Beaver, Thomas M.

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.

AbstractBackgroundThe clinical significance of natural and treatment‐emergent antibodies specific for amustaline/glutathione pathogen‐reduced red blood cells (PRRBCs) is not known.Study Design and MethodsA Phase 3, randomized clinical trial of PRRBCs (ReCePI) compared PRRBCs with conventional RBCs in cardiac or thoracic‐aorta surgery. Subjects transfused during and for 7 days after surgery were screened for PRRBC‐specific antibodies at baseline, 28 and 75 days post‐surgery. Subjects with treatment‐emergent antibodies were assessed for evidence of hemolysis. Cryopreserved subject RBC samples were assayed by flow cytometry for circulating PRRBCs using an acridine‐specific (2S197‐2M1) monoclonal antibody, and for human IgG‐coated RBCs. RBC‐surface acridine density was quantitated using a commercial calibrated phycoerythrin (PE)‐bead panel.ResultsFive of 159 (3.1%) PRRBC and zero of 162 conventional RBC recipients developed treatment‐emergent PRRBC‐specific IgG, low titer antibodies detected 26–80 days post‐surgery after exposure to 1–3 PRRBC units, without clinical evidence of hemolysis. DAT and eluate were weak (w+) positive and PRRBC‐specific in one subject. A monocyte monolayer assay (MMA) was non‐reactive in the three subjects with an interpretable result. Flow cytometry demonstrated circulating PRRBCs in all five subjects expressing surface acridine concentrations at the limit of detection (approximately 150–301 PE molecules/RBC) compared with freshly transfused PRRBCs (approximately 7500 PE molecules/RBC). In some samples, loss of surface acridine expression could not be distinguished from clearance of the PRRBCs.DiscussionTreatment‐emergent PRRBC‐specific antibodies with the characteristics of nonclinically significant antibodies were detected in five subjects transfused with PRRBCs. Flow cytometry demonstrated persistent circulating PRRBCs with minimal surface acridine expression. (www.ClinicalTrials.gov Identifier NCT03459287).

Introduction: Red blood cell (RBC) transfusion is a lifesaving intervention with a low but persistent risk of transfusion-transmitted infection. Amustaline/glutathione RBC pathogen-reduction (PR) technology is designed to proactively inactivate a broad spectrum of viruses, bacteria, protozoa and leukocytes by chemically crosslinking nucleic acids and preventing replication and transcription. The Red Cell Pathogen Inactivation (ReCePI) trial was a Phase III, double-blinded, randomized non-inferiority study comparing PR and conventional RBCs for the support of acute anemia. Methods/Study Design: Complex cardiac or thoracic-aorta surgery patients received conventional (Control) or PR RBCs (Test) during and for 7 days after surgery. The protocol was conducted with ethics committee approval at all participating centers and written informed consent from all participants. Hemoglobin levels, blood utilization and serum creatinine were assessed as indicators of efficacy and oxygenation of tissues (Karkouti et al. Br J Anaesth. 2012; 109 Suppl 1: i29-i38). The primary endpoint was the incidence of acute kidney injury (AKI) measured as change in serum creatinine from baseline within 48 hours of surgery, a predictor of adverse postoperative outcomes including mortality by Day 30 post-surgery (Lassnig et al. Am Soc Nephrol 2004; 1597-1605). Secondary endpoints included AKI occurring up to 7 days post-surgery (KDIGO Clinical Practice Guideline for AKI, Kidney Inter, Suppl. 2012;2:1-138); death or the need for renal replacement therapy by 30 days post-surgery; PR RBC-specific antibodies; and death by day 75 post-surgery. With >292 subjects enrolled, the study had 80% power to demonstrate non-inferiority, assuming an AKI incidence of 30% with conventional RBCs and a non-inferiority margin of half the conventional RBC rate. Under these circumstances, an absolute treatment increase of 5% in the AKI rate in the PR RBC arm would fail the non-inferiority test. This work was supported by a contract with the US Biomedical Advanced Research and Development Authority (HHS010020160009c) with Cerus Corporation. Results: Five-hundred and eighty-one subjects were randomized and 321 (55%) transfused in 18 US hospitals. In the modified intent-to-treat analysis subjects receiving Test and Control RBCs had similar median [IQR] total blood loss (1500 [940-2475] mL Test, 1733 [1060-2880] mL Control, p=0.310) and comparable median hemoglobin levels at baseline and immediately post-surgery (9.8 [8.9-10.9] g/dL Test, 9.6 [8.6-10.6] g/dL Control, p=0.157) and for 7 days after surgery, The PR RBC arm was transfused with fewer RBCs, measured as total RBC Hb transfused over 7-days (169.0 [102.0-240.0] g Hb PR arm, 188.0 [126.0-295.0] g Hb, conventional RBC arm, p=0.008). The incidence of AKI was 29.3% (46/157) for Test and 28.0% (45/161) for Control. The treatment difference was 0.74% (95% CI -8.9, 10.4%, non-inferiority margin 14.0%, p=0.001 for non-inferiority). Non-inferiority was also achieved by the per protocol analysis. Average mean change in serum creatinine within 48 hours of surgery was comparable (Test 0.020, Control 0.23 mg/dL, P=0.515). Adverse events, serious adverse events and deaths on study were not different. Five of 159 (3.1%) PR RBC recipients developed low titer PR RBC-specific antibodies without clinical signs of hemolysis. Flow cytometry analysis revealed persistent circulating PR RBCs with uniform antigen loss (modulation). Low level human IgG antibody binding was demonstrated in 3 of 5 subjects. Conclusions: PR RBCs showed equivalent hemoglobin support for acute bleeding patients undergoing cardiac or thoracic-aorta surgery while using less transfused total RBC Hb over 7 days. The incidence of AKI in patients transfused with PR RBCs was non-inferior to that observed with conventional RBCs, indicative of effective tissue oxygenation. Treatment-related antibodies to PR-RBC were observed only in Test subjects, the antibodies were low titer, transient, without clinical hemolysis, and persistent circulating PR RBCs were detected with modulated low level acridine antigen expression (www.clinicaltrials.gov #NCT03459287).

Abstract Background Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leucocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. Methods ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, paralleldesign, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to Day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥0.3 mg/dL (or 26.5 µmol/L) from presurgery baseline within 48±4 hours of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen reduced RBCs through 75 days after the last study transfusion. With ≥292 evaluable, transfused patients (>146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. Discussion RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBC.

Background: Among patients (pts) with coronary artery disease (CAD) who are candidates for coronary artery bypass graft surgery (CABG), a reduced ejection fraction (EF) identifies a high-risk group. The profile of pre-operative, intra-operative and post-operative factors contributing to 30 day (d) mortality in pts with low EF undergoing CABG has not been well characterized. Methods: The STICH trial enrolled 2136 pts with CAD amenable to CABG with an LVEF < 35% who were treated with medical therapy (MED) alone, MED with CABG, or with MED plus CABG and surgical ventricular resconstruction (SVR). Multivariable logistic regression models utilizing extensive baseline, intra-operative and post-operative care variables were developed to determine factors associated with mortality at 30d in a landmark analysis among pts surviving the first 36 hours (h). Results: Among those enrolled, 1460 pts received CABG; 673 (46.1%) on pump, 160 (11.0%) off pump, 132 (9.0%) with a mitral valve procedure (MVR), 393 (26.9%) with SVR, and 102 (7.0%) received CABG with SVR and MVR. Mortality in the operating room (OR) was 0.3 %, within the first 36h was 1.0%, and at 30d was 5.1%. The rate of in-hospital acute myocardial infarction was 0.8%, stroke 1.6%, mediastinitis 1.7%, worsening renal insufficiency 8.4%, and return to OR was 6.9%. Inotropes were used in 43.6% and intra-aortic balloon pump in 18.6%. At 36h, 148 pts (10.2%) remained intubated. Among pts who survived to 36h, a robust multivariable model (Table, c-statistic 0.89) was developed to predict 30d mortality. A prolonged intubation time (>36h) was the strongest marker of 30d mortality (odds ratio 7.4, 95% CI 3.8, 14.5, p<0.0001). Conclusions: Among pts with ischemic heart failure, CABG can be performed with a low rate of complications and intra-operative mortality. Prolonged intubation time (>36h) after CABG is an integrated clincal marker that may serve to identify those pts with the least likelihood of survival to 30d.

Abstract Aims We sought to evaluate associations between baseline sphericity index (SI) and clinical outcome, and changes in SI after coronary artery bypass graft (CABG) surgery with or without surgical ventricular reconstruction (SVR) in ischaemic cardiomyopathy patients enrolled in the SVR study (Hypothesis 2) of the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Methods and results Among 1000 patients in the STICH SVR study, we evaluated 546 patients (255 randomized to CABG alone and 291 to CABG + SVR) whose baseline SI values were available. SI was not significantly different between treatment groups at baseline. After 4 months, SI had increased in the CABG + SVR group, but was unchanged in the CABG alone group (0.69 ± 0.10 to 0.77 ± 0.12 vs. 0.67 ± 0.07 to 0.66 ± 0.09, respectively; P &lt; 0.001). SI did not significantly change from 4 months to 2 years in either group. Although LV end-systolic volume and EF improved significantly more in the CABG + SVR group compared with CABG alone, the severity of mitral regurgitation significantly improved only in the CABG alone group, and the estimated LV filling pressure (E/A ratio) increased only in the CABG + SVR group. Higher baseline SI was associated with worse survival after surgery (hazard ratio 1.21, 95% confidence interval 1.02 − 1.43; P = 0.026). Survival was not significantly different by treatment strategy. Conclusion Although SVR was designed to improve LV geometry, SI worsened after SVR despite improved LVEF and smaller LV volume. Survival was significantly better in patients with lower SI regardless of treatment strategy.