Optimal Dosage and Administration Practices for Vitamin K Antagonist Reversal With 4-Factor Prothrombin Complex Concentrate

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Abstract

Expert consensus and international guidelines recommend urgent co-administration of vitamin K and 4-factor prothrombin complex concentrates (4F-PCCs) to rapidly reverse VKA-related bleeding. This narrative review examined real-world evidence and strategies to optimize international normalized ratio (INR) reversal, hemostasis, and outcomes in patients receiving 4F-PCC in this setting. Key determinants for success include the appropriate use of alternative dosing and administration strategies, such as fixed dosing and increased infusion speed, adherence to institutional guidelines, and removing significant institutional barriers to reduce time to treatment. In the opinion of authors, minimizing the time to treatment with 4F-PCCs is of paramount importance when treating patients with VKA-related bleeding. Practices that safely and feasibly shorten the time to administration should be included in guidelines for institutions responsible for anticoagulant care, and adhered to in centers that perform invasive procedures on patients receiving VKA therapy. Further studies are required to optimize use of 4F-PCC, particularly in relation to the ideal dosing strategy and the role of INR.

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The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition

Donat R. Spahn, Bertil Bouillon, Vladimir Cerny … (2019)

Background Severe traumatic injury continues to present challenges to healthcare systems around the world, and post-traumatic bleeding remains a leading cause of potentially preventable death among injured patients. Now in its fifth edition, this document aims to provide guidance on the management of major bleeding and coagulopathy following traumatic injury and encourages adaptation of the guiding principles described here to individual institutional circumstances and resources. Methods The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2004, and the current author group included representatives of six relevant European professional societies. The group applied a structured, evidence-based consensus approach to address scientific queries that served as the basis for each recommendation and supporting rationale. Expert opinion and current clinical practice were also considered, particularly in areas in which randomised clinical trials have not or cannot be performed. Existing recommendations were re-examined and revised based on scientific evidence that has emerged since the previous edition and observed shifts in clinical practice. New recommendations were formulated to reflect current clinical concerns and areas in which new research data have been generated. Results Advances in our understanding of the pathophysiology of post-traumatic coagulopathy have supported improved management strategies, including evidence that early, individualised goal-directed treatment improves the outcome of severely injured patients. The overall organisation of the current guideline has been designed to reflect the clinical decision-making process along the patient pathway in an approximate temporal sequence. Recommendations are grouped behind the rationale for key decision points, which are patient- or problem-oriented rather than related to specific treatment modalities. While these recommendations provide guidance for the diagnosis and treatment of major bleeding and coagulopathy, emerging evidence supports the author group’s belief that the greatest outcome improvement can be achieved through education and the establishment of and adherence to local clinical management algorithms. Conclusions A multidisciplinary approach and adherence to evidence-based guidance are key to improving patient outcomes. If incorporated into local practice, these clinical practice guidelines have the potential to ensure a uniform standard of care across Europe and beyond and better outcomes for the severely bleeding trauma patient. Electronic supplementary material The online version of this article (10.1186/s13054-019-2347-3) contains supplementary material, which is available to authorized users.

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The management of antithrombotic agents for patients undergoing GI endoscopy.

Ruben D Acosta, Neena Abraham, Vinay Chandrasekhara … (2016)

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Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study.

Ravi Sarode, Truman Milling, Majed Refaai … (2013)

Patients experiencing major bleeding while taking vitamin K antagonists require rapid vitamin K antagonist reversal. We performed a prospective clinical trial to compare nonactivated 4-factor prothrombin complex concentrate (4F-PCC) with plasma for urgent vitamin K antagonist reversal. In this phase IIIb, multicenter, open-label, noninferiority trial, nonsurgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whether 4F-PCC was noninferior to plasma for the coprimary end points of 24-hour hemostatic efficacy from start of infusion and international normalized ratio correction (≤1.3) at 0.5 hour after end of infusion. The intention-to-treat efficacy population comprised 202 patients (4F-PCC, n=98; plasma, n=104). Median (range) baseline international normalized ratio was 3.90 (1.8-20.0) for the 4F-PCC group and 3.60 (1.9-38.9) for the plasma group. Effective hemostasis was achieved in 72.4% of patients receiving 4F-PCC versus 65.4% receiving plasma, demonstrating noninferiority (difference, 7.1% [95% confidence interval, -5.8 to 19.9]). Rapid international normalized ratio reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC superiority (difference, 52.6% [95% confidence interval, 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start (P<0.02). The safety profile (adverse events, serious adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasma group) patients experienced ≥1 adverse event. 4F-PCC is an effective alternative to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding events, as demonstrated by clinical assessments of bleeding and laboratory measurements of international normalized ratio and factor levels. http://www.clinicaltrials.gov. Unique identifier: NCT00708435.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Appl Thromb Hemost

Journal ID (iso-abbrev): Clin Appl Thromb Hemost

Journal ID (publisher-id): CAT

Journal ID (hwp): spcat

Title: Clinical and Applied Thrombosis/Hemostasis

Publisher: SAGE Publications (Sage CA: Los Angeles, CA )

ISSN (Print): 1076-0296

ISSN (Electronic): 1938-2723

Publication date (Electronic): 14 October 2020

Publication date Collection: Jan-Dec 2020

Volume: 26

Electronic Location Identifier: 1076029620947474

Affiliations

[1 ]UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA

[2 ]Grady Health System, Atlanta, GA, USA

[3 ]University of Mississippi, School of Medicine, Jackson, MS, USA

Author notes

[*]Denise H. Rhoney, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA. Email: drhoney@ 123456unc.edu

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Denise H. Rhoney https://orcid.org/0000-0003-0646-6111

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Publisher ID: 10.1177_1076029620947474

DOI: 10.1177/1076029620947474

PMC ID: 7573754

SO-VID: 6bf9a320-76cf-4958-b217-82f7f04639cb

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This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

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cover-date January-December 2020

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Keywords: hemorrhage,warfarin,anticoagulants,prothrombin complex concentrates

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Keywords: hemorrhage, warfarin, anticoagulants, prothrombin complex concentrates

Optimal Dosage and Administration Practices for Vitamin K Antagonist Reversal With 4-Factor Prothrombin Complex Concentrate

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Most cited references 74

The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition

The management of antithrombotic agents for patients undergoing GI endoscopy.

Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study.

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