Multi-centered evaluation of a novel fixed-dose four-factor prothrombin complex concentrate protocol for warfarin reversal

Dietrich, Scott; Mixon, Mark; Holowatyj, Michael; Werth, Josh C.; Delgado, Stephanie A.; Mascolo, Nicole E.; Meister, Erin; Zoucha, Shane M.; Trujillo, Toby C.

doi:10.1016/j.ajem.2020.06.017

Cited by 9 publications

(9 citation statements)

References 18 publications

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“…After this time, the study institution moved to a fixed-dose protocol. 35,36 Concurrent use or repeat doses with either agent was not recommended.…”

Section: Andexanet Alfa and 4f-pcc Usementioning

confidence: 99%

Retrospective Comparison of Andexanet Alfa and 4-Factor Prothrombin Complex for Reversal of Factor Xa-Inhibitor Related Bleeding

Stevens

Trujillo

Kiser

et al. 2021

Clin Appl Thromb Hemost

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The aim of this retrospective study was to compare andexanet alfa and 4-factor prothrombin complex (4F-PCC) for reversal of factor Xa (FXa)-inhibitor bleeding. Patients that received andexanet alfa for reversal were included. An equivalent number of patients administered 4F-PCC for FXa-inhibitor bleeding were randomly selected as historical controls. The primary outcome was effective hemostasis achievement within 12 h, defined using ANNEXA-4 criteria. Thromboembolic events and mortality within 30 days were also evaluated. A total of 32 patients were included. Baseline characteristics were not statistically different between andexanet alfa (n = 16) and 4F-PCC (n = 16). Intracranial bleeding was the primary reversal indication in 43.8% versus 62.5% of patients, respectively. Effective hemostasis was reached in 75.0% of andexanet alfa patients compared to 62.5% of 4F-PCC patients ( P = .70). Thromboembolic events occurred in 4 (25.0%) patients and 3 (18.8%) patients, respectively ( P = .99). Mortality incidence was 12.5% and 31.3%, respectively ( P = .39). Andexanet alfa and 4F-PCC attained hemostasis in a majority of patients. A high, but a similar rate of thromboembolic events was seen with both treatments. Prospective studies are needed to elucidate comparative risks and benefits of the 2 agents.

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“…After this time, the study institution moved to a fixed-dose protocol. 35,36 Concurrent use or repeat doses with either agent was not recommended.…”

Section: Andexanet Alfa and 4f-pcc Usementioning

confidence: 99%

Retrospective Comparison of Andexanet Alfa and 4-Factor Prothrombin Complex for Reversal of Factor Xa-Inhibitor Related Bleeding

Stevens

Trujillo

Kiser

et al. 2021

Clin Appl Thromb Hemost

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“…1 ; and Supplementary Table 2 , http://links.lww.com/CCM/H489 ). Three studies were prospective RCTs ( 8 – 10 ), one was a prospective cohort of both treatment regimens ( 29 ), two were prospective cohorts treated with a fixed-dose regimen compared with historical data ( 28 , 38 ), and the remainder were retrospective studies ( 13 , 14 , 16 , 17 , 25 – 27 , 30 , 32 , 34 , 39 – 41 ). All studies were conducted in the United States or The Netherlands.…”

Section: Resultsmentioning

confidence: 99%

Fixed- Versus Variable-Dose Prothrombin Complex Concentrate for the Emergent Reversal of Vitamin K Antagonists: A Systematic Review and Meta-Analysis

Alwakeal,

Maas,

Naidech

et al. 2024

Critical Care Medicine

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Objectives: Four-factor prothrombin complex concentrate (4-PCC) is recommended for rapid reversal of vitamin K antagonists (VKAs) such as warfarin, yet optimal dosing remains uncertain. Data Sources: A systematic review was conducted of PubMed, Embase, and Ovid MEDLINE (Wolters Kluwer) databases from January 2000 to August 2023 for clinical studies comparing fixed- vs. variable-dose 4-PCC for emergent VKA reversal with at least one reported clinical outcome. Study Selection: Abstracts and full texts were assessed independently and in duplicate by two reviewers. Data Extraction: Data were extracted independently and in duplicate by two reviewers using predefined extraction forms. Data Synthesis: The analysis comprised three randomized trials and 16 cohort studies comprising a total of 323 participants in randomized trials (161 in fixed dosage and 162 in variable dosage) and 1912 patients in cohort studies (858 in fixed-dose and 1054 in variable dose). Extracranial bleeding was the predominant indication, while intracranial hemorrhage varied. Overall, a fixed-dose regimen may be associated with a lower dose of 4-PCC and results in a reduction in 4-PCC administration time compared with a variable-dose regimen. A fixed-dose regimen also likely results in increased clinical hemostasis. While there is no clear difference between the two regimens in terms of achieving a goal international normalized ratio (INR) less than 2, a fixed-dose regimen is less likely to achieve a goal INR less than 1.5. High certainty evidence indicates that the fixed-dose regimen reduces both mortality and the occurrence of thromboembolic events. Additional subgroup analyses provides exploratory data to guide future studies. Conclusions: A fixed-dose regimen for 4-PCC administration provides benefits over a variable-dose regimen in terms of dose reduction, faster administration time, improved clinical hemostasis, and reduced mortality and thromboembolic events. Further studies are warranted to better refine the optimal fixed-dose regimen.

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“…The outcomes of 25 retrospective studies identified in the literature search are summarized in ►Supplementary Table S5 (available in the online version). Among retrospective studies, the majority (n ¼ 11) reported safety outcomes of 4F-PCC in patients requiring VKA reversal, [34][35][36][37][38][39][40][41][42][43][44] including three studies comparing fixed and standard variable dosing, [34][35][36] one study investigating VKA reversal for intracranial hemorrhage (ICH), 39 and one study comparing outcomes in patients with body weight over or under 100 kg. 40 Nine studies reporting the use of 4F-PCC for OAC (VKA or DOAC) reversal were retrieved, [45][46][47][48][49][50][51][52][53] including three studies examining 4F-PCC for reversal of VKA or DOAC-associated ICH 48,52,53 and one study comparing use of 4F-PCC for onlabel and off-label indications.…”

Section: Safety Outcomes From Retrospective Studiesmentioning

confidence: 99%

“…[56][57][58] The incidence of TEEs reported in the VKA reversal retrospective studies ranged from 1.0 to 11.5%, which was similar to that seen in the phase 3b clinical trials. [34][35][36][37][38][39][40][41][42][43][44] Similarly, TEE rates ranged from 2.1 to 11.4% when Kcentra®/Beriplex® P/N was used for the management of DOAC-associated bleeding. 48,49,[53][54][55] When used for VKA reversal, there were no consistent findings of fixed or stan-dard variable dosing having an effect on the incidence of TEEs, 34,36,39,43,44 including comparisons of patients with body weight over or under 100 kg.…”

Section: Safety Outcomes From Retrospective Studiesmentioning

confidence: 99%

Long-Term Safety of a Four-Factor Prothrombin Complex Concentrate (Kcentra®/Beriplex® P/N): An Updated Pharmacovigilance Review

Milling,

Voronov,

Schmidt

et al. 2024

Thromb Haemost

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Introduction Four-factor prothrombin complex concentrate (4F-PCC) is recommended for vitamin K antagonist reversal in patients with major bleeding or in need of surgery. The most important risk associated with the use of 4F-PCC is the occurrence of thromboembolic events (TEEs). In this review, we aim to evaluate the safety profile of a 4F-PCC (Kcentra®/Beriplex® P/N; CSL Behring, Marburg, Germany) by reviewing pharmacovigilance data. Methods A retrospective analysis of postmarketing pharmacovigilance data of Kcentra®/Beriplex® P/N from February 1996 to April 2022 was performed and complemented by a review of clinical studies published between January 2012 and April 2022. Results A total of 2,321,443 standard infusions of Kcentra®/Beriplex® P/N were administered during the evaluation period. Adverse drug reactions (ADRs) were reported in 614 cases (∼1 per 3,781 standard infusions) and 233 of these cases (37.9%) experienced suspected TEEs related to 4F-PCC (∼1 per 9,963 standard infusions); most of these cases had pre-existing or concomitant conditions likely to be significant risk factors for thrombosis. TEE rates were similar when 4F-PCC was used on-label or off-label for direct oral anticoagulant-associated bleeding. Thirty-six cases (5.9%) reported hypersensitivity type reactions (∼1 per 64,485 standard infusions). No confirmed case of viral transmission related to 4F-PCC use was reported. The published literature also revealed a favorable safety profile of 4F-PCC. Conclusion Analysis of postmarketing pharmacovigilance safety reports demonstrated that treatment with 4F-PCC was associated with few ADRs and a low rate of TEEs across multiple indications and settings, thus confirming a positive safety profile of 4F-PCC.

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Multi-centered evaluation of a novel fixed-dose four-factor prothrombin complex concentrate protocol for warfarin reversal

Cited by 9 publications

References 18 publications

Retrospective Comparison of Andexanet Alfa and 4-Factor Prothrombin Complex for Reversal of Factor Xa-Inhibitor Related Bleeding

Retrospective Comparison of Andexanet Alfa and 4-Factor Prothrombin Complex for Reversal of Factor Xa-Inhibitor Related Bleeding

Fixed- Versus Variable-Dose Prothrombin Complex Concentrate for the Emergent Reversal of Vitamin K Antagonists: A Systematic Review and Meta-Analysis

Long-Term Safety of a Four-Factor Prothrombin Complex Concentrate (Kcentra®/Beriplex® P/N): An Updated Pharmacovigilance Review

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