Risks of major bleeding events were reduced by nearly 50%
In patients experiencing excessive bleeding during cardiac surgery, a concentrated blood product containing proteins that help the blood clot was significantly more effective and caused fewer adverse effects than frozen plasma, the standard therapy, according to a study presented at the American College of Cardiology’s Annual Scientific Session (ACC.25). The concentrated product, known as four-factor prothrombin complex concentrate (4F-PCC), reduced patients’ risk of experiencing a major bleeding event by close to half compared with standard treatment.
“Patients randomly assigned to treatment with 4F-PCC needed significantly fewer interventions to stop their bleeding, lost less blood, received fewer blood transfusions and had fewer surgical complications than those who were randomly assigned to be treated with frozen plasma,” said Keyvan Karkouti, MD, professor of anesthesiology in the department of anesthesiology and pain medicine at the University of Toronto, and the study’s principal investigator. “The results suggest that using 4F-PCC to manage excessive bleeding during cardiac surgery potentially has substantial benefits for patients and the health care system by relieving pressure on the blood supply and other hospital resources.”
As many as 15% of patients undergoing cardiac surgery experience excessive bleeding, often caused by depletion of clotting factors, Karkouti said. A transfusion of frozen plasma is the standard treatment for this bleeding because the platelets and clotting factors in plasma work together to stop bleeding.
About 20% of the more than two million plasma transfusions that occur every year in the United States occur during cardiac surgery. Before a transfusion can occur, the frozen plasma must be thawed and matched to the patient’s blood type, Karkouti said. Adverse effects of frozen plasma transfusions are uncommon but can include severe allergic reactions, infections caused by bacteria or viruses in the plasma, swelling in the lungs and an overload of plasma in the circulatory system, he said.
4F-PCC is a blood product derived from pooled plasma that contains a specific combination of clotting factors and their inhibitors of coagulation that help to stop bleeding by supporting thrombin generation, conventionally promoted by frozen plasma. 4F-PCC contains concentrated clotting factors and does not need to be thawed or matched to a patient’s blood type. However, because 4F-PCC does not contain all the clotting factors found in frozen plasma, it wasn’t clear that it would be effective in stopping excessive bleeding in surgical patients and would not increase patients’ risk for harmful blood clots.
While two previous trials found no significant differences between the two treatment approaches, Karkouti said they may have been too small (100 or fewer patients each) to detect a difference and may have used a PCC dose that was too low to be effective.
The current trial, FARES-II, was conducted at 12 hospitals in Canada and the U.S. and included 420 patients with excessive bleeding during cardiac surgery that involved the use of a heart-lung bypass machine. The patients’ median age was 66 years, 65% were White and 74% were men, reflecting the fact that more men than women undergo cardiac surgery, Karkouti said.
In the operating room, patients who developed excessive bleeding were randomly assigned to be treated with either a standard dose of either PCC or frozen plasma. A second dose could be given if ordered within 24 hours of the initiation of the first dose. If further treatment was needed beyond 24 hours, all patients received frozen plasma.
The study’s primary endpoint was the absence of any need for additional intervention to stop bleeding in the period between one hour and 24 hours after initiation of the first treatment dose. Secondary endpoints included severe to massive bleeding, the amount of blood products transfused and serious adverse events, including blood clots or death within 30 days after surgery.
At 30 days, patients treated with 4F-PCC were 44% less likely than those treated with frozen plasma to need additional intervention to stop bleeding and 49% less likely to experience severe or massive bleeding during the one- to 24-hour period after initiation of the first treatment dose. Compared with patients treated with frozen plasma, those treated with 4F-PCC needed 29% fewer blood transfusions.
Overall, the number of adverse events was similar in the two groups; however, patients treated with PCC were 25% less likely than those treated with frozen plasma to experience a serious adverse event and 45% less likely to experience acute kidney injury. Blood clots occurred in 8.5% of PCC-treated patients and in 7.2% of those treated with frozen plasma, a non-statistically significant difference. Seven patients in the PCC group and eight in the frozen plasma group died.
These findings should prompt reconsideration of existing guidelines for the management of excessive bleeding in patients undergoing complex cardiac procedures such as heart bypass surgery, heart valve replacement surgery or surgery on the aorta, the body’s main artery, Karkouti said.
Frozen plasma is a scarce resource that, in addition to being used for treatment of excessive bleeding, is used to produce other high-demand therapies such as intravenous immunoglobulin.
“Using 4F-PCC instead of frozen plasma could significantly reduce the need for frozen plasma in cardiac surgery,” Karkouti said. This would free up the supply for other therapies.
The study has some limitations. Due to the very different nature of the two therapies for excessive bleeding, doctors administering the randomly assigned treatment in the operating room could not be blinded to which patient was receiving which treatment. However, patients did not know which treatment they had received, and study outcomes were assessed by independent assessors who were also blinded to which treatment patients had been assigned to. Another limitation, Karkouti said, is that the study’s findings may not be generalizable to patients who were excluded from enrollment because of recent treatment for certain other conditions (e.g., a blood clot) or if they were undergoing another surgery at the same time as their cardiac surgery.
The 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 (CIHR). Octapharma AG was also involved in the final design and conduct of the study, as well as in data interpretation and review of the manuscript submitted for publication.
This study was simultaneously published online in the
Journal of the American Medical Association at the time of presentation.
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Karkouti will be available to the media in an embargoed press conference on Saturday, March 29, at 7:00 a.m. CT / 12:00 UTC in Room N226.
Karkouti will present the study, “Four-Factor Prothrombin Complex Concentrate Is Superior To Frozen Plasma In Bleeding Adult Cardiac Surgery Patients With Coagulopathy—Results From A Phase 3, Randomized, Active-Control Study,” on Saturday, March 29, 2025, at 11:30 a.m. CT / 16:30 UTC in the Main Tent, North Hall B.
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