Critical Care Alert: PROCOAG Trial

ARTICLE: 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. Published online March 21, 2023. doi:10.1001/jama.2023.4080

QUESTION
Does administering 4-Factor Prothrombin Concentrate (4F-PCC) to patients at risk of massive transfusion due to trauma reduce the amount of blood product consumption within the first 24 hours?

OBJECTIVE
To investigate the efficacy of 4F-PCC administration in patients at risk of massive transfusion

BACKGROUND
A staple in the management of major trauma is rapid hemorrhage control. In the prehospital and emergency department setting, the goal is to limit critical hypoperfusion until surgical hemostasis is achieved. For severely injured patients, this may require massive transfusion, defined as administration of at least 3 packed red blood cells (pRBC) within 1 hour of arrival or transfusion of 10 units of pRBC within a 24-hour period.¹ One obstacle to massive transfusion is trauma-induced coagulopathy, in which coagulation factors are rapidly consumed and diluted from volume expansion of fluids and/or blood products transfused. This creates a positive feedback loop of worsening coagulopathy leading to altered hemostasis and worsened patient outcomes. Prior trials of fixed ratio-based blood product transfusion (PROPPR trial²) or use of viscoelastic testing to guide management (RETIC trial³) have shown improved outcomes with transfusing coagulation factors in concert with pRBCs as soon as possible.

4F-PCC is commonly used for reversal of life-threatening bleeding due to warfarin and DOAC anticoagulation, consisting of vitamin-K dependent blood clotting factors II, VII, IX, and X as well as proteins S and C.⁴ Previous observational studies have shown that early administration of 4F-PCC can boost thrombin generation to reduce blood product consumption; however, concerns for an increased risk of thromboembolic events remains.⁵ Recent observational studies have shown the coadministration of 4F-PCC and fresh frozen plasma (FFP) reduced blood product consumption and mortality without an increase of thromboembolic events.⁶ The PROCOAG RCT was thus designed to test the hypothesis that 4F-PCC administration combined with a ratio-based transfusion is superior to ratio-based transfusion alone in reducing 24-hour blood product consumption in patients at risk of massive transfusion. 

DESIGN
This was a superiority, randomized, placebo-controlled clinical trial that took place across 12 level 1 trauma centers in France from December 2017 to August 2021. The starting time for each study measure was arrival to the trauma bay. Consent was either obtained from participants via the patient, next of kin, or through emergency inclusion with consent being obtained after stabilization.

Randomization was performed within 1 hour of admission. Patients were randomized in blocks of 2-6, stratified by center through a randomization sequence.  The clinician investigator and all team members involved in the care of the patient were blinded to the assigned treatment. The site and coordinating pharmacy remained unblinded. All personnel in data handling and statistical analysis were blinded.

The experimental group included 4F-PCC at a dose of 25U of factor IX per kg (1 mL/kg). The placebo group received 1 mL/kg of normal saline.  Doses were administered at a speed of 120 mL/h as soon as possible after admission.

Both groups were treated with fluid expansion and early transfusion of blood products with a PRBC:FFP ratio between 1:1 and 2:1. TXA was administered within 3 hours at a loading dose of 1 g followed by 1 g over 8 hours. The source of bleeding was identified and treated as soon as possible. Fibrinogen was administered if measured fibrinogen was low or viscoelastic criteria (VET) showed a functional deficiency.  Platelets were transfused to maintain a count higher than 50x10⁹/L. 

Arterial or venous thromboembolic events were recorded through day 28.  Surveillance was passive. Every clinical suspicion of thromboembolic event was confirmed by ultrasonography and/or contrast enhanced CT.

INCLUSION CRITERIA

• Patients 18 years or older with trauma admitted directly from injury scene to participating trauma center with the highest level of trauma activation
• Patients considered at risk for massive transfusion:
  • Transfusion of at least 1 unit of pRBC during prehospital care or within 1 hour of admission
  • Assessment of Blood Consumption (ABC) score⁷ of at least 2
    • +1 point for each, scores above 2 are likely to require massive transfusion
      • Penetrating mechanism
      • Systolic blood pressure (BP) <90 in emergency department (ED)
      • Heart rate (HR) >120 in ED
      • Positive Focused Assessment with Sonography for Trauma (FAST)
    • Clinical assessment by attending physician determining patient is at risk of massive transfusion

EXCLUSION CRITERIA

• Traumatic cardiac arrest before randomization
• Patients with catastrophic injuries expected to die within first hour of admission
• Secondary admission from a different health care facility
• Pre-injury treatment with anticoagulants
• Pregnant patients
• Known hypersensitivity to 4F-PCC and its analogues
• Patients under guardianship
• Any inclusion in another trial within past 30 days
• Known pre-injury terminal condition
• Patients without health insurance (according to French Law)

PRIMARY OUTCOME

• Total number of all blood product units (RBC, FFP, and platelets) consumed within the first 24 hours after arrival in the trauma bay

SECONDARY OUTCOMES

• Individual blood product units consumed within the first 24 hours
• Time to Prothrombin Time (PT) less than 1.5
• Time to hemorrhage control
• 24-hour and 28-day mortality
• Number of intensive care unit-free days, ventilator-free days, and hospital-free days through day 28
• Hospitalization status at 28 days
• Glasgow Outcome Scale-Extended score in patients with brain injury seen on computed tomography (CT) on admission (Abbreviated Injury Scale score >2) 

KEY RESULTS
Of the 4313 patients with the highest level of trauma activation admitted among the 12 centers, 350 were eligible for inclusion. Of these, 324 were analyzed with 164 in the 4F-PPC group and 160 in the placebo group.  

Primary Outcome
There was no clinically or statistically significant difference between the two groups for 24-hour total blood product consumption 12 [5-19]U vs 11 [6-19]U; absolute difference (0.2 [95% CI -2.99 to 3.33]U; P=.72) in the 4F-PCC group and placebo group, respectively. 

Secondary Outcome
There were no statistically significant differences in any of the secondary outcomes.

Safety Outcome
There was a statistically significant difference between patients with at least 1 thromboembolic event in the 4F-PCC group vs the placebo group (56 [35%] vs 37 [24%]; absolute difference 11% [95% CI, 1%-21%]; relative risk 1.48 [95% CI, 1.04-2.10]; P = .03). There were 63 total thromboembolic events in the 4F-PCC group and 46 in the placebo group.

A post hoc analysis revealed a higher percentage of thromboembolic events in patients with a PTr greater than 1.2 who received 4F-PCC. The percentage of thromboembolic events in patients with a PTr less than 1.2 were comparable between the two groups.

LIMITATIONS

• 4F-PCC was administered in combination with FFP without prior viscoelastic testing (VET). The combination of these drugs without VET may expose patients without coagulopathy to a risk of coagulation factor overdosing
• The primary outcome of 24-hour blood product use is a less patient-centered outcome than others such as mortality
• Despite randomization, there was a delay to FFP administration in the placebo group
• The definition of the pre-specified “massive transfusion” subgroup could be influenced by the intervention
• The composition of other commercially available 4F-PCC may differ from the one in this study
• This trial was only in an adult patient population and is not applicable to pediatric patients

EM TAKE-AWAYS
The empiric use of 4F-PCC in patients at risk of massive transfusion was not supported by this RCT as it did not reduce 24-hour blood product consumption and was associated with more thromboembolic events. Fixed-ratio blood product transfusion and expedient hemorrhage control remain the gold standard in the management of the severely bleeding trauma patient.

References

1. Jennings LK, Watson S. Massive transfusion. In: StatPearls. StatPearls Publishing; 2023.
2. Holcomb JB, Tilley BC, Baraniuk S, et al., PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5), 471–482.
3. Innerhofer P, Fries D, Mittermayr M, et al. (2017). 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.
4. Quinlan DJ, Eikelboom JW, Weitz JI. Four-factor prothrombin complex concentrate for urgent reversal of vitamin k antagonists in patients with major bleeding. Circulation. 2013;128(11):1179-1181.
5. Schöchl H, Nienaber U, Maegele M, et al. (2011). Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Crit Care. 2011;15(2):R83.
6. Zeeshan M, Hamidi M, Feinstein AJ, 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;87(2):274–281.
7. ABC score for massive transfusion. MDCalc.