PROCOAG
PubMed • Full text • ClinicalTrials.gov
Clinical Question
In adult trauma patients at risk of massive transfusion, dose use of 4-Factor Prothrombin Complex Concentrate (PCC) decrease blood product consumption within the first 24 hours?
Bottom Line
4-factor PCC did not show benefit of decreasing blood product exposure at 24 hours and may increase the risk of thrombotic events.
Major Points
Following major trauma, morbidity and mortality due to blood loss remains high. Utilization of tranexamic acid (TXA) was demonstrated to offer some benefit in the CRASH-2 trial but does not correct the coagulopathy. Four-factor Prothrombin Complex Concentrate (4F-PCC) contains clotting factors II, VII, IX, and X and the natural anticoagulants protein C and protein S. Originally intended for reversal of major bleeding associated to warfarin exposure, difference commercial products contain different ratios of the clotting factors. Utilization of 4F-PCC may be helpful in other major bleeding events by providing those clotting factors.
The PROCOAG trial was a superiority, placebo matched, randomized-controlled trial that included 327, adult, major trauma patients who were at risk of requiring a massive transfusion that presented to one of 12 Level-1 trauma centres in France. The authors included 327 patients, randomized to receive either 4F-PCC (25 units of Factor IX per kg) or matched placebo. All patients received pRBC:FFP at a ratio of 1:1 to 2:1 and tranexamic acid (TXA) at CRASH-2 dosing. For the primary outcome of total median blood product consumption in first 24 hours, they found no difference with 12 units for the 4F-PCC arm vs. 11 units in the placebo arm (P = 0.72). All of their secondary outcomes, sub-group analysis, or mortality at 24hours and 48hours also found no difference. For safety outcomes, there was a signal for increased rate of thrombotic events in 4F-PCC arm (35%) as compared to 24% in the placebo arm (P = 0.03); which was also observed in the sub-group analysis.
There were some opportunities for bias within the trial: the time from randomization to first product was longer in the placebo arm by 20 minutes. Their main outcome was a surrogate outcome but an important one, given the high resource requirements. Physicians could also override one of the inclusion criteria if their clinical gestalt suggested the patient would be at risk. There is also challenges with external validity as it was only conducted in adults and difference 4F-PCC have different ratios of the coagulation factors therein. Overall, this trial demonstrated that 4F-PCC did not confer benefit to patients at risk of massive transfusion and may increase risk of thrombotic events.
Guidelines
As of April 2023, no guidelines have been published that reflect the results of this trial.
Design
- Superiority, placebo matched, randomized-controlled trial
- N=327
- 4-Factor PCC (n=165)
- Placebo (n=162)
- Setting: 12 Level-1 trauma centres in France
- Enrollment: 29 December 2017 - 4 August 2021
- Analysis: Intention-to-treat
- Primary Outcome: total blood product units (pRBC, FFP, platelet concentrate) consumed in first 24 hours of arrival in trauma bay
Population
Inclusion Criteria
- Adult (≥18 years)
- Trauma
- at risk of massive transfusion, defined as:
- ≥1 packed red blood cell concentrate (pRBC) during pre-hospital or within 1 hour of admission, and Assessment of Blood Consumption score [1] of at least 2, or
- clinical assessment of attending physician of risk of massive transfusion, defined as ≥3 pRBC within the hour of admission or ≥10 pRBC within first 24 hours
Exclusion Criteria
- traumatic cardia arrest before randomization
- expected mortality within first hour of admission
- secondary admission from another health care facility
- pre-injury treatment with anticoagulants
- pregnancy
- known hypersensitivity to study treatment
- known pre-injury terminal condition
- patient unable to make medical decisions
- inclusion in other trial in past 30 days
- patients without health insurance (according to French law)
Baseline Characteristics
4-Factor PCC Group displayed
- Demographics: 29% female, 82% blunt trauma, 18% penetrating trauma
- Physiologic parameters: heart rate 119 bpm, SBP 80 mmHg, median Assessment of Blood Consumption score 2
- median Labs: hemoglobin 105 g/L, lactate 4.5 mmol/L, platelet 214 x10^9/L, fibrinogen 1.7 g/L, revis
- 70% need for hemostasis control procedure, 42% ≥3 units pRBC within the first hour of admission, 26% ≥10 units pRBC within first 24 hours, 86% Fibrinogen treatment, 73 minutes median time form arrival to FFP transfusion
Interventions
- 4-factor PCC at a dose of 25 units of Factor IX per kg (1mL/kg), administered at 120 mL/h
- Placebo 1 mL/kg of 0.9% saline, administered at 120 mL/h
All patients received:
- pRBC:Fresh Frozen Plasma (FFP) ratio 1:1 to 2:1
- Tranexamic Acid (TXA) IV within 3 hours after injury with 1g load followed by 1g over 8 hours, aligning with the CRASH-2 trial
- Fibrinogen concentrate when fibrinogen below 1.5 g/L or viscoelastic criteria showing a functional deficiency
- Platelet transfusions to keep platelets above 50 ×10^9/L
Outcomes
Comparisons are 4F-PCC vs. Placebo.
Primary Outcomes
- Total median blood product consumption in first 24 hours
- 12 units vs. 11 units (difference 0.2, 95% CI -2.99 to 3.33) P = 0.72
Secondary Outcomes
- Median pRBC (packed red blood cell) consumption
- 6 units vs. 6 units (difference -0.3, 95% CI -1.8 to 1.3) P = 0.3
- Median FFP (Fresh Frozen Plasma) consumption
- 4 units vs. 4 units (difference 0.1, 95% CI -1.3 to 1.5) P = 0.56
- Platelet concentrate consumption
- 1 unit vs. 1 unit (difference 0, 95% CI -0.3 to 0.3) P = 0.0.83
Subgroup Analysis
- Median 24-hour total blood product consumption in patients who received a massive transfusion
- 18.5 units vs. 19 units (difference -0.6, 95% CI -6 to 4.9) P = 0.929
- Thrombotic Events in patients who received study interventions within first hour after arrival in trauma bay (per-protocol)
- 34% vs. 25% (difference -0.09, 95% CI -0.2 to 0.02) P = 0.076
Adverse Events
- Patients with ≥ thromboembolic event
- 35% vs. 24% (ARI 11, 95% CI 1 to 21) P = 0.03
- Mortality at 24 hours
- 11% vs. 13% (Difference -2, 95% CI -9 to 5) P = 0.67
- Mortality at 48 hours
- 17% vs. 21% (Difference -3, 95% CI -12 to 5) P = 0.48
Criticisms
- physician override ABC score 2 to enroll n=162 patients
- trial was a combination of 4F-PCC with FFP, not 4F-PCC alone
- without confirming coagulopathy, giving product without testing may lead to coagulation factor over exposure and increase risk of clotting
- main outcome was a surrogate (consumption of blood products) not hard outcome
- Greater time to FFP infusion (20 minutes) in placebo group, possibly creating bias in findings
- Only included adult patients
- Different commercially available PCC may have different ratios of clotting factors, thus external validity may be affected
Funding
- French Ministry of Health Programme Hospitalier de Recherche Clinique Inter-regional 2015
- French manufacturer (LFB, Les Ullis, France) distributed the product free to study centres