FARES II: PCC vs FFP in Cardiac Surgery

Prothrombin Complex Concentrate vs Frozen Plasma for Coagulopathic Bleeding in Cardiac Surgery The FARES-II Multicenter Randomized Clinical Trial

Karkouthi. JAMA 2025; doi:10.1001/jama.2025.3501

Clinical Question

• In adults undergoing cardiac surgery with cardiopulmonary bypass, is the use of a 4-factor prothrombin complex concentrate (PCC), compared to fresh frozen plasma (FFP), safe and efficacious in treating active or anticipated bleeding?

Background

• Bleeding post cardiac surgery is common, often necessitating the transfusion of blood and blood products, and is often associated with increased morbidity and mortality
• Depletion of coagulation factors in the setting of bleeding, is an important contributor to this complex issue. Although FFP has been the historical mainstay for factor replacement, there is very little robust data regarding its haemostatic effectiveness, and it has recognised adverse and life-threatening complications
• A 4-factor prothrombin complex concentrate (Factors II, VII, IX, X, and some protein C and S) has many favourable features compared to FFP including standardised amounts of clotting factors, purification, concentration, pathogen reduction and no need for thawing. Recent data shows PCC may be a suitable alternative to FFP

Design

• Phase 3, multi-centre, parallel group, unblinded, randomized control trial
• Patients & outcome assessors blinded to treatment allocation
• 1:1 randomization to receive PCC or frozen plasma (standard ABO-compatible product)
• Permuted block randomisation schedule, stratified by site
• Patients randomised when order for PCC or FFP was received by blood bank
• Treatment allocation maintained in the blood bank or pharmacy in sequential opaque sealed envelopes
• To maintain allocation concealment PCC/FFP products were stored in tamper proof box and transported to operating room and only opened when final decision to administer products had been made
• Funded by Octapharma AG & the Canadian Institutes of Health Research
• Sample size: 500 participants required to yield 90% power to demonstrate noninferiority for the primary outcome of haemostatic effectiveness. This was based on assuming an effectiveness of 70% and 65% in the PCC and frozen plasma groups, respectively, with a  noninferiority margin of 0.10, and a 1-sided α of .025, and a predicted 20% dropout rate

Setting

• 12 sites in Canada and the Unites States of America
• November 30, 2022, to May 28, 2024

Population

• Inclusion: Adults undergoing cardiac surgery, with cardiopulmonary bypass (CPB), in whom the clinician has requested either FFP or PCC after the termination of CPB
• Exclusion:

• • Heart transplant
  • Insertion/ removal of ventricular assist devices
  • Repair of thoraco-abdominal aneurysm
  • Any concomitant non cardiac surgery

• 538 screened for eligibility, 528 randomized; 213 in the PCC group and 207 in the FFP group included in the primary analysis. 108 patients excluded post randomisation (Did not receive either treatment n=60; Did not meet inclusion criteria n=56)
• Baseline characteristics of PCC vs. FFP group were well matched:
  • Median age: 67 vs. 64
  • Female: 26.3% vs. 26.6%
  • Well-matched on other baseline characteristics, including patient and surgical factors:

• • • • Hb: 13.7 vs. 13.6, Plt: 201 vs. 199, INR: 1.1 vs. 1.1
      • Type of surgery: elective vs. emergency, grafts vs. valves
      • Mean CPB duration: 171 minutes vs. 176 minutes

Intervention

• A 4-factor prothrombin complex concentrate
  • Most formulations contained factors II, VII, IX, X, and small amounts of anticoagulant proteins C and S and small amounts of heparin.
  • Intervention group received intravenous PCC at a dose of 24IU/kg, to a maximum of 2 doses within 24 hours of initiation
  • 1500 IU if weight ≤60kg or 2000 IU if weight >60kg
  • Maximum permuted cumulative dose of PCC was ~50 IU/kg

Control

• FFP
  • 3 units for those weighing ≤60kg and 4 units for those > 60 kg, to a maximum of 2 doses within 24 hours of initiation
  • Non-investigational product PCC was allowed in the control group, to a maximum of 50 IU/kg, if the care team deemed it necessary after the initial 2 doses of investigational FFP

Management common to both groups

• The final decision to administer investigational product (PCC or FFP) was determined using a combination of the following criteria: at least moderate bleeding using a validated score and INR result
• For any further factors replacement, both groups received non-investigational product (FFP) at the dose specified by the caring team
• Established bleeding management protocols at individual sites were not modified
• Antifibrinolytic agents were used routinely at all sites

Outcome

• Primary outcome: haemostatic response: defined as no additional haemostatic intervention required from 60 minutes to 24 hours after initiation of the first dose of PCC/FFP

• • Haemostatic interventions included the following:
    • Surgical re-opening for bleeding
    • Administration of a second dose of PCC/FFP
    • Transfusion of any allogenic blood products (excluding red blood cells)
    • Transfusion of any coagulation factor concentrates
  • Haemostatic effectiveness achieved in 166 patients (77.9%) in the PCC group vs 125 (60.4%) in the frozen plasma group with a significant risk reduction in haemostatic failure: RR 0.56; 95%CI, 0.41-0.75; P<0.001
  • Components for response, comparing PCC vs. FFP
    • Surgical re-opening for bleeding: 5.2% vs. 7.3%
    • Second dose of PCC/FFP: 8.9% vs. 19.3%
    • PCC given outside trial protocol: 0% vs. 6.8%
    • Platelets: 15% vs. 30.4%
    • Factor VII: 0% vs. 4.4%
  • Ineffective haemostatic response analysis in all a-priori defined sub-groups and per- protocol analysis favoured PCC

• Secondary outcomes:

• • • Comparing PCC vs. FFP group, significantly lower:
      • Severe to massive bleeding (class III or IV haemorrhage),  RR 0.51 (95% CI, 0.31 to 0.76), P = 0.001
      • Cumulative requirement of allogenic blood products and non-investigational PCC/FFP administered in the PCC group
      • Chest tube drainage at both 12hr (mean Δ171ml) and 24 hrs (mean Δ232ml) post operatively

• Safety outcome:

• • • Significantly reduced serious adverse events due to treatment occurred in PCC compared with FFP group
      • 36.2% vs. 47.3% (RR 0.76, 95% CI, 0.61 – 0.96, P = 0.02)
    • Death, thromboembolic events, duration of mechanical ventilation and both ICU and hospital LOS were not significantly different between groups

Authors’ Conclusions

• PCC had superior haemostatic efficacy and may have safety advantages over frozen plasma in patients requiring coagulation factor replacement for bleeding during cardiac surgery

Strengths

• Well designed, multi-centre RCT, in an important patient group, who frequently experience bleeding and coagulopathy
• The larger dose of PCC used represents standard clinical practice and may explain why the study observed a difference between groups
• Good allocation concealment protocol and assessors were blinded
• Pragmatic design to allow randomisation and commencement of investigational product within operating theatre, continuation of local transfusion/ bleeding protocols, and use of antifibrinolytic agents
• Appropriate safety outcome of serious adverse events and thromboembolic events recorded to detect potential risks with PCC

Weaknesses

• Clinicians unblinded, but good allocation concealment and attempts to maintain clinician blinding until commencement of investigational product
• Non-standardization of transfusion protocol may have resulted in within group heterogeneity of timing, rate and sequence of blood product administration
• 20% of those randomized to treatment were excluded, and although this could have affected the outcome, most were excluded as they did not need the intervention
• The primary outcome of haemostatic efficacy is not well validated, recognised or universally accepted, so the analysis represents a composite of outcome measures that are a surrogate for important clinical outcomes
• The outcomes are not necessarily generalisable outside the cardiac surgical population, or to those who have had recent thromboembolic events, in which PCC may still represent a risk as a prothrombotic agent

The Bottom Line

• The FARES-II trial offers good evidence to support the preferential use of PCC over plasma to manage bleeding in coagulopathic cardiac surgical patients
• Of note the trial demonstrates important safety outcomes and absence of increased thrombotic events in this high-risk patient group
• Other than the favourable haemostatic effects of PCC, the pragmatic benefits of smaller infusion volumes and faster infusion times makes it an attractive agent. It will become a more common part of my practice, especially when volume state and right ventricular dysfunction are a concern
• Further cost-effectiveness assessments are needed to see whether the x10 greater cost of PCC are balanced by the potential cost savings from reduced blood product usage, and this may affect the generalisability of the findings

External Links

• Prothrombin Complex Concentrate vs Frozen Plasma for Coagulopathic Bleeding in Cardiac Surgery: The FARES-II Multicenter Randomized Clinical Trial FARES II
• Prothrombin complex concentrate vs. fresh frozen plasma in adult patients undergoing heart surgery – a pilot randomised controlled trial – PROPHESY

Metadata

Summary author: Aniket Nadkarni – @AniketNadkarni1
Summary date: 1^st May 2025
Peer-review editor: david slessor

Picture by: author/site