The use of amustaline/glutathione pathogen-reduced red blood cells in cardiac surgery: a commentary

Introduction

Red blood cell (RBC) concentrates are indispensable and valuable, but their use might be associated with increased morbidity and mortality. Therefore, patient blood management (PBM) programs have been endorsed by international societies (1-3) and by the World Health Organization (WHO) (4,5). PBM is a proactive, patient-centered and multidisciplinary concept to manage anemia, optimize hemostasis, minimize iatrogenic blood loss, and harness tolerance to anemia (1,3,6,7). Today, PBM is considered as standard of care in modern perioperative medicine (7). By promoting the rational use of allogeneic blood transfusion and reducing inappropriate blood product use, PBM ultimately aims to improve patient outcome, as highlighted in the latest PBM definition by the Society of Advanced Blood Management (SABM) (5,7).

In cardiac surgery, PBM programs recommend a restrictive transfusion regimen by applying a hemoglobin trigger below 75 g/L in hemodynamically stable patients (1,3,8). Nonetheless, the perioperative requirements of blood transfusion including RBC, plasma, and platelet concentrates remain high in cardiac surgery. The rate of perioperative transfusion varies from 20% to 90% of all cases, depending on the population, the complexity of the surgical procedure, and the various hemostasis and transfusion protocols implemented in institutions worldwide.

Allogeneic blood transfusion has been associated with higher mortality (9) and morbidity, including acute kidney injury (AKI), postoperative infections, ischemic events, transfusion-associated volume overload, and transfusion-related immunomodulation (TRIM) (8,10). Further, transmission of pathogens is generally rare but might occur, especially with newly emerging viruses and bacteria, which cannot be identified with routinely used pathogen screening tests. Of note, transfusion-transmitted infections can result in relevant mortality and morbidity among recipients of blood products (11).

In recent years, TRIM has gained some attention. It has been proposed as mechanism by which allogeneic blood transfusion might interact with the patient’s immune system and suppress the patient’s immune surveillance. By this mechanism, transfusion of allogeneic blood products might increase the postoperative risk of infection and cancer recurrence or progression including formation of new metastasis (12,13). Modification of blood products leading to less immunomodulation in the recipient might, thus, be beneficial and be associated with fewer adverse events after transfusion of allogeneic blood products.

The use of nucleic acid targeted pathogen reduction system utilizing amustaline and glutathione aims to inactive blood-borne pathogens and leucocytes in RBCs, thereby minimizing the persistent risk of potential transmission of infection, graft-versus-host disease, and immunomodulation (14). Their safety has been proven in animal studies (14), as well as in patients with transfusion-dependent thalassemia (15). However, data about the safety and potential benefits of amustaline/glutathione pathogen-reduced RBCs in other settings is limited. Finally, the significantly higher costs of pathogen-reduced RBCs as compared to standard RBCs must be considered.

The red cell pathogen inactivation (ReCePI) trial

This study investigated whether the RBCs with pathogen reduction by amustaline/glutathione could be safely used in cardiac surgery patients and would fulfill the regulatory requirements of the USA. Food and Drug Administration (FDA) (16). This prospective randomized double-blinded noninferiority phase 3 clinical trial included 581 patients undergoing complex cardiac and thoracic-aorta surgery at 18 U.S. cardiac surgery centers over a period of 59 months. Patients were randomized to receive conventional RBCs or pathogen-reduced RBCs when they fell below the restrictive transfusion threshold of 70–80 g/L. The primary outcome was the incidence of AKI defined as an increase in creatinine of ≥3 mg/L or 26.5 μmol/L from the preoperative baseline within 48 hours of surgery after transfusion of at least one RBC unit. Of the randomized patients, 321 (55%) were eventually transfused and therefore included in the intention-to-treat analysis. In the intervention and control arm, a mean number (interquartile range) of 2 [1–3] and 3 [2–4] RBC units were transfused (p=0.01), respectively. The nadir hemoglobin value on day 3 was comparable in both groups (about 85 g/L). A total of 29.3% and 28% of patients with transfusion of pathogen-reduced or conventional RBCs, respectively, developed AKI in the intention-to-treat analysis, showing a noninferiority of pathogen-reduced RBCs. In the per-protocol analysis, pathogen-reduced RBCs showed a slightly reduced incidence of AKI (treatment difference −2.6%, 95% confidence interval −13.0% to 7.8%). Combined adverse events including stroke, myocardial ischemia, heart rhythm abnormalities, delirium, and infections were common in both groups with no difference between them. The authors concluded that pathogen-reduced RBCs are non-inferior to conventional RBCs with respect to the occurrence of AKI after cardiac surgery. In addition, the study proved preliminary evidence of lack of adverse events associated with transfusion of pathogen-reduced RBCs during cardiac surgery.

A secondary analysis of the ReCePI trial

Welsby and colleagues recently published a post hoc analysis (17) of the ReCePI trial, focusing on hemoglobin utilization and safety outcomes. The authors found that patients treated with pathogen-reduced RBCs tended to require fewer total RBCs (3.5±2.7 units vs. 4.0±3.5 units, P=0.08) despite a 5.2% lower hemoglobin content in pathogen-reduced RBCs caused by manufacturing volume loss. Accordingly, they concluded that patients in the intervention group required less transfusion of total hemoglobin compared to the control group to maintain equivalent daily hemoglobin levels. In addition, this study suggested no clinically relevant differences in the overall incidences of adverse events and AKI. Of note, the original publication suggested a higher incidence of AKI stadium III in the pathogen-reduced RBC transfusion group (16). The present publication (17) suggested that the higher incidence of the most severe AKI stadium in patients in the pathogen-reduced RBC group might be explained by a relative under-transfusion of high-risk patients with blood products.

Discussion

The original report and the post hoc analysis of the ReCePI trial deserve some comments. First, the post hoc analysis suggested a lower transfusion requirement despite lower total hemoglobin content due to a better hemoglobin preservation. However, it remains unclear how and why pathogen-reduced RBCs should lead to such an effect. If such an effect was real, this would mean that pathogen-reduced RBCs could be an additional strategy in PBM (17). However, more data from larger studies are necessary to prove these findings.

Second, the use of pathogen-reduced RBCs might primarily be able to reduce the risk of transmission of viruses and bacteria. With modern RBCs, the risk of transmission of viruses such as human immunodeficiency virus (HIV) or hepatitis C virus (HCV) is less than one in a million (Table 1) (18,19). These data were estimated based on an HIV incidence in blood donors of 2.1 per 100,000 person-years, resulting in an estimated risk of 6.8 infections per 10 million transfused blood components (20). Similarly, the HCV incidence in blood donors was reported to be 5.1 per 100,000 person-years resulting in an estimated risk of 8.7 infections per million transfused blood components (20). This estimated risk is only 10 to 20 times lower than the risk of aviation crash or lightning strike fatalities (18,19). However, outbreaks of newer pathogens might carry a higher burden, which is difficult to estimate. Tests for new pathogens must be developed, evaluated, and implemented in clinical practice before they become efficient in promoting safer blood products. Nonetheless, the transmission of pathogens by transfusion is a rare event, but this risk might be further reduced with pathogen-reduced RBCs. Finally, RBC pathogen reduction might offer an important safety option in regions with high prevalence of different pathogens such as malaria, viruses, and bacteria, for which often only insufficient testing is available or where nucleic acid testing is not a standard of care or not affordable.

Third, the authors decided to use AKI as the primary outcome in the original trial (16). The ReCePI trial reported a 22% and 26% incidence of AKI in the pathogen-reduced and conventional RBC groups, respectively (P=0.47). These numbers are in good agreement with a recent review, which reported AKI after cardiac surgery in 20% to 30% of patients (21). AKI after cardiac surgery is a relevant outcome as it contributes to increased morbidity and mortality. Further, AKI is known to be associated with perioperative RBC transfusion in cardiac surgery (22). However, it is unclear whether there is a direct relationship between RBC transfusion and AKI or whether this is an association possibly explained by: I. more severe comorbidities of the patients leading to both higher risk of RBC transfusion and AKI; II. pre-existing renal failure leading to anemia and therefore higher perioperative RBC transfusion, and/or; III. more complications during and after surgery increasing both AKI and requirements of RBC transfusion (8,23). It seems at least questionable why the transfusion of pathogen-reduced RBCs should especially affect the incidence of AKI. Accordingly, it seems unlikely that pathogen-reduced RBCs would be inferior to conventional RBCs. Further, the choice of the noninferiority margin in the original study by Sekela and colleagues has been questioned (24). Noninferiority was claimed if the upper bound 95% confidence interval of the treatment difference was less than 50% of the observed conventional arm incidence (16). Accordingly, AKI incidences of up to 42% in the intervention arm would be non-inferior based on the reported AKI incidence of 28% in the control arm (16). It seems rather unlikely to find such differences due to transfusion of pathogen-inactivated RBCs. At least, it leaves considerable tolerance for an outcome with potentially major impact on long-term outcome (24). Finally, clinically most relevant stage III AKI was about twice as common in the intervention group as compared to the control group (16).

Fourth, it seems also unlikely that the pathogen-reduced RBCs might affect most safety endpoints included in the ReCePI trial. The safety outcomes included adverse events that are rather common in the postoperative period, such as heart rhythm abnormalities occurring in about 50% and postoperative delirium being present in about 10% of patients of the ReCePI trial (16). Such outcomes are important but unlikely to be affected by pathogen-reduced- compared to conventional RBCs. Further, it has been shown that mistakes in patient identifications and blood probes are much more common (about 1 per 800 blood group testing) (19). Such human errors might lead to relevant risks associated with transfusion of allogeneic blood products, which are higher than pathogen transmission. However, to conclusively establish the safety of these products, much larger numbers of patients with transfusion of pathogen-reduced RBCs are required.

Fifth, the transfusion of RBCs is commonly associated with preexisting anemia (23) or intraoperative coagulopathy and bleeding (8,25). Anemia might be more predictive for outcomes such as AKI rather than intraoperative RBC transfusion (23). Further, patients with intra- and postoperative coagulopathy will not only need the transfusion of RBCs but also other allogeneic blood products such as platelets. Of note, pathogen reduction is feasible for RBCs, while platelets and coagulation factor concentrates such as cryoprecipitate are not very well preserved. In the original ReCePI study, about 55% of all patients included in the intention-to-treat analysis were transfused with a median of two units of platelets (16). The potential advantage of pathogen-reduced RBCs might, therefore, be blurred by transfusion of other blood products. In agreement, a recent analysis U.S. hemovigilance study concluded that bacterial contamination of platelets was among the most frequently reported etiologies of transfusion-transmitted infections (11).

Sixth, it has been supposed that pathogen reduction might also reduce TRIM. The latter entity encompasses effects attributable to allogeneic blood transfusion by immunomodulatory or pro-inflammatory mechanisms (26). TRIM might lead to cancer recurrence, postoperative infections, reactivation of viruses such as varicella, multi-organ failure, and eventually increased mortality (26). However, evidence from RCTs has questioned whether perioperative blood transfusion leads to long-term immunosuppression and eventually increased mortality (26,27). In fact, perioperative stress reaction and major surgery itself might lead to more relevant immunomodulation and, hence, the additional immunomodulatory effect of transfusion of allogeneic blood products might be limited. The use of white blood cell reduction techniques or autologous blood transfusion including cell savers or acute normovolemic hemodilution (ANH) might further reduce TRIM.

Finally, cost effectiveness of pathogen-reduced RBCs must be evaluated. The additional acquisition costs of the pathogen-reduced RBCs are not clear but seem to be relatively higher than normal RBCs (28). Of course, transmission of pathogens to patients might have severe consequences and relevantly impact healthcare economics. However, given that they are extremely rare with modern RBCs in the Europe and the U.S., the potential cost benefit of pathogen-reduced RBCs must be re-evaluated (5).

How to deal with this dilemma?

PBM is a key intervention in modern perioperative medicine. Perioperative physicians must prevent anemic patients from proceeding to elective cardiac surgery without correct diagnosis and treatment with iron or erythropoiesis-stimulating agents (4,23). Anemia remains the most important contributing factor for the need for RBC transfusion in cardiac surgery (23,29). Timely diagnosis and correct treatment of anemia is feasible and is one of the most important goals in PBM in cardiac surgery (1,29). Further, intraoperative blood saving techniques and meticulous hemostasis by the surgeon in combination with coagulation management guided by viscoelastic coagulation testing are of utmost importance. It has been shown that PBM was most effective when a high percentage of suggested PBM interventions were implemented in daily clinical practice (30). Pathogen-reduced RBCs, as demonstrated by Welsby and colleagues, might be a further means to reduce RBC need. However, pathogen-reduced RBCs might only be the second-best solution to improve the outcome of patients undergoing cardiac surgery as compared to surgery with no allogeneic blood usage (31).

Conclusions

The ReCePi trial (16) and the post hoc analysis (17) showed that the transfusion of pathogen-reduced RBC is most probably safe in patients with need for RBC transfusion during cardiac surgery. However, definitive conclusions cannot be drawn given the low number of patients transfused with amustaline/glutathione pathogen-reduced RBCs and the above discussed limitations of the original study design. Further studies are warranted to support broader adoption of pathogen-reduced RBCs and to evaluate their efficacy on anemia correction, impact on long-term outcomes and cost effectiveness.

Acknowledgments

The author thanks Allison Dwileski, MSc, Clinic for Anesthesia, Intermediate Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, University of Basel, Basel, Switzerland, for editorial assistance.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0077/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0077/coif). The author has no conflicts of interest to declare.

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