulants in emergency department: where we are and where we are going

“…However, when andexanet alfa is available, this should be preferred to the use of PCC for treatment of patients with major bleeding on oral direct FXa inhibitors. 19 , 20 …”