Transfusion of Amustaline/Glutathione Pathogen-reduced Red Blood Cells in Cardiac Surgery: A Randomized Phase 3 Clinical Trial

Abstract

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 noninferior to conventional transfusions for support of acute surgical blood loss.

Methods: A phase 3, double-blinded, noninferiority 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 7 days postsurgery. The primary endpoint was the proportion of patients with acute kidney injury (AKI), which is defined as an increase from baseline of greater than or equal to 0.3 mg/dl serum creatinine within 48 h of surgery. Noninferiority was claimed if the upper bound 95% CI 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: A total of 581 subjects were randomized, and 321 (55%) were 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 (8.6 g/dl [7.8 to 9.2] in the pathogen-reduced arm; 8.4 g/dl [7.8 to 9.3] in the conventional arm; P = 0.52) were comparable. Incidence of AKI by 48 h was 46 of 157 (29.3%) in the pathogen-reduced arm and 45 of 161 (28.0%) in the conventional arm (treatment difference, 0.7%; 95% CI, -8.9 to 10.4%; noninferiority margin, 14.0%; P = 0.001 for noninferiority). AKI within 7 days by Kidney Disease Improving Global Outcomes staging criteria was not different (59 of 159 [37.1%] in the pathogen-reduced arm; 55 of 162 [34.0%] in the conventional arm; P = 0.53), but stage III was more common in the pathogen-reduced arm (pathogen-reduced arm, 15 of 159 [9.4%]; conventional arm, 7 of 162 [4.3%]; P = 0.075). Of 159 pathogen-reduced red cell recipients, 5 (3.1%) developed specific, low-titer antibodies without evidence of hemolysis.

Conclusions: The incidence of AKI in recipients of pathogen-reduced red cells was noninferior to conventional red cell transfusion. Treatment-emergent antibodies were uncommon and not clinically significant.

Trial registration: ClinicalTrials.gov NCT03459287.

Graphical abstract

Fig. 1.

Consolidated Standards of Reporting Trials (CONSORT) diagram of study flow. f/up, follow-up; PP, per protocol; RBC, red blood cell.

Fig. 2.

Daily mean (SD) patient hemoglobin concentration at baseline (day −1) and by day after completion of surgery. Number at risk represents the number of subjects with hemoglobin concentrations recorded in their medical records.

Fig. 3.

Primary efficacy endpoint of acute kidney injury. The treatment difference and 95% confidence interval (CI) were analyzed by subgroups. The vertical dashed line represents the 14.0% noninferiority margin in the modified intention to treat population analysis. The treatment difference (test − control) and two-sided 95% CI were calculated using the stratified Miettinen–Nurminen score method controlling for baseline stratification variables. ABO, blood group; AKI, acute kidney injury; Hb, hemoglobin; mITT, modified intention-to-treat; PP, per protocol; RBC, red blood cell; TRUST, Transfusion Risk Understanding Scoring Tool.