Transfusion of Amustaline/Glutathione Pathogen-Reduced Red Blood Cells in Cardiac Surgery - A Randomized Phase III Clinical Trial

Background: Transfusion has a persistent low risk of transfusion-transmitted infection and transfusion-associated graft-versus-host disease that may be addressed using pathogen-reduction. The Red Cell Pathogen Inactivation (ReCePI) trial tested whether amustaline/glutathione pathogen-reduced Red Cells are non-inferior to conventional transfusions for support of acute surgical blood loss. Methods: A Phase III, double-blinded, non-inferiority trial randomized cardiac or thoracic-aorta surgery patients with increased risk of Red Cell transfusion to receive pathogen-reduced or conventional Red Cells during and for seven days post-surgery. The primary endpoint was the proportion of patients with acute kidney injury (AKI) defined as an increase from baseline of ≥0.3 mg/dL serum creatinine within 48 hours of surgery. Non-inferiority was claimed if the upper bound 95%C.I. of the treatment difference was less than half (50%) of the observed conventional arm incidence. Adverse events and treatment-emergent Red Cell antibodies were assessed for 28 and 75-days, respectively. Results: Five hundred eighty-one subjects were randomized and 321 (55%) transfused with study Red Cells. Transfused subjects in both arms had similar baseline demographics, medical histories, hemoglobin levels and surgical procedures. Hemoglobin Day 3 nadir levels (8.6g/dL [7.8-9.2] pathogen-reduced; 8.4g/dL [7.8-9.3] conventional arm, P=0.52) were comparable. Incidence of AKI by 48 hours was 46/157 (29.3%) in the pathogen-reduced, and 45/161 (28.0%) in the conventional arm (treatment difference 0.7%, 95%C.I. -8.9, 10.4%, non-inferiority margin 14.0%, P=0.001 for non-inferiority). AKI within 7 days by KDIGO staging criteria was not different (59/159 [37.1%] pathogen-reduced; 55/162 [34.0%] conventional arm; p=0.53) but stage III was more common in the pathogen-reduced arm (pathogen-reduced 15/159 [9.4%]; conventional arm 7/162 [4.3%], p=0.075). Five of 159 (3.1%) pathogen-reduced Red Cell recipients developed specific, low-titer antibodies without evidence of hemolysis. Conclusions: The incidence of AKI in recipients of pathogen-reduced Red Cells was non-inferior to conventional Red Cell transfusion. Treatment-emergent antibodies were uncommon and not clinically significant.