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Cited by 461Blood transfusion and managementTrauma, Hemostasis, Coagulopathy, ResuscitationBlood Coagulation and Thrombosis Mechanisms

Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial

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Goldstein, Joshua N, Refaai, Majed A, Milling, Truman J, Lewis, Brandon, Goldberg-Alberts, Robert, Hug, Bruce A, Sarode, Ravi·2015·The Lancet
DOI 10.1016/s0140-6736(14)61685-8PMC PMC6633921
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Abstract

Background Rapid reversal of vitamin K antagonist (VKA)-induced anticoagulation is often necessary for patients needing urgent surgical or invasive procedures. The optimum means of VKA reversal has not been established in comparative clinical trials. We compared the efficacy and safety of four-factor prothrombin complex concentrate (4F-PCC) with that of plasma in VKA-treated patients needing urgent surgical or invasive procedures.Methods In a multicentre, open-label, phase 3b randomised trial we enrolled patients aged 18 years or older needing rapid VKA reversal before an urgent surgical or invasive procedure. We randomly assigned patients in a 1:1 ratio to receive vitamin K concomitant with a single dose of either 4F-PCC (Beriplex/Kcentra/Confidex; CSL Behring, Marburg, Germany) or plasma, with dosing based on international normalised ratio (INR) and weight. The primary endpoint was effective haemostasis, and the co-primary endpoint was rapid INR reduction (≤1·3 at 0·5 h after infusion end). The analyses were intended to evaluate, in a hierarchical fashion, first non-inferiority (lower limit 95% CI greater than -10% for group difference) for both endpoints, then superiority (lower limit 95% CI >0%) if non-inferiority was achieved. Adverse events and serious adverse events were reported to days 10 and 45, respectively. This trial is registered at ClinicalTrials.gov, number NCT00803101.Findings 181 patients were randomised (4F-PCC n=90; plasma n=91). The intention-to-treat efficacy population comprised 168 patients (4F-PCC, n=87; plasma, n=81). Effective haemostasis was achieved in 78 (90%) patients in the 4F-PCC group compared with 61 (75%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 14·3%, 95% CI 2·8-25·8). Rapid INR reduction was achieved in 48 (55%) patients in the 4F-PCC group compared with eight (10%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 45·3%, 95% CI 31·9-56·4). The safety profile of 4F-PCC was generally similar to that of plasma; 49 (56%) patients receiving 4F-PCC had adverse events compared with 53 (60%) patients receiving plasma. Adverse events of interest were thromboembolic adverse events (six [7%] patients receiving 4F-PCC vs seven [8%] patients receiving plasma), fluid overload or similar cardiac events (three [3%] patients vs 11 [13%] patients), and late bleeding events (three [3%] patients vs four [5%] patients).Interpretation 4F-PCC is non-inferior and superior to plasma for rapid INR reversal and effective haemostasis in patients needing VKA reversal for urgent surgical or invasive procedures.Funding CSL Behring.

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  • In a multicentre randomized trial of 188 patients undergoing urgent surgical or invasive procedures, four-factor prothrombin complex concentrates achieved more rapid INR reversal and effective haemostasis than plasma.

    “In a multicentre randomized trial of 188 patients, four-factor prothrombin complex concentrates achieved more rapid INR reversal and effective haemostasis than plasma in patients undergoing urgent surgical or invasive procedures.507”

    From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [507]

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Authors
Goldstein, J. N., Refaai, M. A., Milling, T. J., Lewis, B., Goldberg-Alberts, R., Hug, B. A., & Sarode, R.
Affiliations
  • Massachusetts General Hospital (US)
  • University of Rochester Medicine (US)
  • University Medical Center Brackenridge (US)
  • Texas A&M Health Science Center (US)
  • CSL (United States) (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Goldstein, Joshua N
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2015-05
Volume
385
Issue
9982
Pages
2077-2087
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(14)61685-8
PMC
PMC6633921
OpenAlex
W2142187440
Cited by
461
References
28
Citations by year
2026: 12 · 2025: 22 · 2024: 30 · 2023: 22 · 2022: 33 · 2021: 43 · 2020: 47 · 2019: 50 · 2018: 52 · 2017: 62 · 2016: 63 · 2015: 23
FWCI
45.73
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Alexion Pharmaceuticals
  • CSL Behring
  • National Heart, Lung, and Blood Institute (K23HL127227)
Topics
  • Health Sciences › Medicine › Biochemistry › Blood transfusion and management
  • Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Trauma, Hemostasis, Coagulopathy, Resuscitation
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Keywords
four-factor prothrombin complex concentrate, plasma transfusion, vitamin K antagonist reversal, anticoagulant reversal, urgent surgery, invasive procedures, non-inferiority, vitamin K, bleeding risk, adverse events, non-inferiority margin, international normalized ratio, factor replacement therapy
MeSH terms
Aged, Analysis of Variance, Blood Coagulation Factors, Female, Hemostasis, Surgical, Hemostatics, Humans, Male, Plasma, Preoperative Care, Vitamin K, Blood Loss, Surgical, Treatment Outcome, International Normalized Ratio

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