4F-PCC bests frozen plasma as factor replacement for cardiac surgery bleeds

For physicians requiring coagulation factor replacement to control bleeding after cardiopulmonary bypass (CPB) during surgery, four-factor prothrombin complex concentrate (4F-PCC) provides superior haemostatic efficacy over frozen plasma, along with some safety advantages, as shown in the FARES-II trial presented at ACC.25.

In the unblinded phase III trial conducted in North America, an effective haemostatic response was achieved in 77.9 percent of patients randomized to receive 4F-PCC vs 60.4 percent in those receiving frozen plasma. Thus, the rate of haemostatic response failure was lower with 4F-PCC by 17.55 percentage points, which met both the criteria for noninferiority at a margin of 10 percentage points with one-sided α of 0.025 and for superiority (relative risk [RR], 0.56, 95 percent confidence interval [CI], 0.41–0.75; p<0.001). [ACC.25, abstract 103-07]

“This shows that haemostatic failure was cut by almost half in the PCC arm,” said Professor Keyvan Karkouti, a cardiovascular anaesthesiologist at the University Health Network, Toronto General Hospital, Ontario, Canada, during a late-breaking session. “Based on this, we can conclude that PCC is noninferior and superior to plasma for haemostatic effectiveness.”

Regarding safety, the incidence of thromboembolic adverse events (AEs) within 30 days after surgery started was similar between the two factor replacements (8.5 percent vs 7.2 percent). However, 4F-PCC significantly reduced the incidence of serious AEs (36.2 percent vs 47.3 percent; RR, 0.76, 95 percent CI, 0.61–0.96; p=0.02).

“There's actually a 24-percent reduction in the incidence of serious AEs in the PCC arm,” added Karkouti. “The results are basically showing that not only was PCC more effective, but it actually reduced serious AEs.”

Benefits for patients and healthcare system

Unlike frozen plasma, which contains the full complement of procoagulant and anticoagulant factors, 4F-PCCs contain the four vitamin K-dependent coagulation factors and two vitamin K-dependent anticoagulant proteins. A small amount of heparin is also present in the preparation used in FARES-II.

Despite this distinction, the predecessor randomized pilot FARES trial (n=131) has already hinted that 4F-PCC may be superior to frozen plasma in achieving haemostasis for excessive bleeding during cardiac surgery, with blood loss and red blood cell (RBC) transfusions required being significantly reduced. [JAMA Netw Open 2021;4:e213936] FARES-II (n=528) was designed as a confirmatory trial with sufficient power to compare the treatment response between the interventions. [JAMA 2025;doi:10.1001/jama.2025.3501]

Haemostatic response in FARES-II was defined as effective if no additional haemostatic intervention was required from 60 min to 24 h after the initiation of the first dose of the study drug.

As a secondary measure of haemostatic efficacy, 4F-PCC also significantly reduced the requirement for allogeneic blood product transfusions, with treated patients requiring a least squares (LS) mean of 2.7 fewer total units of RBC, platelets, and noninvestigational frozen plasma within 24 h after CPB termination (6.6 vs 9.3 units; LS mean ratio, 0.71, 95 percent CI, 0.57–0.88; p=0.002).

“Preferentially using PCC over frozen plasma for bleeding management in cardiac surgery could have benefits for patients by reducing bleeding and exposure to allogeneic blood products and for the healthcare system by relieving pressures on the blood supply and hospital resources,” said Karkouti and colleagues in a simultaneously published manuscript.

Is it time to replace plasma with PCC in cardiac surgery?

“FARES-II provides substantial evidence that PCC, when used with a structured algorithm and point-of-care international normalized ratio testing, is more effective than frozen plasma at treating bleeding after cardiac surgery due to factor deficiency,” said Dr Ryan Wang from the Icahn School of Medicine at Mount Sinai, New York City, New York, US, in an accompanying editorial. [JAMA 2025;doi:10.1001/jama.2025.3644]

“Administration of PCC may be beneficial in coagulopathic patients who cannot receive a large volume of frozen plasma or for whom rapid reversal is important,” specified Wang. “However, the modest differences in blood products administered in FARES-II and no differences in mortality or hospital outcomes may argue against a major clinical benefit for most patients.”