Comparison of 3-factor versus 4-factor prothrombin complex concentrate for emergent warfarin reversal: a systematic review and meta-analysis

Margraf, David; Brown, Sarah Jane; Blue, Heather L; Bezdicek, Tamara L; Wolfson, Julian; Chapman, Scott A

doi:10.1186/s12873-022-00568-x

Cited by 8 publications

(5 citation statements)

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“…Several 3F-PCCs are available, and although no head-to-head randomized comparison with 4F-PCC has been performed, a recent meta-analysis showed that 4F-PCC was more than 3 times as likely to correct the INR compared with 3F-PCC. 26 The main drawback of that meta-analysis was that the included studies were retrospective and examined only laboratory values (INRs) without clinical measures of hemostatic efficacy. Concerns regarding 3F-PCCs include not only that their Factor VII content might be insufficient to correct the INR but also that they lack anticoagulant proteins C and S, which may be critical to mitigating a hypercoagulable state, especially after major surgical procedures.…”

Section: Discussionmentioning

confidence: 99%

Vitamin K Antagonist Reversal for Urgent Surgery Using 4-Factor Prothrombin Complex Concentrates

Sarode,

Goldstein,

Simonian

et al. 2024

JAMA Netw Open

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ImportanceMillions of people take vitamin K antagonists (VKAs). Some people who need urgent surgical procedures require rapid VKA reversal to prevent excessive intraoperative bleeding.ObjectiveTo evaluate the hemostatic noninferiority of an investigational 4-factor prothrombin complex concentrate (4F-PCC) to a control 4F-PCC for rapid VKA reversal before urgent surgery.Design, Setting, and ParticipantsThis phase 3, double-blind, noninferiority randomized clinical trial (LEX-209) was conducted in 24 hospitals in the US, Russia, Georgia, Belarus, Ukraine, and Romania from June 7, 2017, through November 8, 2021; the study was stopped in February 2022. Participants were adult patients taking VKA who had an international normalized ratio (INR) of 2 or higher and needed urgent surgery with a substantial bleeding risk (≥50 mL). Patients were randomized 1:1 to a single infusion of either the investigational 4F-PCC or the control 4F-PCC. Data analysis followed intention-to-treat and per-protocol approaches.InterventionsSingle intravenous infusion was dosed by body weight and baseline INR. A dose of 25, 35, or 50 IU/kg of investigational 4F-PCC or control 4F-PCC was administered for baseline INR of 2 to less than 4, 4 to 6, or over 6, respectively.Main Outcome and MeasureThe primary end point was hemostatic efficacy at surgery end. An independent adjudication board, blinded to the 4F-PCC treatment allocation, assessed hemostatic efficacy using an objective 4-point scale.ResultsA total of 208 patients (median [range] age, 67.5 [31-92] years; 118 males [56.7%]) received the investigational (n = 105) or the control (n = 103) 4F-PCC. The median (range) dose was 25 (16-50) IU/kg in the investigational group and 25 (15-50) IU/kg in the control group, with a median (range) infusion time of 12 (8-50) minutes and 13 (7-30) minutes and a median (range) time from infusion to surgery start of 1.42 (0.25-15.25) hours and 1.50 (0.42-18.50) hours, respectively. Baseline median (range) INR was 3.05 (1.97-21.10) in the investigational group and 3.00 (2.00-11.30) in the control group. In the intention-to-treat analysis, the investigational 4F-PCC was noninferior to the control 4F-PCC, resulting in effective hemostasis in 94.3% of patients vs 94.2% of patients (proportion difference, 0.001; 95% CI, −0.080 to 0.082; P &lt; .001), meeting the prespecified noninferiority margin of 0.15. An INR of 1.5 or lower at 30 minutes after infusion occurred in 78.1% of patients in the investigational group vs 71.8% of patients in the control group (proportion difference, 0.063; 95% CI, −0.056 to 0.181). Thrombotic events (2.9% vs 0%, respectively) and mortality (4.8% vs 1.0%, respectively) were no different than expected for 4F-PCC use. One patient in each treatment group discontinued due to adverse events (cardiac disorders unrelated to 4F-PCC).Conclusions and RelevanceThis randomized clinical trial found that the investigational 4F-PCC was hemostatically noninferior to the control 4F-PCC for rapid VKA reversal in patients needing urgent surgery with considerable bleeding risk; the safety profile of these two 4F-PCCs was similar. These results support the investigational 4F-PCC as a therapeutic option for surgical patients requiring rapid VKA reversal.Trial RegistrationClinicalTrials.gov Identifier: NCT02740335

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Section: Discussionmentioning

confidence: 99%

Vitamin K Antagonist Reversal for Urgent Surgery Using 4-Factor Prothrombin Complex Concentrates

Sarode,

Goldstein,

Simonian

et al. 2024

JAMA Netw Open

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“… 3 A meta-analysis showed that the four-factor PCCs are more effective when used in this indication than the three-factor PCCs. 155 With the increased use of DOACs, PCCs are now also considered to treat the coagulopathy induced by those agents in trauma and surgical patients. 156 Although PCCs are increasingly used off-label to treat acquired coagulopathy in trauma and surgical patients, the evidence remains poor.…”

Section: Management Options To Treat Microvascular Bleeding and Rever...mentioning

confidence: 99%

Perioperative Considerations in Management of the Severely Bleeding Coagulopathic Patient

et al. 2023

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Inherited and acquired coagulopathy are frequently associated with major bleeding in severe trauma, cardiac surgery with cardiopulmonary bypass, and postpartum hemorrhage. Perioperative management is multifactorial and includes preoperative optimization and discontinuation of anticoagulants and antiplatelet therapy in elective procedures. Prophylactic or therapeutic use of antifibrinolytic agents is strongly recommended in guidelines and has been shown to reduce bleeding and need for allogeneic blood administration. In the context of bleeding induced by anticoagulants and/or antiplatelet therapy, reversal strategies should be considered when available. Targeted goal-directed therapy using viscoelastic point-of-care monitoring is increasingly used to guide the administration of coagulation factors and allogenic blood products. In addition, damage control surgery, which includes tamponade of large wound areas, leaving surgical fields open, and other temporary maneuvers, should be considered when bleeding is refractory to hemostatic measures.

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“…Os concentrados de complexo protrombínico possuem um papel bem estabelecido e investigado por ensaios clínicos randomizados para reversão rápida da anticoagulação com antagonista da vitamina K, com estudos comprovando redução da mortalidade, correção rápida do INR e sem aumento do risco de eventos tromboembólicos (Arachchillage et al, 2019;Margraf et al, 2022). No entanto, seu uso off-label aumentou expressivamente, alguns autores relataram até 40% das vezes, já numa coorte retrospectiva, a utilização off-label do CCP de 4 fatores (CCP-4) ocorreu em 76% dos pacientes tratados (Scharman et al, 2018;Roberts et al, 2021).…”

Section: Discussão Composições Existentes E Indicações On-label E Off...unclassified

O papel do concentrado de complexo protrombrínico no manejo da coagulopatia induzida por trauma: uma revisão integrativa

Santos

Silva²,

Moura³

et al. 2023

RSD

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Introdução: O trauma é uma doença que vitimiza quase 6 milhões de pessoas todos os anos. O sangramento decorrente do trauma desencadeia uma coagulopatia complexa, que necessita de tratamento imediato para melhorar a sobrevida do paciente. O tratamento é baseado em remover a fonte de sangramento, utilizar hemoderivados e concentrados de fatores da coagulação, associado com hipotensão permissiva e reposição controlada de fluídos cristaloides. Objetivo: Avaliar os efeitos da utilização dos concentrados de complexo de protrombina no manejo da coagulopatia induzida por trauma no departamento de emergência. Metodologia: este estudo trata-se de uma revisão integrativa da literatura. O mecanismo de busca utilizado dentro das bases de dados foi: (Bleeding OR Hemorrhage OR Hemostasis OR “Blood Coagulation Disorders") AND (“Prothrombin Complex Concentrates”). Foram incluídos artigos de 2017 a 2022, textos completos disponíveis, em inglês, português e espanhol. Foram excluídos cartas, editoriais e relatos de caso, não correspondentes à temática e os duplicados. Resultados: Após a aplicação dos critérios de inclusão e exclusão, 37 artigos foram selecionados para leitura na íntegra, resultando numa amostra final de 15 artigos para compor esta revisão integrativa, sendo nove artigos da MEDLINE, cinco da SCOPUS e um da SCIENCEDirect. Conclusão: O concentrado de complexo de protrombina é um importante adjuvante no manejo da coagulopatia induzida por trauma, devido à capacidade para reduzir a razão normalizada internacional e a mortalidade sem aumentar o risco de eventos tromboembólicos.

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Comparison of 3-factor versus 4-factor prothrombin complex concentrate for emergent warfarin reversal: a systematic review and meta-analysis

Cited by 8 publications

References 50 publications

Vitamin K Antagonist Reversal for Urgent Surgery Using 4-Factor Prothrombin Complex Concentrates

Vitamin K Antagonist Reversal for Urgent Surgery Using 4-Factor Prothrombin Complex Concentrates

Perioperative Considerations in Management of the Severely Bleeding Coagulopathic Patient

O papel do concentrado de complexo protrombrínico no manejo da coagulopatia induzida por trauma: uma revisão integrativa

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