Brief ReportExperiences with an activated 4-factor prothrombin complex concentrate (FEIBA) for reversal of warfarin-related bleeding☆,☆☆
Introduction
Warfarin has remained the most commonly prescribed oral anticoagulant in the US since its approval by the Food and Drug Administration in 1954. Currently up to 2% of the US population receive this medication [1]. Roughly 6.5% of patients treated with oral anticoagulants per year will experience major bleeding, and up to 1% will die as a result of major hemorrhage [2]. Reversal of anticoagulation, therefore, remains a critical therapeutic hurdle. The American College of Chest Physicians guidelines currently provide several options for the management of warfarin-related bleeding, including fresh frozen plasma (FFP), recombinant factor VIIa (rfVIIa), or a prothrombin complex concentrate (PCC) [3].
FFP is currently the most frequently utilized treatment for warfarin reversal in the US, but has several limitations when used for emergent reversal of warfarin-related bleeding. FFP requires blood-type matching and thawing of the product, as well as a relatively prolonged infusion time owing to large volumes (usually several units totaling 0.75-2 L of fluid). It also conveys a risk of infectious disease transmission, circulatory overload, and transfusion-related acute lung injury (TRALI) [4], [5].
Many of the limitations of FFP are not shared by a PCC, however. They require only a small infusion volume (usually 20-40 mL) and short infusion period (usually 5-10 minutes). There is minimal risk of TRALI, as PCC lacks the antigens which precipitate this event. A PCC can be reconstituted in minutes, versus 30 to 60 minutes needed to thaw FFP. Furthermore, the effects of PCC on the international normalized ration (INR) occur within minutes after administration [6]. These benefits are tempered by the potential risk of thrombosis and cost of the products. While a single unit of FFP may cost ~$100, a 1000-U dose of aPCC costs ~$2000. Inpatient costs of an intracranial hemorrhage, for example, may range from $10,000 to 20,000 [7].
There are 3 types of PCC which vary based on clotting factor content [8]. A three-factor PCC contains (primarily) factors II, IX, and X. A 4-factor PCC contains II, VII, IX, and X. A 4-factor PCC may also be “activated,” signifying the presence of activated factor VII. Furthermore, some PCCs contain anticoagulants such as heparin, protein C, protein S, or antithrombin. Currently, only 3-factor PCCs (Bebulin VH, Baxter, Deerfield, IL; and Profilnine SD, Grifols Biologicals, Inc, Los Angeles, CA) and an activated 4-factor PCC (FEIBA, Baxter) are available in the United States, although a non-activated 4-factor PCC has recently received Food and Drug Administration approval.
Reports have described suboptimal reversal of warfarin-related bleeding with 3-factor PCC [9], [10]. In practice, they are often combined with FFP to improve efficacy, thereby negating several of the benefits of PCC as previously outlined. In an effort to improve this efficacy, a recent report outlined the successful use of a combination of three-factor PCC and low-dose rfVIIa [11]. Despite these findings, the utility of an activated 4-factor PCC (aPCC) for management of warfarin-related bleeding remains poorly elucidated; only a handful of studies discuss this treatment modality [12], [13].
Following the methods of Wójcik et al, a protocol was implemented at our institution for reversal of warfarin-related bleeding utilizing aPCC at a fixed, low-dose based on INR. Although a wide range of PCC doses have been studied, ranging from 10 to 50 U/kg, a lower fixed dose has been shown to effectively and rapidly reverse an elevated INR. Data were collected retrospectively on patients treated via this protocol between September 2011 and July 2012 to assess the degree of control of coagulopathy related to warfarin. The use of the protocol was based on prescriber preference during this time frame. This report will summarize the outcomes of patients treated with the protocol.
Section snippets
Methods
After approval by the Pharmacy and Therapeutics committee, a protocol was implemented on March 9, 2011, which outlined the use of aPCC for the emergent reversal of warfarin-related bleeding (Fig. 1). The definition of “emergent” was left up to the discretion of the prescriber but included life-threatening bleeding or the need for normalization of INR for life-saving procedures. The protocol called for a dose of 500 U of aPCC for an INR less than 5 and 1000 U if the INR is greater than or equal
Results
Sixteen patients were treated with aPCC for the management of warfarin related bleeding, per the established protocol (Table 1, Table 2). Mean patient age was 73 years (range, 54-89). Eight of the patients were female. Atrial fibrillation and a history of deep vein thrombosis/pulmonary embolism (DVT/PE) were the most common indications for anticoagulation. Seven of the sixteen patients were taking an antiplatelet agent at the time of reversal: 3 were taking aspirin only, 2 were taking
Discussion
We sought to evaluate the safety and effectiveness of a protocol utilizing a fixed low dose of aPCC for the reversal of warfarin related bleeding in a community hospital. Although relatively few patients have thus far received the product, almost all patients treated via protocol showed a control of bleeding (where observable). Furthermore, these patients showed strong reductions in the INR with relatively few additional doses needed.
Controversy exists regarding the optimal reversal agent. The
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Cited by (22)
Protocolized use of Factor Eight Inhibitor Bypassing Activity (FEIBA) for the reversal of warfarin induced coagulopathy
2020, American Journal of Emergency MedicineCitation Excerpt :In addition to the dose of FEIBA, these studies have wide variations in the timing of FEIBA administration, patient characteristics, and the type of major bleeding. As in these studies, we did not record whether our subjects were on chemical venous thromboembolism (VTE) prophylaxis [18,19,22]. In clinical practice, the decision to start the patients with major bleeding on VTE prophylaxis occurs on a case-by-case basis [26,27].
Safety and effectiveness of Factor Eight Inhibitor Bypassing Activity for direct oral anticoagulant-related hemorrhage reversal
2019, American Journal of Emergency MedicineCitation Excerpt :Finally, our patient population includes patients from a single academic center. Although, this could decrease the generalizability of our findings to other centers, our patients with DOAC-associated hemorrhagic complications were very similar to those described in previous reports [9-12]. In conclusion, this case series suggests that FEIBA administration is relatively safe and effective to reverse DOACs in the setting of hemorrhage or need for urgent surgical procedures.
Factor Eight Inhibitor Bypassing Agent (FEIBA) for Reversal of Target-Specific Oral Anticoagulants in Life-Threatening Intracranial Bleeding
2017, Journal of Emergency MedicineCitation Excerpt :Finally, FEIBA dosing in our institutional protocol is based on literature from the hemophilia population rather than drug-specific data. Although FEIBA has already been studied on a variable-dose regimen for supratherapeutic Coumadin (Bristol-Myers Squibb) dose-related hemorrhages, its usage for TSOA remains purely anecdotal, with a weight-based dosing between 26 and 100 U/kg (19–24). The Neurosurgical Care Society currently recommends a higher FEIBA dosing at 50 U/kg, which may impact both its hemorrhage stabilization and thrombotic complication risk profile (25).
Multidisciplinary consensus document on the management of massive haemorrhage (HEMOMAS document)
2016, Revista Espanola de Anestesiologia y ReanimacionMultidisciplinary consensus document on the management of massive haemorrhage (HEMOMAS document)
2015, Medicina IntensivaPotential antidotes for reversal of old and new oral anticoagulants
2014, Thrombosis Research
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Disclosures: Neither author has any potential or actual conflict of interest to disclose.
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Support: The authors have not received support in the form of equipment, drugs, or grants as part of this research. The authors have no conflicts of interest to report.