Four-factor prothrombin complex concentrate (PCC) proved superior in both hemostatic response and safety to frozen plasma for coagulation factor replacement for bleeding during cardiac surgery, according to a Late-Breaking Clinical Trial presented at ACC.25 in Chicago and simultaneously published in JAMA.

In an unblinded phase 3 noninferiority trial conducted from November 2022 to May 2024 across 12 hospitals in Canada and the U.S., 420 cardiac patients (median age 66 years, 74% men, 65% White) were randomized to receive either PCC (n=213; either 1,500 IU or 2,000 IU based on weight of 60 kg) or frozen plasma (n=207; either 3U or 4U based on weight of 60 kg) after developing bleeding due to coagulations factor deficiency during surgery (70% of surgeries were categorized as complex). Baseline characteristics were similar between the two arms. Patients were followed for 30 days.

The primary endpoint was hemostatic efficiency, determined by whether an additional intervention was required from one to 24 hours after the initial dose. Additional intervention was not required in 166 patients in the PCC arm (77.9%) and 125 patients in the frozen plasma arm (60.4%), with hemostatic response failure 17.6% lower in the PCC group (relative risk [RR] ratio, 0.56; 95% confidence interval, 0.41-0.75; p<0.001).

Looking at secondary outcomes, there were also statistically significant reductions between the PCC and frozen plasma arms, including rates of surgical reopening for bleeding (5.2% vs. 7.3%), red blood cell transfusions (45.5% vs. 63.8%), severe or massive bleeding (14.1% vs. 27.5%) and allogenic blood product transfusions.

PCC was also shown to be safer, with fewer patients experiencing serious adverse events in that arm compared to the frozen plasma arm (36.2% vs. 47.3%), and fewer experiencing acute kidney injury (10.3% vs.18.8%) (p=0.02 for both comparisons). There were a comparable number of deaths in the PCC and frozen plasma arms (seven and eight) and thromboembolic adverse events (26 and 18).

"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 principal investigator, Keyvan Karkouti, MD. "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 most significant clinical benefit of PCCs is their ability to more rapidly restore factor levels because their small dosing volume allows for more rapid administration," write Ryan Wang, MD, and Elliott Bennett-Guerrero, MD, in an accompanying editorial comment. "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 also note the cost of treatment, where PCC could cost 10-times more than frozen plasma, could be a potential barrier, when, "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."