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

Abstract

BACKGROUND AND OBJECTIVES\nAndexanet 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.\n\n\nMETHODS\nWe 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.\n\n\nRESULTS\nTraining 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.\n\n\nDISCUSSION\nEven 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.