A groundbreaking clinical trial has demonstrated that four-factor prothrombin complex concentrate (4F-PCC) significantly outperforms frozen plasma in controlling excessive bleeding during cardiac surgery, potentially transforming standard treatment protocols for surgical hemorrhage management.
The findings from the FARES-II trial, presented at the American College of Cardiology's Annual Scientific Session (ACC.25), revealed that 4F-PCC—a concentrated blood product containing clotting proteins—reduced patients' risk of experiencing major bleeding events by nearly half compared to the standard frozen plasma therapy.
"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," explained Dr. Keyvan Karkouti, professor of anesthesiology at the University of Toronto and the study's principal investigator.
Trial Design and Patient Population
The FARES-II trial was an unblinded, randomized, noninferiority study conducted across 12 sites in the United States and Canada. Researchers enrolled 528 adult patients who had undergone cardiac surgery requiring coagulation factor replacement due to excessive bleeding after cardiopulmonary bypass. Of these, 265 patients received 4F-PCC and 263 received frozen plasma in the operating room, with the possibility of a second dose within 24 hours if clinically indicated.
The study population included in the primary analysis consisted of 420 patients with a median age of 66 years. Notably, 74% were male, 65% were white, and 296 underwent complex cardiac surgical procedures.
Superior Hemostatic Effectiveness
The primary outcome measure—hemostatic effectiveness—was defined as the absence of hemostatic interventions from 60 minutes to 24 hours after treatment initiation. Results showed decisively superior outcomes in the 4F-PCC group:
- 77.9% of patients in the 4F-PCC group achieved hemostatic effectiveness compared to 60.4% in the frozen plasma group
- The absolute difference of 17.6% (95% CI, 8.7% to 26.4%) demonstrated both noninferiority and superiority (P < .001)
- Patients receiving 4F-PCC required significantly fewer blood transfusions, including red blood cells, platelets, and non-investigational frozen plasma units (mean 6.6 units vs. 9.3 units; difference 2.7; 95% CI, 1.0 to 4.4; P=.002)
Improved Safety Profile
The safety analyses revealed substantial advantages for 4F-PCC over frozen plasma:
- Serious adverse events occurred in 36.2% of the 4F-PCC group versus 47.3% of the frozen plasma group (Relative Risk 0.76; 95% CI, 0.61 to 0.96; P=.02)
- Acute kidney injury was observed in 10.3% of patients receiving 4F-PCC compared to 18.8% in those receiving frozen plasma (RR, 0.55; 95% CI, 0.34 to 0.89; P=.02)
Clinical and Healthcare System Implications
Dr. Karkouti emphasized the broader implications of these findings: "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."
The adoption of 4F-PCC could significantly reduce reliance on frozen plasma in cardiac surgery, freeing up this limited resource for other therapeutic applications. This is particularly relevant given ongoing challenges with blood product availability in many healthcare systems.
Expert Commentary
In an accompanying editorial published in JAMA, Dr. Ryan Wang of Icahn School of Medicine at Mount Sinai and Dr. Elliott Bennett-Guerrero of Renaissance School of Medicine at Stony Brook University provided perspective on the findings:
"The FARES-II trial provides substantial evidence that PCC, when used with a structured algorithm and point-of-care INR testing, is more effective than thawed frozen plasma at treating bleeding after cardiac surgery due to factor deficiency," they wrote.
However, they noted that "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."
Future Directions
While the FARES-II trial demonstrates clear advantages of 4F-PCC over frozen plasma for managing coagulopathic bleeding in cardiac surgery, questions remain about cost-effectiveness and specific patient populations who might benefit most from this approach.
The findings suggest that 4F-PCC may be particularly beneficial for patients who cannot tolerate large volumes of frozen plasma or who require rapid reversal of coagulopathy. Further research will help refine clinical protocols and identify optimal treatment strategies for different patient subgroups.
As healthcare systems continue to face challenges with blood product availability and resource allocation, the potential for 4F-PCC to reduce reliance on frozen plasma represents a significant advancement in perioperative hemostasis management for cardiac surgery patients.
