KEY POINTS:
- Significant bleeding is a common complication of cardiac surgery. Frozen plasma is the standard therapy but prothrombin complex concentrate offers an alternative treatment option.
- In the Factor Replacement in Surgery study (FARES II) patients experiencing significant bleeding during cardiac surgery who received PCC were 44% less likely to require additional intervention to control bleeding, compared to frozen plasma.
The standard treatment for significant bleeding during cardiac surgery is the use of frozen plasma (FP), a blood product that contains clotting factors that promote hemostasis. Drawbacks to use of FP include the need for ABO compatibility and risk of volume overload. As an alternative, 4-Factor prothrombin complex concentrate (PCC) is derived from human plasma, does not require ABO compatibility and is concentrated in a small volume, allowing it to be administered more rapidly than FP. However, PCC lacks some of the clotting factors present FP.
The FARE II trial was an unblinded randomized noninferiority controlled clinical trial at 12 hospitals in Canada and the US involving adults (≥18 years) who had developed bleeding related to coagulation factor deficiency after termination of cardiopulmonary bypass during surgery (November 30, 2022, to May 28, 2024). Final 30-day follow-up visit was completed on June 28, 2024. This trial aimed to compare the safety and efficacy of PCC versus FP in patients undergoing cardiac surgery, with a coagulopathy defined as a normalized ratio (INR) of 1.5 or higher.
According to Dr. Keyvan Karkouti who presented the findings at the 2025 annual ACC conference, “As many as 15% of patients undergoing cardiac surgery experience excessive bleeding, often caused by depletion of clotting factors.” He pointed out that two previous trials failed to find a difference in hemostasis between PCC and FP but may have been underpowered.
Dr. Karkouti shared the results of the FARES-II trial at the 2025 annual ACC conference and the results were published in the Journal of the American Medical Association.
FARES II was a prospective, randomized, unblinded trial conducted across the United States and Canada. It enrolled patients undergoing cardiac surgery with cardiopulmonary bypass with known or suspected coagulation factor deficiency based on INR. However, patients undergoing heart transplant, mechanical support, repair of aortic aneurysm, or TEE within 3 months of surgery were excluded. A total of 420 patients were randomized in a 1:1 fashion and included in the final analysis. The median age was 67 (IQR 58-73) and 26% female, with similar baseline characteristics in the FP group.
The primary endpoint was hemostatic response, defined as no need for additional clotting agents or intervention (e.g. surgical reopening for bleeding) from 60 minutes to 24 hours after the first dose of either FP or PCC. If required, a second dose of the assigned treatment could be given within 24 hours, however, if further treatment was needed within 24 hours or beyond that timeframe, all patients received FP. Hemostasis was achieved in 77.9% of the PCC group (166 patients) compared to 60.4% (125 patients) in the FP group, reflecting a 17% reduction with PCC (CI 8.7-26.4, P<0.001).
Secondary outcomes included rates of massive bleeding based on the universal definition of perioperative bleeding (classes 3 or 4), and total blood products. Patients receiving PCC experienced significantly lower rates of massive bleeding (14.1%), compared to those in the FP group (27.5%) (RR: 0.51 (0.34-0.76) p= 0.001). Furthermore, PCC recipients required fewer transfusions of blood products including red blood cells, platelets, and frozen plasma. 45.5% of the PCC-treated patients required transfusions compared to 63.8% in the FP (RR, 0.71; 95% CI, 0.60-0.85).
Regarding safety outcomes, PCC was associated with a lower incidence of acute kidney (RR, 0.55; 95% CI, 0.34-0.89; P = .02). There was no difference in thromboembolism, ICU stay or mortality between the two groups.
In conclusion, this randomized and unblinded clinical trial demonstrated that PCC was more effective than FP in achieving hemostasis in patients with an INR ≥ 1.5 undergoing cardiac surgery with fewer adverse events. These findings suggest that PCC may serve as a superior alternative to FP for managing significant bleeding in this surgical population.