REBEL Cast Ep 118: The PROCOAG Trial – 4F-PCC for Trauma Patients?

Background: Hemorrhage is the leading cause of mortality in trauma patients.  Interventions such as early application of hemorrhage control, tranexamic acid, reduction of crystalloid  fluid administration and balanced ratio blood product transfusion have improved many patients’ outcomes. However, mortality still remains high due to trauma-induced coagulopathy. Some clinicians have advocated for early administration of 4-factor prothrombin complex concentrate (4F-PCC) based on limited observational data. 4F-PCC contains factors II, VII, IX, X as well as Proteins S and C. This could potentially help  improve thrombin generation, reduce blood product consumption, but also could increase the risk of thromboembolic events. High-quality studies are needed to determine the utility of this intervention.

REBEL Cast Ep118:  The PROCOAG Trial – 4F-PCC in Trauma Patients?

Paper: Bouzat 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. PMID: 36942533

Clinical Question: Does 4F-PCC administration reduce 24 hour blood product consumption in adult patients with trauma at risk of massive transfusion compared to placebo?

What They Did:

• Double-blind, randomized, placebo-controlled superiority trial
• Performed in 12 French designated level 1 trauma centers
• Consecutive patients with trauma at risk of massive transfusion
  • At risk = transfusion of at least 1U blood products during prehospital care or within 1 hour of admission AND an Assessment of Blood Consumption (ABC) Score of at least 2 OR clinical assessment of the attending physician of risk of massive transfusion
  • Massive transfusion = Administration of at least 3U blood products within the hour of admission or at least 10U blood products within the first 24 hours
  • Acute traumatic coagulopathy = PT >1.2
  • Severe acute traumatic coagulopathy = PT >1.5
  • Admission = Arrival in the trauma bay
• All patients received trauma resuscitation management including:
  • Restricted crystalloid fluid expansion
  • Early ratio-based transfusion (PRBCs:FFP in a ratio of 1:1 to 2:1)
  • IV TXA within 3 hours after injury at a loading dose of 1g followed by 1g over 8 hours
  • Early hemorrhage control
  • Fibrinogen concentrate if fibrinogen level <1.5g/L OR viscoelastic criteria showing a functional deficiency
  • Platelets as needed to maintain platelet count >50 x 10⁹/L
• Patients randomized within 1 hour of arrival to:
  • 4F-PCC: 1mL/kg (25IU of factor IX/kg)
  • Placebo: 1mL/kg of saline solution
  • Given at 120mL/hr

Outcomes:

• Primary:
  • Efficacy: Median 24hr all product consumption (RBC, FFP, and Platelets)
• Secondary:
  • Safety: Arterial or venous thromboembolic events (PE, DVT, Stroke, MI, Mesenteric Ischemia, and Extremity Ischemia) through day 28
  • Individual blood component units consumed within first 24 hours
  • Time to PT <1.5 (severe acute traumatic coagulopathy)
  • Time to hemorrhage control
  • 24hr and 28d mortality
  • Number of ICU free days through day 28
  • Ventilator free days through day 28
  • Hosptial free days through day 28

 Inclusion:

• Adult patients (≥18 years of age)
• Trauma requiring transfer from injury scene directly to one of the participating level I trauma centers
• At risk for massive transfusion

Exclusion:

• Traumatic cardiac arrest before randomization
• Patients with devastating injuries expected to die within the first hour of admission
• Secondary admission from another health care facility
• Preinjury treatment with anticoagulants
• Know pregnancy
• Known hypersensitivity to 4F-PCC
• Known preinjury terminal condition
• Patients under guardianship
• Any inclusion in another trial within the last 30 days
• Patients without health insurance (This was due to French law)

Results:

• 4313 trauma patients evaluated
  • 350 were eligible for emergency inclusion
  • 327 patients were randomized
  • 324 patients were analyzed
• Patient Characteristics
  • Median age: 39 years (Range 27 to 56)
  • Injury Severity Score: 36 (Range 26 to 50)
  • Blunt Trauma ≈80% of patients
  • Transfusion of ≥10U Blood Products ≈27%
  • Admission Lactate Level: 4.6mmol/L (Range 2.8 to 7.4)
  • Prehospital SBP <90mmHg: 59% of patients
  • Higher percentage of placebo group patients received TXA compared to 4F-PCC group: 86% vs 76%
  • Patients in the placebo group had a higher median total dose of fibrinogen concentrate given compared to 4F-PCC: 3g (Range 3 to 6g) vs 3g (Range 3 to 7.5g)
• Median 24hr All Product Consumption (Primary Outcome)
  • 4F-PCC: 12U (Range 5 to 19)
  • Placebo: 11U (Range 6 to 19)
  • Absolute Diff: 0.2U; 95% CI-2.99 to 3.33; P = 0.72
  • NOT STATISTICALLY SIGNIFICANT
  • Also no difference in individual components given
• Thromboembolic Events:
  • 4F-PCC: 35%
  • Placebo: 24%
  • Absolute Diff: 11%; 95% CI 1 to 21%
  • Relative Risk 1.48; 95% CI 1.04 to 2.10; P = 0.03
  • STATISTICALLY SIGNIFICANT
• There were no differences between groups in any of the other secondary outcomes including time to hemorrhage control, 24hr or 28d mortality

Strengths:

• Double-blind, randomized, placebo-controlled superiority trial
  • Patients, investigators, and data analysts were blinded to treatment assignment
  • 4F-PCC and placebo both prepared in a protected dedicated space by a nurse not involved in the resuscitation or subsequent care of patients
  • 4F-PCC and placebo administered in opaque syringes to avoid unblinding
• No major changes to the protocol or outcome occurred after the start of the trial

• After complete patient enrollment and before data analysis the authors confirmed that the time spent in the study (up to 24 hours) did not differ between the 2 groups to prevent survivor bias for the primary outcome
• Groups were fairly well balanced in terms of characteristics, prehospital vital signs, prehospital interventions, admission vital signs, admission labs, surgical/radiologic hemorrhage control
• Majority of patients (95%) received study intervention (4F-PCC or placebo) within the first hour of admission
• Pragmatic inclusion criteria helped recruit patients with severe bleeding who might potentially benefit the most from 4F-PCC which increases generalizability and external applicability of these results

Limitations:

• Surveillance with CT scanning was passive to reduce radiation exposure and extremity ultrasound was left to the discretion of the attending physician. This may have caused an underreporting of thromboembolic events
• A higher percentage of patients in the placebo group received TXA prehospitally (86% vs 76%) and a higher median total dose of fibrinogen concentrate compared to the 4F-PCC group which could dilute the effectiveness of 4F-PCC
• Study drug was administered in combination with FFP without prior viscoelastic testing. This may have exposed some patients without coagulopathy to the risk of coagulation factor “overdosing”
• The primary outcome, 24 hour blood product use, is not a patient-centered outcome
• Although multicenter performed in only one country which may have different systems of health care compared to other countries which could limit generalizability

Discussion:

• Based on 1 year data from the Northern French Alps registry the mean total blood product consumption was estimated at 12U of blood products (PRBC, FFP, and platelets) in the first 24 hours. A reduction by 3U per 24 hours or a decrease of 25% in 24hours was considered to be clinically significant
• Three previous trials on 4F-PCC included:
  • 2 observational trials comparing FFP-only vs FFP plus 4F-PCC [3][4]
  • Single center open-label trial comparing fibrinogen concentrate, factor XIII, and 4F-PCC vs FFP
  • All 3 observed a reduction in blood product consumption with 4F-PCC
• Compared to previous work on this topic the PROCOAG trial included a higher percentage of patients in shock (59% with prehospital SBP <90mmHg vs 30 to 45% in previous 3 studies)

Author Conclusion: “Among patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour plod 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.”

Clinical Take Home Point: In adult patients with trauma at risk of massive transfusion, receiving standard trauma resuscitation management, the addition of 4F-PCC did not result in a decrease in blood product consumption over 24 hours compared to placebo.  Additionally, the use of 4F-PCC resulted in a higher rate of thromboembolic events compared to placebo.  At this time the use of 4F-PCC is not supported in patients with trauma at risk of massive transfusion.

References:

1. Bouzat 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. PMID: 36942533
2. Innerhofer P 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. PMID: 28457980
3. Jehan F et al. The Role of Four-Factor Prothrombin Complex Concentrate in coagulopathy of Trauma: A Propensity Matched Analysis. J Trauma Acute Care Surg 2018. PMID: 29664892
4. Zeeshan M et al. Four-Factor Prothrombin Complex Concentrate is Associated with Improved Survival in Trauma-Related Hemorrhage: A Nationwide Propensity-Matched Analysis. J Trauma Acute Care Surg 2019. PMID: 30889141

 Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)