A 2016 guidance statement from the Neurocritical Care Society and the Society of Critical Care Medicine suggest activated charcoal 50 g to intubated intracranial hemorrhage patients presenting within 2 hours of ingestion of an oral factor Xa inhibitor. If the intracranial hemorrhage occurred within 3-4 half-lives of ingestion, then Kcentra® (4-factor prothrombin complex concentrate [4F-PCC]) 50 units/kg or activated PCC (aPCC) 50 units/kg is recommended. However, since Andexxa® (andexanet alfa) was not approved at time of the statement's publication, it was not mentioned in this guideline. [1]
A 2019 guidance document from the Anticoagulation Forum suggests treatment with andexanet alfa in patients with rivaroxaban-associated or apixaban-associated major bleeding in whom a reversal agent is warranted. If andexanet alfa is not available, treatment with 4F-PCC 2,000 units is suggested. Similarly, Praxbind (idarucizumab) 5 g IV is recommended for dabigatran-associated major bleeding and aPCC 50 units/kg IV is suggested if idarucizumab is unavailable. In patients with edoxaban-associated or betrixaban-associated major bleeding in whom a reversal agent is warranted, off-label treatment with either high dose andexanet alfa (800 mg bolus given at 30 mg/min followed by a continuous infusion of 8 mg/min for up to 120 min) or 4F-PCC 2,000 units is suggested. These recommendations come from clinical trials involving andexanet alfa and prospective, cohort studies involving 4F-PCC for reversal of factor Xa-associated major bleeding. While some authors recommend weight‐based dosing of 4F-PCC (50 units/kg) for factor Xa inhibitor reversal, the Anticoagulation Forum prefers a fixed dose of 2000 units because it has been studied in patients with factor Xa inhibitor‐associated bleeding. Additional advantages of fixed dosing include greater simplicity for the ordering provider and pharmacy and reduced cost. [2]
A 2019 meta-analysis, including 10 studies with 340 patients, evaluated the safety and efficacy of 4F-PCC as an alternative for managing major bleeding caused by direct factor Xa (fXa) inhibitor. No comparative studies were found, so the studies selected included only patients who received 4F-PCCs for direct fXa inhibitor-related bleeding. Two studies used the International Society on Thrombosis and Haemostasis (ISTH) to define the effectiveness of major bleeding management, while the other eight did not. In these two studies, 69% (95% CI 0.61 to 0.76) of patients were successfully managed with 4F-PCCs. In the studies that did not use ISTH criteria, 77% (95% confidence interval [CI] 0.63 to 0.92; i^2 85%) of patients were managed. Out of the nine studies that reported mortality, 16% (95% CI 0.07 to 0.26) of patients died during the follow-up period. The authors highlight the limitation of not having a comparator group, but nevertheless suggest 4F-PCC may be a reasonable option for reversal of fXa inhibitor-related bleeding. [3]
A 2021 meta-analysis compared hemostatic effectiveness and thromboembolic event rates between andexanet (n= 396) and PCC (n= 1,428). A pooled proportion of Annexa-4 criteria patients demonstrated a hemostatic effectiveness of 0.82 (95% CI, 0.78‐0.87) in andexanet studies and 0.85 (95% CI, 0.80‐0.90) in PCC. Thromboembolic events were 0.11 (95% CI, 0.04‐0.18) in andexanet studies and 0.03 (95% CI, 0.02‐0.04) in PCC. The authors concluded the products have similar efficacy but andexanet-treated patients may have a comparatively higher rate of thromboembolic events. The study was limited by lack of a control in all identified studies which limits pooled comparison. [4]
A 2020 cost comparative study predicted the cost of andexanet alfa would exceed the national average hospital reimbursement/patient in nearly 75% of patients by over USD $7,500 per hospitalization. The authors concluded 4F-PCC was significantly less expensive, had lower rates of thrombosis, but also lower rates of hemostasis compared to published data for andexanet alfa. [5]