An in-depth analysis of the groundbreaking clinical trial 'EFFICACY AND SAFETY OF EARLY ADMINISTRATION OF 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE IN PATIENTS WITH TRAUMA AT RISK OF MASSIVE TRANSFUSION'
Introduction
Trauma-induced coagulopathy is a critical condition that potentially endangers life, and early intervention can significantly alter the patient's clinical outcome. Many strategies have been tested, and the use of 4-factor prothrombin complex concentrate (4F-PCC) has emerged as a promising one. The randomized clinical trial "Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients with Trauma at Risk of Massive Transfusion" investigates the efficacy and safety of administering 4F-PCC in trauma patients at risk of a massive transfusion. The study paints a vivid, detailed picture of its potential benefits and drawbacks.
The PROCOAG Trial
The PROCOAG trial was a multicenter, double-blind, randomized, placebo-controlled superiority trial conducted in 12 level 1 trauma centers in France. It sought to answer the question: "Does 4-factor prothrombin complex concentrate (4F-PCC) reduce 24-hour blood product requirements in trauma patients at risk of massive transfusion?".
The trial included adult trauma patients directly from the injury scene, considered at risk of massive transfusion. The risk was defined by several criteria, including requiring 1 unit of packed red blood cell concentrate (PRBC) prehospital or <1 hour of admission, an Assessment of Blood Consumption (ABC) score >2, or a clinical assessment of risk by a physician. Some patients were excluded, such as those with traumatic cardiac arrest, devastating injuries, pre-injury anticoagulant use, or pregnant individuals. The participants were randomized within 1 hour of admission to receive 4F-PCC 25 IU/kg or a saline placebo.
RESULTS
Out of the 324 patients analyzed, 164 received 4F-PCC, and 160 received placebo. The two groups were well matched at baseline, with the only significant difference being a higher proportion of prehospital TXA in the placebo group.
Interestingly, the trial found no significant difference in median 24-hour blood product consumption between 4F-PCC and placebo (12 vs. 11 units, p = 0.72). Similarly, no differences were seen in any of the secondary outcomes, which included time to INR < 1.5, time to hemorrhage control, mortality, ICU- and ventilator-free days, and thrombotic events.
However, a crucial finding was noted in the safety analysis. 35% of patients who received 4F-PCC (n = 56) presented with at least one thromboembolic event, as compared to 24% (n = 37) in the placebo group (RR 1.48, 95% CI 1.04-2.10).
Implications and Interpretations
This randomized, double-blind, placebo-controlled superiority trial aimed to evaluate the efficacy and safety of 4F-PCC in conjunction with a ratio-based transfusion strategy in patients at risk of massive transfusion. Interestingly, the trial revealed no decrease in 24-hour blood product consumption or any noteworthy differences in secondary outcomes when compared to the placebo. Furthermore, a statistically significant increase in thromboembolic events was identified in the group that received 4F-PCC.
The trial's results challenge earlier physiological, observational, and interventional evidence that suggested 4F-PCC might provide benefits through enhancing factor concentration and thrombin generation. This contradiction might be attributed to the complex nature of trauma-induced coagulopathy, which involves various hemostatic interactions.
There are three comparable studies to the current trial. Two are observational studies, and one is a single-center open-label trial. These studies observed a reduction in blood product consumption with 4F-PCC administration, contrasting with the current trial's findings. Differences in trial design and patient demographic may explain the discrepancy.
One essential aspect that the current trial highlights is the safety concern regarding 4F-PCC use due to increased thromboembolic events. Thromboembolic risk reporting has been inconsistent across studies, and some suggest underreporting. The current trial reported a higher overall relative risk of thromboembolic events, further intensifying these safety concerns, especially in patients with posttraumatic coagulopathy.
The study has a few limitations. It administered the study drug in combination with FFP without prior VET, potentially exposing patients without coagulopathy to the risk of coagulation factor "overdosing". Also, the 24-hour blood product use as the primary endpoint might be considered an inadequate surrogate for a patient-centered outcome, such as mortality. Furthermore, despite randomization, the placebo group had a longer delay to FFP administration.
Conclusion
The trial did not find any beneficial effects of adding 4F-PCC to a ratio-based transfusion strategy in patients with severe trauma at risk of massive transfusion. On the contrary, it noted potential harm due to a higher rate of thromboembolic events, particularly in patients with increased PTr. Therefore, the findings do not support the systematic use of 4F-PCC in patients with trauma at risk of massive transfusion.
References
Bouzat P, Charbit J, Abback P, et al. 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. JAMA. 2023;329(16):1367–1375. doi:10.1001/jama.2023.4080 [Link]
Innerhofer P, Fries D, Mittermayr M, et al. Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial.  Lancet Haematol. 2017;4(6):e258-e271. doi:10.1016/S2352-3026(17)30077-7 [PubMed]
Jehan F, Aziz H, OʼKeeffe T, et al. The role of four-factor prothrombin complex concentrate in coagulopathy of trauma: a propensity matched analysis.  J Trauma Acute Care Surg. 2018;85(1):18-24. doi:10.1097/TA.0000000000001938 [PubMed]
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