Evaluation of andexanet alfa and four‐factor prothrombin complex concentrate (4F‐PCC) for reversal of rivaroxaban‐ and apixaban‐associated intracranial hemorrhages

Abstract

Background/Objective: Before approval of andexanet alfa, off-label treatment with 4-factor prothrombin complex concentrate (4F-PCC) was often utilized for the management of life-threatening hemorrhages associated with oral factor Xa inhibitors. We evaluated the operational processes and outcomes of patients with oral factor Xa inhibitor-associated intracranial hemorrhages (ICH) treated with andexanet alfa or 4F-PCC. Methods:We performed a retrospective, single-center case series of rivaroxaban or apixaban-associated ICH between 2016-2019 treated with andexanet alfa or 4F-PCC. Good or excellent hemostatic effectiveness, good functional outcome (Glasgow Outcome Score [GOS]> 3) at hospital discharge, and incidence of thrombosis within 30 days were reported.Results: Eighteen patients were included in the andexanet alfa cohort and 11 in the 4F-PCC cohort. Excellent or good hemostasis occurred in 88.9% of andexanet alfa-treated patients and 60% of 4F-PCC-treated patients. Good functional outcome on discharge occurred in 55.6% of andexanet alfa-treated patients and 9.1% of 4F-PCC-treated patients. Thrombotic complications occurred in 16.7% of andexanet alfa-treated patients and 9.1% of 4F-PCC-treated patients. Median order-to-administration time was 1.1 hours [0.8-1.4] versus 0.5 hours [0.1-0.8] in the andexanet alfa and 4F-PCC group, respectively. The median cost of therapy was $29970/patient versus $6925/patient in the andexanet alfa and 4F-PCC group, respectively. Conclusions:We observed higher rates of occurrence of good or excellent hemostasis and GOS > 3 on hospital discharge and increased incidence of thrombosis in patients who received andexanet alfa compared to 4F-PCC for oral factor Xa inhibitor reversal.However, patients receiving 4F-PCC had lower pre-reversal Glasgow Coma Scale (GCS) score and larger pre-reversal ICH volume.

Quality evaluation of case series describing four-factor prothrombin complex concentrate in oral factor Xa inhibitor-associated bleeding: a systematic review

“…Even conscientious investigators are limited by the data available to them (contained within their electronic health record), particularly when data is collected retrospectively. The flaws discussed previously and the inherent limitations of case series may explain much of the substantial variance in haemostatic effectiveness (ranging from 60% 20 to 94% 23 ) reported with 4F-PCC in identified series, 18–40 and further underscores the importance of reporting quality metrics for case series when evaluating medical literature.…”

“…Similarly, only three case series clearly described and used the requirement for a validated measure (ie, ultrasound) to objectively confirm and report the diagnosis of a thrombotic event. 20 27 28 43 Less than one-quarter of case series performed (independent or secondary) adjudication of outcomes. 44 More frequent use of a prospective study design (only 21% of identified case series reported being prospective) would allow for many of these concerns to be addressed.…”

“…On the full-text review, 14 case series met inclusion criteria for this systematic review without exclusions. [18][19][20][21][22][23][24][25][26][27][28][29][30][31] An additional nine case series available as abstracts only were included in the sensitivity analysis only. [32][33][34][35][36][37][38][39][40] Characteristics of case series The impact factor of journals in which case series were published ranged from 0.0420 to 16.562 (median, 2.873) (online supplemental eTable 1).…”

Apixaban and rivaroxaban anti-Xa level utilization and associated bleeding events within an academic health system

“…Furthermore, anti-Xa levels may be useful in guiding decisions for reversal of anticoagulation in emergent settings, especially in the absence of a complete history from a patient or when the last dose of drug is unknown and they have risk factors for drug accumulation [ 9 , 34 ]. Given that andexanet alfa is not widely accessible across all institutions, it is vital to consider the role of other reversal strategies and agents including fresh frozen plasma, blood products, and 4F-PCC [ [35] , [36] , [37] ]. Some comparative data between andexanet alfa and 4F-PCC are emerging [ 36 ], and further studies investigating the utility of anti-Xa levels to guide reversal agent use in the setting of unknown last dose of FXaI are needed [ 38 ].…”

“…Given that andexanet alfa is not widely accessible across all institutions, it is vital to consider the role of other reversal strategies and agents including fresh frozen plasma, blood products, and 4F-PCC [ [35] , [36] , [37] ]. Some comparative data between andexanet alfa and 4F-PCC are emerging [ 36 ], and further studies investigating the utility of anti-Xa levels to guide reversal agent use in the setting of unknown last dose of FXaI are needed [ 38 ]. Nonetheless, it may still be appropriate to utilize 4F-PCC for FXaI-associated major bleeding if andexanet alfa is not available, and this is endorsed by a recent consensus statement from the American College of Cardiology [ 39 ].…”