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Clinical Trial
. 2025 May 27;333(20):1781-1792.
doi: 10.1001/jama.2025.3501.

Prothrombin Complex Concentrate vs Frozen Plasma for Coagulopathic Bleeding in Cardiac Surgery: The FARES-II Multicenter Randomized Clinical Trial

Keyvan Karkouti  1   2   3 , Jeannie L Callum  4   5 , Justyna Bartoszko  1   2   3 , Kenichi A Tanaka  6 , Sigurd Knaub  7 , Sukhpal Brar  8   9 , Kamrouz Ghadimi  10 , Antoine Rochon  11 , Darren Mullane  12   13 , Etienne J Couture  14 , Yulia Lin  15   16 , Christopher Harle  17   18 , Michelle Zeller  19   20 , Diem T T Tran  21 , Cristina Solomon  7 , Vivek Rao  2   22 , Michael Law  8   9 , Amir L Butt  6 , Edward P Chen  23 , Maria Rosal Martins  11 , Tarit Saha  24 , Andrew W Shih  13   25 , Marie-Claude Vézina  14 , Fuad Moussa  22   26 , Raffael Pereira Cezar Zamper  17 , Summer Syed  27   28 , Hakan Buyukdere  29 , Sylvia Werner  30 , Deep Grewal  1   2 , Daniel Wong  31   32 , Kofi B Vandyck  6 , Robert Tanzola  24 , Bevan Hughes  12   13 , Olivier Royer  14 , Sophia Wong  3   33 , Jerrold H Levy  34 ; FARES-II Study Group
Collaborators, Affiliations
Clinical Trial

Prothrombin Complex Concentrate vs Frozen Plasma for Coagulopathic Bleeding in Cardiac Surgery: The FARES-II Multicenter Randomized Clinical Trial

Keyvan Karkouti et al. JAMA. .

Abstract

Importance: Excessive bleeding is a common and prognostically important complication of cardiac surgery. For bleeding related to coagulation factor deficiency, frozen plasma is the most used therapy. Preliminary trials indicate that 4-factor prothrombin complex concentrate (PCC) may be a suitable alternative.

Objective: To compare the efficacy and safety of PCC with frozen plasma in patients undergoing cardiac surgery with coagulopathic bleeding.

Design, setting, and participants: 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.

Intervention: A total of 265 patients were randomized to receive PCC (1500 IU ≤60 kg; 2000 IU >60 kg) and 263, frozen plasma (3 U ≤60 kg; 4 U >60 kg) in the operating room. A second dose was allowed over the next 24 hours if indicated; thereafter, only frozen plasma could be used.

Main outcomes and measures: The primary outcome was hemostatic response (effective if no hemostatic interventions occurred from 60 minutes to 24 hours after treatment initiation). The noninferiority of PCC vs frozen plasma was assessed using a 10% margin and a 1-sided α of .025, with subsequent testing for superiority if noninferiority was demonstrated. Secondary outcomes included allogeneic blood transfusions and adverse events. Patients were followed up until postoperative day 30.

Results: Of 538 enrolled patients, 420 patients (median age, 66 years [IQR, 57-73 years]; 74%, male; 10%, Asian; 1%, Black; and 65%, White) were included in the primary analysis; of those, 296 (70%) underwent complex surgeries. Compared with the 207 patients in the frozen plasma group, the 213 patients in the PCC group had higher hemostatic effectiveness (166 [77.9%] vs 125 [60.4%]; difference, 17.6%; 95% CI, 8.7%-26.4%; P < .001 for noninferiority and superiority) and had received fewer transfusions including red blood cells, platelets, and noninvestigational frozen plasma units (mean, 6.6 units; 95% CI, 5.7-7.7 vs 9.3 units; 95% CI, 8.0-10.8; difference, 2.7; 95% CI, 1.0-4.4; P = .002). Seventy-seven patients (36.2%) in the PCC group vs 98 (47.3%) in the frozen plasma group experienced serious adverse events (relative risk [RR], 0.76; 95% CI, 0.61-0.96; P = .02). Twenty-two patients (10.3%) in the PCC group and 39 (18.8%) in the frozen plasma group had acute kidney injury (RR, 0.55; 95% CI, 0.34-0.89; P = .02).

Conclusions and relevance: In this unblinded randomized clinical trial, PCC had superior hemostatic efficacy and safety advantages to frozen plasma among patients requiring coagulation factor replacement for bleeding during cardiac surgery.

Trial registration: ClinicalTrials.gov Identifier: NCT05523297.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Karkouti reported receiving personal fees from Octapharma-Werfen outside the submitted work. Dr Callum reported serving on the advisory board of Octapharma and receiving grants from the Canadian Blood Services outside the submitted work. Dr Bartoszko reported receiving grants from Canadian Blood Services, Grifols, and the Heart and Stroke Foundation outside the submitted work. Dr Tanaka reported receiving grants from Grifols, Hikari Dx, and VarmX outside the submitted work. Dr Knaub reported being an employee of Octapharma USA Inc during the conduct of the study. Dr Ghadimi reported receiving personal fees from UptoDate/Wolter Kluwer outside the submitted work. Dr Couture reported receiving personal fees from Edwards Lifesciences outside the submitted work. Dr Lin reported receiving grants from the Canadian Blood Services, consulting fees from Choosing Wisely Canada, and honoraria from Pfizer outside the submitted work. Dr Harle reported receiving grants from Octapharma outside the submitted work. Dr Zeller reported receiving grants from Pfizer Global Medical; serving on the advisory board and scientific committee of Pfizer; and receiving travel expenses from Pfizer, honoraria from the American Society of Hematology, speaker fees from McMaster University, Queens University, and Oregon Health and Science University, and grants from CIHR and Canadian Blood Services all outside the submitted work. Dr Solomon reported being an employee of Octapharma AG. Dr Rao reported serving as a consultant to Medtronic and Abbott outside the submitted work. Dr Butt reported receiving grants from Cellphire Therapeutics and HemoSonics Inc outside the submitted work. Dr Shih reported receiving personal fees from CSL Behring and Octapharma Canada; grants from CSL Behring, Octapharma Canada, and Takeda Canada outside the submitted work. Dr Werner reported being an employee of Octapharma. Dr Grewal reported receiving support from Octapharma AG outside the submitted work. Dr Levy reported serving on research steering committee for Bayer, Octapharma, Takeda, and Werfen and as an advisor to Grifols outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Enrollment, Randomization, and Treatment of Patients in the Factor Replacement in Surgery II Trial
Figure 2.
Figure 2.. Difference in Hemostatic Response Failure Rates
Ineffective hemostatic response rates in the primary analysis set, the per-protocol analysis set, and a priori defined subgroups. Difference in the proportion of patients who had ineffective hemostatic response (ie, received any hemostatic therapies or interventions from 60 minutes to 24 hours after the initiation of the first dose of investigational medicinal product [IMP]) in the prothrombin complex concentrate (PCC) group minus the frozen plasma group. The blue dotted line indicates the noninferiority margin. Tests for noninferiority were 1-sided Farrington-Manning score tests with a noninferiority margin of 10% and a significance level of 2.5%. If the 95% CI for the treatment effect (PCC minus frozen plasma) lay not only below 10% (the noninferiority margin) but also below 0, then there was evidence of superiority. Complex surgery was defined as procedures other than coronary artery bypass graft only, single valve only, or repair of atrial septal defect only.
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References

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