Dataset Information

Four-factor prothrombin complex concentrate to reduce allogenic blood product transfusion in patients with major trauma, the PROCOAG trial: study protocol for a randomized multicenter double-blind superiority study.

ABSTRACT:

Background

Optimal management of severe trauma patients with active hemorrhage relies on adequate initial resuscitation. Early administration of coagulation factors improves post-traumatic coagulation disorders, and four-factor prothrombin complex concentrate (PCC) might be useful in this context. Our main hypothesis is that four-factor PCC in addition to a massive transfusion protocol decreases blood product consumption at day 1 in severe trauma patients with major bleeding.

Methods

This is a prospective, randomized, multicenter, double-blind, parallel, controlled superiority trial. Eligible patients are trauma patients with major bleeding admitted to a French level-I trauma center. Patients randomized in the treatment arm receive 1 mL/kg (25 IU/ml of Factor IX/Kg) four-factor PCC within 1-h post-admission while patients randomized in the controlled group receive 1 mL/kg of saline solution 0.9% as a placebo. Treatments are given as soon as possible using syringe pumps (120 mL/h). The primary endpoint is the amount of blood products transfused in the first 24 h post-admission (including red blood cells, frozen fresh plasma, and platelets). The secondary endpoints are the amount of each blood product transfused in the first 24 h, time to achieve prothrombin time ratio < 1.5, time to hemostasis, number of thrombo-embolic events at 28 days, mortality at 24 h and 28 days, number of intensive care unit-free days, number of ventilator-free days, number of hospital-free days within the first 28 days, hospitalization status at day 28, Glasgow outcome scale extended for patients with brain lesions on initial cerebral imaging, and cost of each strategy at days 8 and 28. Inclusions have started in December 2017 and are expected to be complete by June 2021.

Discussion

If PCC reduces total blood consumption at day 1 after severe trauma, this therapy, in adjunction to a classic massive transfusion protocol, may be used empirically on admission in patients at risk of massive transfusion to enhance coagulation. Moreover, this treatment may decrease blood product-related complications and may improve clinical outcomes after post-traumatic hemorrhage.

Trial registration

ClinicalTrials.gov NCT03218722 . Registered on July 14, 2017.

SUBMITTER: Bouzat P

PROVIDER: S-EPMC8444177 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceOptimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption.ObjectiveTo investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion.Design, setting, and participantsDouble-blind, randomized, placebo-controlled superiority trial in 12 French designated level I trauma centers from December 29, 2017, to August 31, 2021, involving consecutive patients with trauma at risk of massive transfusion. Follow-up was completed on August 31, 2021.InterventionsIntravenous administration of 1 mL/kg of 4F-PCC (25 IU of factor IX/kg) vs 1 mL/kg of saline solution (placebo). Patients, investigators, and data analysts were blinded to treatment assignment. All patients received early ratio-based transfusion (packed red blood cells:fresh frozen plasma ratio of 1:1 to 2:1) and were treated according to European traumatic hemorrhage guidelines.Main outcomes and measuresThe primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety).ResultsOf 4313 patients with the highest trauma level activation, 350 were eligible for emergency inclusion, 327 were randomized, and 324 were analyzed (164 in the 4F-PCC group and 160 in the placebo group). The median (IQR) age of participants was 39 (27-56) years, Injury Severity Score was 36 (26-50 [major trauma]), and admission blood lactate level was 4.6 (2.8-7.4) mmol/L; prehospital arterial systolic blood pressure was less than 90 mm Hg in 179 of 324 patients (59%), 233 patients (73%) were men, and 226 (69%) required expedient hemorrhage control. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 U [95% CI, -2.99 to 3.33]; P = .72). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs 37 patients (24%) in the placebo group (absolute difference, 11% [95% CI, 1%-21%]; relative risk, 1.48 [95% CI, 1.04-2.10]; P = .03).Conclusions and relevanceAmong patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour blood product consumption after administration of 4F-PCC, but thromboembolic events were more common. These findings do not support systematic use of 4F-PCC in patients at risk of massive transfusion.Trial registrationClinicalTrials.gov Identifier: NCT03218722.

Project description:OBJECTIVES:Clinicians often need to rapidly reverse vitamin K antagonists (VKAs) in the setting of major hemorrhage or urgent need for surgery. Little is known about the safety profile of the traditional reversal agent, plasma, or the newly approved agent, four-factor prothrombin complex concentrate (4F-PCC), in a randomized setting. This is an integrated analysis of safety data from two clinical trials that evaluated 4F-PCC versus plasma for the treatment of patients requiring rapid VKA reversal for acute major bleeding or prior to an urgent surgical/invasive procedure. METHODS:This descriptive analysis comprised adverse event (AE) data from two phase IIIb, randomized, controlled trials. The bleeding and surgical studies were performed across 36 and 33 sites, respectively, in nine countries, with the integrated analysis comprising 388 patients (4F-PCC, n = 191; plasma, n = 197) aged ? 18 years, who required VKA reversal due to major bleeding or prior to an urgent surgical/invasive procedure. Patients received either 4F-PCC, containing nonactivated factors II, VII, IX, and X and proteins C and S (Beriplex/Kcentra, CSL Behring) or plasma, both dosed according to baseline international normalized ratio and body weight. Patients were also to receive vitamin K1. AEs and serious AEs (SAEs) were assessed up to days 10 and 45, respectively. RESULTS:The proportion of patients with AEs (4F-PCC, 115/191 [60.2%]; plasma, 124/197 [62.9%]) and SAEs (4F-PCC, 54/191 [28.3%]; plasma, 49/197 [24.9%]) was similar between groups. The proportion of patients with thromboembolic events was also similar between groups (4F-PCC, 14/191 [7.3%]; plasma, 14/197 [7.1%]). There were 13 (6.8%) deaths in the 4F-PCC group and 13 (6.6%) in the plasma group. Fluid overload events occurred in more patients in the plasma group than the 4F-PCC group (25 [12.7%] and 9 [4.7%], respectively). CONCLUSIONS:These safety data represent the largest controlled assessment of a 4F-PCC to date. For patients requiring urgent VKA reversal, 4F-PCC had a safety profile similar to that of plasma (AEs, SAEs, thromboembolic events, and deaths), but was associated with fewer fluid overload events.

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