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Abstract Introduction The Phase 3 FIBRES study demonstrated that fibrinogen concentrate (FC) was non-inferior to cryoprecipitate for the treatment of coagulopathic bleeding related to acquired fibrinogen deficiency (hypofibrinogenemia) in cardiac surgery patients. To further understand the role of FC, this post-hoc analysis explored the efficacy and safety of FC versus cryoprecipitate in patients from FIBRES stratified by surgical risk. Methods The FIBRES study (NCT03037424), conducted in accordance with the Declaration of Helsinki, enrolled adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) for whom fibrinogen replacement was ordered in response to clinically significant postbypass bleeding deemed related to acquired hypofibrinogenemia. Patients were randomized (1:1) to receive either 4 g FC or 10 units (U) of cryoprecipitate for each ordered dose within 24 h after CPB. Patients were stratified as high surgical risk if they were adjudicated by the principal investigator to be in a critical state before surgery, i.e., they underwent emergency surgery and had any of the following conditions: ventricular tachycardia, fibrillation, or cardiac arrest; preoperative cardiac massage; preoperative ventilation before anesthetic room; hemodynamic support requiring preoperative inotropes or ventricular assist devices; preoperative acute renal failure; or acute aortic dissection. All other patients were assigned to the category “non-high surgical risk”. The primary endpoint, allogeneic blood products (ABPs) administered during the first 24 h after termination of CPB, was analyzed in these subgroups. Safety was also examined in these subgroups through 28 days. Some patients experienced catastrophic bleeding necessitating transfusion of a large number of ABP units (U), likely reflecting multiple/severe underlying coagulopathies and potentially requiring surgical re-exploration. As it is also informative to compare the efficacy of fibrinogen replacement therapies in the most common surgical patient population, an exploratory analysis was also performed excluding the most extreme cases in the high surgical risk subgroup, i.e., patients who received ≥35 U of ABP transfusions within 24 h after CPB end. Results In total, 735 patients were included in the primary analysis (N=372 FC, N=363 cryoprecipitate). The large majority (634; 86.3%) were classified as non-high surgical risk (N=309 FC, N=325 cryoprecipitate), with 101 (13.7%) classified as high surgical risk (N=63 FC, N=38 cryoprecipitate). In the non-high-risk group (N=634), during the first 24 h after termination of CPB a mean (SD) of 13.6 (14.1) U ABPs were transfused in the FC group vs 16.2 (16.1) U in the cryoprecipitate group. FC was shown to be both non-inferior (mean ratio 0.84; 95% CI 0.00–0.87; p<0.0001) and superior (mean ratio 0.84; 95% CI 0.80–0.87; p<0.0001) to cryoprecipitate. In the high-risk group (N=101), a mean (SD) of 29.6 (21.5) U ABPs were transfused in the FC group vs 23.8 (14.4) U in the cryoprecipitate group (mean ratio 1.24; 95% CI 0.00–1.34; p=0.7928 for non-inferiority). When patients who received ≥35 U of ABPs within 24 h post-CPB were excluded, a mean (SD) of 18.3 (9.2) U ABPs were transfused in the FC group (N=42) vs 19.5 (7.4) U in the cryoprecipitate group (N=33), demonstrating non-inferiority of FC to cryoprecipitate (mean ratio 0.94; 95% CI 0.00–1.04; p<0.0001) but not superiority (mean ratio 0.94; 95% CI 0.84–1.04; p=0.2212). In the non-high-risk group, a total of 455 treatment-emergent adverse events (TEAEs) occurred in 196 (63.4%) patients in the FC group vs 577 TEAEs in 230 (70.8%) patients in the cryoprecipitate group. In the high-risk group, a total of 168 TEAEs occurred in 52 (82.5%) patients in the FC group vs 96 TEAEs in 34 (89.5%) patients in the cryoprecipitate group. Conclusion In this post-hoc analysis of the Phase 3 randomized FIBRES study, FC was superior to cryoprecipitate for the number of blood components transfused within 24 h after CPB in the patients who were not high surgical risk, representing 86% of the bleeding cardiac surgery population. Moreover, FC was non-inferior to cryoprecipitate in high-risk surgical patients when excluding the most extreme atypical clinical cases characterized by catastrophic bleeding and massive transfusion. These findings reinforce the main outcomes from the FIBRES study and support the use of FC for management of bleeding in cardiac surgical patients with acquired hypofibrinogenemia.