, 2025-04-17 13:16:00
For patients who experience excessive bleeding during cardiac surgery, four-factor prothrombin complex concentrate (4F-PCC), a blood product that contains clotting factors, is significantly more effective at stopping bleeding than frozen plasma and causes fewer adverse effects, the FARES-II trial showed.
“Patients who received 4F-PCC needed significantly fewer interventions to stop their bleeding, lost less blood, received fewer blood transfusions, and had fewer surgical complications and adverse events than those who were given frozen plasma,” said lead investigator Keyvan Karkouti, MD, from Toronto General Hospital, Toronto, Ontario, Canada.
“The results suggest that using 4F-PCC to manage excessive bleeding during cardiac surgery will have substantial benefits for patients and the healthcare system by relieving pressure on the blood supply and other hospital resources,” he explained during his presentation of the FARES-II results, which were simultaneously published online in JAMA, at the American College of Cardiology (ACC) Scientific Session 2025 in Chicago.
“We believe that these findings support the use of 4F-PCC over plasma for bleeding management in cardiac surgery,” he said.
Around 15% of patients who undergo cardiac surgery experience excessive bleeding, Karkouti reported. The standard treatment is transfusion of frozen plasma, but that must be thawed and matched to the patient’s blood type before use. Adverse effects of frozen plasma transfusions are uncommon but can include allergic reactions, infections, and an overload of plasma in the circulatory system.
4F-PCC is a blood product derived from pooled plasma that contains the vitamin K–dependent coagulation factors II, VII, IX, and X, the anticoagulant proteins C and S, and small amounts of heparin. The recognized advantages of 4F-PCC over frozen plasma are that it has undergone purification, concentration, and pathogen reduction; it contains a standard amount of coagulation factors; and it does not require thawing or blood type matching.
However, until now, the ability of 4F-PCC to stop excessive bleeding in surgical patients has not been tested, and previous studies that have looked at this have been underpowered and inconclusive.
The FARES-II Trial
The FARES-II trial, conducted at 12 hospitals in the United States and Canada, assessed 420 patients who experienced excessive bleeding during cardiac surgery that involved the use of a heart-lung bypass machine.
In the operating room, patients who developed excessive bleeding were randomly assigned to treatment with a standard dose of either 4F-PCC or frozen plasma. A second dose could be given if ordered in the 24 hours after initiation of the first dose. If treatment was needed beyond 24 hours, all patients received frozen plasma.
The study’s primary endpoint was hemostatic response — the absence of additional interventions to stop bleeding from 1 hour to 24 hours after initiation of the first treatment dose.
Hemostatic effectiveness was better in the 4F-PCC group than in the frozen plasma group (77.9% vs 60.4%) and was significant for both noninferiority and superiority.
And in the subsequent 30 days, the 4F-PCC group needed fewer transfusions, including red blood cells, platelets, and frozen plasma (mean, 6.6 vs 9.3 units) than the frozen plasma group.
The rate of severe or massive bleeding with 4F-PCC was almost half that with frozen plasma (14.1% vs 27.5%).
Serious adverse events were significantly lower in the 4F-PCC group than in the frozen plasma group (36.2% vs 47.3%), particularly acute kidney injury (10.3% vs 18.8%).
“Our hypothesis is that by stopping bleeding early, reducing transfusions, this reduces the adverse events that are associated with transfusions, which can be serious,” Karkouti said.
The difference in thromboembolic events between the 4F-PCC group and the frozen plasma group was not statistically significant (8.5% vs 7.2%). Seven patients in the 4F-PCC group and eight in the frozen plasma group died.
‘Impactful Results’
These 4F-PCC products are already used a fair amount in cardiac surgery to stem bleeding during the procedure, Toby Trujillo, PharmD, clinical pharmacy specialist in cardiovascular pharmacotherapy and anticoagulation at the University of Colorado Hospital in Aurora, Colorado, said during an ACC press conference.
Still, “this is an important study because it actually provides some literature and some support that we didn’t have previously in terms of its efficacy, compared to plasma transfusion,” and its reduction in adverse events, he added. “PCCs are expensive, and these results are going to really help support the use of PCCs as a standard of care in cardiac surgery, when needed, to help stop bleeding.”
FARES-II was “a very important, well-designed, and well-per formed trial,” said Mario Gaudino, MD, PhD, cardiothoracic surgeon at NewYork-Presbyterian Hospital and Weill Cornell Medicine Center in New York City.
However, the investigators were not blinded to the treatment administered, which could have led to some bias and may have contributed to the very large treatment effect seen in the trial, he said.
The surgeons “didn’t know which product they were going to use until they started treatment. They were then unblinded,” Karkouti pointed out, although he acknowledged this as a “limitation of this study.”
However, he noted, the results were consistent over several timepoints, and there was no evidence of bias sufficient to explain a 30% reduction in blood transfusions.
“I think it will be very important to follow these patients” who have undergone bypass surgery for a longer period, said Gaudino, “because generally graft thrombosis is silent in the first months after surgery and becomes apparent in the months after that.”
The FARES-II trial excluded high-risk patients with a recent history of thromboembolism, and the use of laboratory-driven transfusion thresholds in the study may have reduced the thromboembolic risk of administering PCC to patients without factor deficiency, according to an editorial accompanying the JAMA publication by Elliott Bennett-Guerrero, MD, from the Renaissance School of Medicine at Stony Brook University, Stony Brook, New York, and Ryan Wang, MD, from the Icahn School of Medicine at Mount Sinai, New York City.
In a previous study, 4F-PCC was given to bleeding trauma patients without first confirming factor deficiency, so the product was associated with significantly higher rates of thromboembolic events, they explained.
Editorialists Urge Caution
In the title of their editorial, Bennett-Guerrero and Wang asked: “Is it time to replace plasma with prothrombin complex concentrate in cardiac surgery?”
They then tried to answer that. “The FARES-II trial provides substantial evidence that PCC, when used with a structured algorithm and point-of-care INR [international normalized ratio] testing, is more effective than thawed frozen plasma at treating bleeding after cardiac surgery due to factor deficiency. Administration of PCC may be beneficial in coagulopathic patients who cannot receive a large volume of thawed frozen plasma or for whom rapid reversal is important.”
However, they added, “the differences in blood products administered were modest in the FARES-II trial, and no differences were observed in mortality or in ICU or hospital length-of-stay, which may argue against a major clinical benefit for most patients.”
The FARES-II study was funded by Octapharma AG of Switzerland, which manufactures the 4F-PCC used in the study, and by the Canadian Institutes of Health Research. Karkouti reported receiving personal fees from Octapharma-Werfen outside the submitted work.