Four-Factor Prothrombin Complex Concentrate is Superior to Frozen Plasma for Coagulopathic Bleeding in Cardiac Surgery—The FARES-II (LEX-211) Phase 3, Multicentre, Randomized, Clinical Trial

Abstract

Introduction

Cardiac surgery with cardiopulmonary bypass (CPB) is often complicated by coagulopathic bleeding, leading to morbidity and mortality. Although guidelines recommend using either frozen plasma (FP) or four-factor prothrombin complex (PCC) for bleeding management, the mainstay of therapy in North America is FP. This randomized controlled non-inferiority trial compared the efficacy and safety of PCC with FP in cardiac surgery.

Design and Methods

FARES-II (LEX-211; NCT05523297) included patients aged ≥18 years undergoing cardiac surgery with CPB. After protamine administration, patients who developed coagulopathic bleeding with INR ≥1.5 were randomized 1:1 to receive PCC (1500 IU if ≤60 kg; 2000 IU if >60 kg) or FP (3 U if ≤60 kg; 4 U if >60 kg). The clinical team was blinded to group allocation until treatment initiation. The primary endpoint was hemostatic response (effective if no additional hemostatic interventions were administered from 60 min to 24 h after treatment initiation). Safety endpoints included 30-day treatment-emergent serious adverse events, thromboembolic events and death.

Results

Of 538 enrolled patients at 12 sites, 420 were randomized, treated, consented and included in the analysis (PCC=213; FP=207). Baseline characteristics were comparable between groups; median (range) age was 66 years (20–88) and 74% of patients were male. Effective hemostasis was achieved in 77.9% (n=166) of PCC patients vs. 60.4% (n=125) of FP patients (difference 17.6%; 95% CI 8.7, 26.4; p< 0.0001 for non-inferiority and superiority). Overall, the mean (95% CI) number of allogeneic blood product units transfused within 24 h post-CPB, including intervention FP, was 6.6 (5.9, 7.5) in PCC patients and 13.8 (12.3, 15.5) in FP patients (ratio 0.48; 95% CI 0.41, 0.57; p< 0.0001). Treatment-emergent thromboembolic events and mortality occurred in 8.5% (n=18) and 3.3% (n=7) of PCC patients and 7.2% (n=15) and 3.9% (n=8) of FP patients, respectively. Treatment-emergent serious adverse events (36.2% vs. 47.3%; relative risk 0.76; 95% CI 0.61, 0.96; p=0.02) and acute kidney injury (10.3% vs. 18.8%; relative risk 0.55; 95% CI 0.34, 0.89; p=0.02) were significantly less frequent in the PCC group compared with the FP group.

Conclusion

PCC has superior hemostatic efficacy and may have safety advantages over FP in patients requiring coagulation factor replacement for bleeding during cardiac surgery. These findings support the use of PCC over FP for bleeding management in cardiac surgery.