Modeling the Clinical Implications of Andexanet Alfa in Factor Xa Inhibitor–Associated Intracerebral Hemorrhage

Abstract

Background and Objectives:Andexanet alfa was recently approved as a reversal agent for the Factor Xa inhibitors (FXai) apixaban and rivaroxaban, but its impact on long-term outcomes in FXai-associated intracerebral hemorrhage (ICH) is unknown. We aimed to explore potential clinical implications of andexanet alfa in FXai-associated ICH in this simulation study.Methods:We simulated potential downstream implications of andexanet alfa across a range of possible hemostatic effects using data from a single center that treats FXai-associated ICH with prothrombin complex concentrate (PCC). We determined baseline probabilities of inadequate hemostasis across FXai and non-FXai patients via multivariable regression models, then determined probabilities of unfavorable 3-month outcome (modified Rankin Scale 4-6) using models comprising established predictors and each patient’s calculated probability of inadequate hemostasis. We applied bootstrapping with model parameters from this derivation cohort to simulate a range of hemostatic improvements and corresponding outcomes, then calculated absolute risk reduction (relative to PCC) and projected number needed to treat (NNT) to prevent one unfavorable outcome.Results:Training models using real-world patients (n=603 total; 55 FXai) had good accuracy in predicting inadequate hemostasis (AUC 0.78) and unfavorable outcome (AUC 0.78). Inadequate hemostasis was strongly associated with unfavorable outcome (OR 4.5, 95% CI 2.0-9.9) and occurred in 11.4% of FXai patients. Across simulated FXai patients comparable to those in the ANNEXA-4 study, predicted absolute risk reduction of unfavorable outcome was 4.9% (95% CI 1.3%-7.8%) when the probability of inadequate hemostasis was reduced by 33%, and 7.4% (95% CI 2.0%-11.9%) at 50% reduction, translating to projected NNTs of 21 (cumulative cost $519,750) and 14 ($346,500), respectively.Discussion:Even optimistic simulated hemostatic effects suggest that the costs and potential benefits of andexanet alfa should be carefully considered. Placebo-controlled randomized trials are needed before its use can definitively be recommended.

Author Reply to “Intravenous thrombolysis in patients taking direct oral anticoagulants (European stroke organisation intravenous thrombolysis guidelines comment)

“…We came to different voting results between idarucizumab and andexanet mainly because of their different speeds of administrations. Idarucizumab, the dabigatran reversal agent, can be administered as two bolus infusions, no more than 15 min apart 10 , while andexanet, the reversal agent of apixaban and rivaroxaban requires a bolus over a period of 15-30 minutes followed by a 2-h infusion 11 , leading to a considerable delay in the door-to-IVT times. Therefore, we voted in favour of idarucizumab, but not in favour of andexanet prior to IVT.…”

Andexanet Alfa for Factor Xa Inhibitor–Associated Intracerebral Hemorrhage

“…This issue of Neurology ® delivers a meticulously crafted study by Chuck et al 7 to explore some of the unknowns described above. The authors use a simulated dataset derived from a single-center ICH registry to model the potential hemostatic effects, patient-oriented outcomes, and costs associated with andexanet alfa in fXa inhibitor–associated ICH.…”