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Randomized Controlled Trial
. 2023 Apr 25;329(16):1367-1375.
doi: 10.1001/jama.2023.4080.

Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial

Pierre Bouzat  1 , Jonathan Charbit  2 , Paer-Selim Abback  3 , Delphine Huet-Garrigue  4 , Nathalie Delhaye  5 , Marc Leone  6 , Guillaume Marcotte  7 , Jean-Stéphane David  8 , Albrice Levrat  9 , Karim Asehnoune  10 , Julien Pottecher  11 , Jacques Duranteau  12 , Elie Courvalin  2 , Anais Adolle  13 , Dimitri Sourd  14 , Jean-Luc Bosson  14 , Bruno Riou  15 , Tobias Gauss  3 , Jean-François Payen  1 ; PROCOAG Study Group
Collaborators, Affiliations
Randomized Controlled Trial

Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial

Pierre Bouzat et al. JAMA. .

Abstract

Importance: Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption.

Objective: To investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion.

Design, setting, and participants: Double-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.

Interventions: Intravenous 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 measures: The primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety).

Results: Of 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 relevance: Among 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 registration: ClinicalTrials.gov Identifier: NCT03218722.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bouzat reported receiving personal fees from Werfen, Octapharma, and LFB outside the submitted work. Dr Charbit reported receiving personal fees from LFB and Octapharma outside the submitted work. Dr Huet-Garrigue reported receiving personal fees from LFB, nonfinancial support from Octapharma, personal fees from Boehringer-Ingelheim, personal fees from AstraZeneca, and personal fees from Bayer outside the submitted work. Dr Leone reported receiving personal fees from AOP Pharma, Gilead, Viatris, and LFB outside the submitted work. Dr Marcotte reported receiving personal fees from LFB and Octapharma outside the submitted work. Dr David reported receiving personal fees from LFB outside the submitted work. Dr Asehnoune reported receiving personal fees from LFB during the conduct of the study and personal fees from Baxter, Fisher and Paykel, and Edwards Lifesciences outside the submitted work. Dr Pottecher reported receiving research and educational grants from and serving on an advisory board for LFB during the conduct of the study and receiving educational grants from Masimo, Edwards Lifesciences, AOP Orphan, and RDS outside the submitted work. Dr Duranteau reported receiving personal fees from Octapharma and LFB during the conduct of the study and personal fees from Edwards Lifesciences, Fresenius, RenalSense, and Amomed and grants from Sophysa outside the submitted work. Dr Gauss reported receiving personal fees from Laboratoire du Biomédicament Français outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Participants in a Study of Administration of 4-Factor Prothrombin Complex Concentrate (4F-PCC) in Patients With Trauma at Risk of Transfusion
aHighest level of trauma activation corresponds to patients with a Glasgow Outcome Scale score less than 9, systolic arterial blood pressure less than 90 mm Hg, and/or acute respiratory distress on arrival at the trauma bay. bRandomization was stratified by center.
Figure 2.
Figure 2.. Transfusion-Related Secondary Outcomes by Treatment Group
A, Lines within box indicate median values, lower and upper box edges are 25th and 75th percentile values, whiskers extend to ±1.5 times the interquartile range, and points outside are the most extreme values. Total blood product consumption at 24 hours (primary outcome) was not different between the 2 groups (median [IQR], 12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 [95% CI, −2.99 to 3.33] U; P = .72). Individual product consumption (secondary outcome) was also not different between the 2 groups (see Table 2 for data). Mann-Whitney tests were applied for all comparisons. B, Mean time course and 95% CI (bars) of prothrombin time ratio (PTr) between the groups. PTr is the ratio between the prothrombin time of the patient and the prothrombin time reference value of the laboratory. A PTr higher than 1.2 indicates posttraumatic coagulopathy and a PTr higher than 1.5 indicates severe posttraumatic coagulopathy. A mixed-effects linear regression model found no between-group difference (P = .14). 4F-PCC indicates 4-factor prothrombin complex concentrate.
See this image and copyright information in PMC

Comment in

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