In this episode, I’ll discuss a company-sponsored indirect comparative study looking at andexanet alfa vs 4 factor prothrombin complex concentrate (4FPCC) for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage.
There are two methods used for reversing acute major bleeding from factor Xa inhibitors:
1. Prothrombin Complex Concentrate (PCC), which is an indirect reversal strategy that attempts to create a pro-coagulant effect by providing extra clotting factors II, VII, IX, and X.
2. Andexanet alfa, which acts as a direct reversal agent by binding and inactivating circulating factor Xa inhibitors
To date there has not been a prospective head-to-head comparison of these two strategies.
The manufacturers of Andexanet alfa have recently published in the open access journal Critical Care what they describe as a two-cohort comparison study of andexanet alfa patients enrolled in the prospective ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system.
202 radiographically confirmed ICH patients who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included in the analysis. 107 patients received andexanet alfa and 95 received 4FPCC. The authors found that:
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.
A 2021 meta-analysis published in Critical Care Medicine suggested that despite andexanet alfa’s higher quality of evidence, a conclusion of superiority cannot be drawn and it may be reasonable to consider either agent until definitive data becomes available.
The present study seems to simply represent the comparison of 2 separate cohorts of patients, which is not a robust method of determining the superiority of a given treatment against another. As the authors acknowledge in the study’s limitation section, while they soughtto mitigate the risk of confounding by implementing propensity score-overlap weighting, residual confounding due to unobserved or unmeasured covariates cannot be ruled out due to the two-cohort design of the study.
Does this data add anything to the current literature to help decide whether to use andexanet alfa or 4FPCC for ICH from apixaban or rivaroxaban? Please let me know your thoughts in the comments below.
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