Emergent reversal of oral factor Xa inhibitors with four-factor prothrombin complex concentrate
Introduction
Oral factor Xa (fXa) inhibitors are anticoagulants with demonstrated utility in the treatment and prevention of thromboembolic disease including venous thromboembolism and reduction in the risk of stroke or systemic embolism in patients with nonvalvular atrial fibrillation [1,2]. FXa inhibitors prevent fibrin clot formation by binding to the active site of coagulation fXa leading to the inhibition of the coagulation cascade [3]. Conveniently, fXa inhibitors have consistent pharmacokinetic and pharmacodynamic properties that allow for a fixed dosing strategy without obligatory routine laboratory monitoring of anticoagulation effect. Commercially available oral fXa inhibitors in the United States include rivaroxaban, apixaban, edoxaban, and betrixaban.
The use of fXa inhibitors may increase a patient's risk for bleeding due to their inhibition of the coagulation cascade [3]. There may be a reduced risk of intracranial hemorrhage when compared to warfarin, a vitamin K antagonist [1,2]. To a greater extent than vitamin K antagonists, controversy exists regarding reversal strategies for oral fXa inhibitors [4]. Andexanet alfa, now labeled as inactivated coagulation fXa (recombinant) with trade name Andexxa®, was FDA approved in May of 2018 to reverse apixaban and rivaroxaban. The Phase 3b/4 trial evaluating the safety and efficacy of andexanet alfa, ANNEXA-4, was completed in February 2019 [5]. Ciraparantag is an investigational small molecule that binds and inactivates several anticoagulants and is currently undergoing clinical trials for reversal of bleeding associated with fXa Inhibitors [6].
4-factor prothrombin complex concentrate (4F-PCC), with trade name Kcentra®, was FDA approved in 2013 for the urgent reversal of oral vitamin-K antagonist associated coagulopathy. It contains the clotting factors II, VII, IX, and X, and antithrombotic proteins C and S [7]. Additionally, 4F-PCC is frequently used off-label to urgently reverse the anticoagulant effects of oral fXa inhibitors [8]. Although it is not FDA approved for this indication, limited evidence and current guidelines suggest prothrombin complex concentrate (PCC) and activated prothrombin complex concentrate (aPCC) are options for reversal of anticoagulation in the case of life-threatening bleeding in patients on fXa Inhibitors [[9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]]. The recent approval of andexanet alfa, with its high acquisition cost and safety concerns, has added to the controversy regarding optimal oral fXa inhibitor reversal strategies. We aimed to perform a comprehensive evaluation of the effectiveness and safety of 4F-PCC for the management of emergent bleeding related to oral fXa inhibitors including a strict subgroup with inclusion/exclusion criteria similar to the ANEXXA-4 trial. This study will add to the body of literature surrounding this controversial topic and provide a cost analysis for health systems and formulary committees to consider.
Section snippets
Study design
This was a retrospective, observational study conducted at a multicenter health system in the United States. The health system consists of a flagship academic hospital, four community hospitals, and three critical access hospitals. The flagship hospital is a level 1 trauma center and comprehensive stroke center. Radiographic imaging, medication administration records, and laboratory data were collected from the electronic medical record. In-hospital mortality and thromboembolic events were
Results
A total of 145 patients were screened of which 119 were eligible for inclusion. Eighty-five of the 119 patients (71%) required reversal due to intracranial bleeding. Prior to reversal, 70 patients (59%) were taking apixaban and 49 patients (41%) were taking rivaroxaban. A successful hemostatic outcome was achieved in 106 of 119 patients (89%). (See Table 2) In the ANNEXA-4 criteria subgroup, 74 of 83 patients (90%) achieved a successful clinical outcome. The mortality rate prior to discharge
Discussion
This study evaluated the clinical effectiveness, safety, and financial impact of using 4F-PCC for the reversal of oral fXa inhibitors. In an effort to compare our outcomes using 4F-PCC to previously published outcomes using andexanet alfa, we analyzed a subgroup created utilizing ANNEXA-4 inclusion and exclusion criteria.
The rate of successful clinical outcome of 89% in this study compares favorably to previously reported success rates with the use of 4F-PCC for this indication. A meta-analysis
Conclusion
Administration of 4F-PCC for the reversal of oral fXa inhibitors was effective with relatively low thrombotic risk. 4F-PCC appear to have similar clinical success rates when indirectly compared with andexanet alfa with reduced prothrombotic risk and cost. Randomized, prospective studies are warranted to further compare safety, efficacy and cost of 4F-PCC and andexanet alfa for this indication.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
All authors have declared they have no conflict of interest relevant to this work.
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Cited by (12)
Lower mortality with andexanet alfa vs 4-factor prothrombin complex concentrate for factor Xa inhibitor-related major bleeding in a U.S. hospital-based observational study
2023, Research and Practice in Thrombosis and HaemostasisFour-factor prothrombin complex concentrate for the treatment of oral factor Xa inhibitor-associated bleeding: a meta-analysis of fixed versus variable dosing
2023, Research and Practice in Thrombosis and HaemostasisContemporary Perioperative Management of Direct Oral Anticoagulants
2022, Advances in AnesthesiaCitation Excerpt :Similarly, a 2021 retrospective review of FXaI reversal for hemorrhage found effective hemostasis in 75% with andexanet versus 62.5% with PCCs and TECs rate of 25% and 18.8%, respectively [35]. Following the ANDEXXA-4 trial, Lipari and colleagues [36] retrospectively applied the strict andexanet alfa use criteria to their PCC use for FXaI-related bleeding and demonstrated a clinical success of 90% with a TEC rate of 2.5%. They estimated that had they used andexanet alfa in this patient pool, the per patient costs would increase by US$29,500 [36].
Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants
2021, Journal of the American College of CardiologyCitation Excerpt :Of these, 1,888 reports were excluded after review of the title and abstract and 67 additional references were excluded after checking of full text (see Supplemental Appendix 2 for the list of excluded reports and causes of exclusion). Sixty studies met the inclusion criteria (19–78). The majority were retrospective cohorts (n = 48), followed by prospective cohorts (n = 10) and clinical trials (n = 2) (Table 1).