Effects of Donor-recipient Sex-matched Blood Transfusion on Patient Outcomes

Official title

Effects of Donor-recipient Sex-matched Versus Sex-mismatched Red Blood Cell Transfusion on Outcomes in Critically Ill Adult Patients

Overview

Red blood cell (RBC) transfusions are selected based upon matching donor and recipient blood group: donor and recipient sex are not considered when selecting blood for transfusion. Hence, transfused patients can currently receive sex-matched and/or unmatched RBCs when transfusions are given. Sex-matched stem cell transplants, and some solid organ transplants, have shown that sex-matching donor to recipient improves patient outcomes. Recent exploratory studies have also suggested that patient outcomes could be improved by sex-matching for RBC transfusion. There is emerging evidence of underlying biologic mechanism(s) to support these observations. This study is designed as a randomized controlled trial and will explore the impact on patients who receive RBC transfusions from donors of the same sex ("sex-matched") compared with donors of the opposite sex ("sex-mismatched"). The trial will study adult patients admitted to the Intensive Care Unit who require an RBC transfusion. Patients will be assigned (through a process called randomization) to receive sex-matched RBCs or sex-mismatched RBCs to determine if there is a difference in mortality between those receiving matched versus mismatched RBCs. The results of this trial could have direct implications on resources, blood inventory, and RBC transfusion ordering practices.

Detailed description

Background: Red blood cell (RBC) transfusions are selected based upon donor and recipient blood group compatibility without consideration of donor and recipient sex. Stem cell transplants, and some solid organ transplants, have shown that sex-matching donor to recipient improves patient outcomes. The Principal Investigator has completed a systematic review/meta-analysis and a 40,000 patient exploratory analysis; both showed a signal of benefit from sex-matched RBC transfusion. Biological findings to support the hypothesis that sex-matched RBC transfusions improve survival in recipients are also emerging.

Controversial results have emerged from observational studies and a randomized controlled trial (RCT) regarding recipient mortality from sex-mismatched RBC transfusions; hence, equipoise exists.

The Principal Investigator completed a multisite pilot RCT that showed feasibility for conducting a large-scale RCT and has helped to inform design for this study proposal. The goal of this research project is to develop a precision transfusion strategy based on sex-matching of blood donor and recipient to minimize adverse effects and improve patient outcomes post-transfusion.

Overall Research Question: In transfused adult patients admitted to the Intensive Care Unit (ICU), do donor-recipient sex-matched RBC transfusions result in improved mortality compared to sex-mismatched RBC transfusions?

Methods: This study is a superiority RCT with pragmatic features that will occur across participating sites in Canada.

Study population: adult patients (age≥18) who are hospitalized with admission to an eligible ICU and requiring RBC transfusion.

Intervention: donor-recipient sex-matched RBC transfusions. Comparison: donor-recipient sex-mismatched RBC transfusions.

Primary Outcome: 30 day mortality from time of randomization. Secondary Outcomes: time to death, 30 day in-hospital mortality, 90 day mortality, hemoglobin and creatinine increment, ICU and hospital lengths of stay, number/type of transfused products and cost effectiveness analysis. Subgroup analyses will consider recipient sex, age, transfusion exposure, blood type, admitting diagnosis, baseline hemoglobin/creatinine.

Expertise: The study team is uniquely positioned with extensive knowledge and expertise in transfusion medicine, research methodology, conduct of large pragmatic trials, and biostatistics. The study team will collaborate with Canadian Blood Services and experts in blood utilization, and operational modeling. This study is supported and endorsed by the Canadian Transfusion Trials Group.

Importance \& Outcomes: Anemia is common in critically ill patients; as many as 90% of patients will become anemic by the third day of their ICU admission. Between 20% and 40% of critically ill patients admitted to the ICU will require RBC transfusion; each patient will receive on average 2 to 5 RBC units. The Age of Blood Evaluation (ABLE) study showed a 90 day all cause mortality rate of 35-37% in the transfused ICU population studied. The pilot study reflected similar mortality rates. If providing sex-matched transfusions can decrease mortality, this could translate to high numbers of preventable deaths given that 85 million RBC units are transfused globally each year. If this study finds that donor-recipient sex-matching saves lives, this would require changes at the level of the blood supplier to identify sex on each RBC unit, and changes at the hospital level that would incorporate sex-matching into the selection of compatible blood for each patient.

Interventions

• Biological Sex-mismatched red blood cell transfusions
  Sex-mismatched red blood cell transfusions
• Biological Sex-matched red blood cell transfusions
  Sex-matched red blood cell transfusions

Primary outcome measures

• 30 day mortality [Time frame: From randomization to 30 days post-randomization.]

Secondary outcome measures (9)

• 30 day in-hospital mortality [Time frame: From randomization to 30 days post-randomization.]
• 90 day mortality [Time frame: From randomization to 90 days post-randomization.]
• Time to 30 day in-hospital mortality [Time frame: From randomization to 30 days post-randomization.]
• Hemoglobin increment [Time frame: From time of randomization until death or discharge from ICU; up to 90 days post randomization.]
• Need for renal replacement therapy [Time frame: From time of randomization during ICU admission, until death or discharge from ICU; up to 90 days post randomization.]
• ICU/hospital length of stay [Time frame: From randomization to 30 days post-randomization.]
• Number/type/volume/dose of transfused product [Time frame: From randomization to 90 days post-randomization.]
• Transfusion reactions [Time frame: From randomization to 30 days post-randomization.]
• Cost effectiveness [Time frame: From randomization to 90 days post-randomization.]

Eligibility criteria

Inclusion criteria

• Adults (age ≥18);
• Admission to a participating ICU;
• Requiring RBC transfusion.

Exclusion criteria

• Requirement for a specialized RBC product or unit not readily available in inventory (e.g., rare blood type, washed RBCs, complex RBC antibodies, etc.);
• Massively bleeding patient (i.e., ≥4 units of blood ordered at one time, or Massive Hemorrhage Protocol initiated, or an urgent blood request made);
• Sex unknown or sex other than male or female (i.e. intersex);
• Do not have a valid Ontario Health Insurance Plan (OHIP) health card number.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Health services research

Study locations

Canada · 8 centers

• Hamilton General Hospital — Hamilton
• Kingston Health Sciences Centre — Kingston
• London Health Sciences Centre — London
• Lakeridge Health Oshawa — Oshawa
• The Ottawa Hospital — Ottawa
• Sunnybrook Health Sciences Centre — Toronto
• Mount Sinai Hospital — Toronto
• Toronto General Hospital — Toronto

Publications

• Alshalani A, van Manen L, Boshuizen M, van Bruggen R, Acker JP, Juffermans NP. The Effect of Sex-Mismatched Red Blood Cell Transfusion on Endothelial Cell Activation in Critically Ill Patients. Transfus Med Hemother. 2021 Nov 24;49(2):98-105. doi: 10.1159/000520651. eCollection 2022 Apr. PMID 35611381
• Aubron C, Nichol A, Cooper DJ, Bellomo R. Age of red blood cells and transfusion in critically ill patients. Ann Intensive Care. 2013 Jan 15;3(1):2. doi: 10.1186/2110-5820-3-2. PMID 23316800
• Zeller MP, Barty R, Aandahl A, Apelseth TO, Callum J, Dunbar NM, Elahie A, Garritsen H, Hancock H, Kutner JM, Manukian B, Mizuta S, Okuda M, Pagano MB, Poglod R, Rushford K, Selleng K, Sorensen CH, Sprogoe U, Staves J, Weiland T, Wendel S, Wood EM, van de Watering L, van Wordragen-Vlaswinkel M, Ziman A, Jan Zwaginga J, Murphy MF, Heddle NM, Yazer MH; Biomedical Excellence for Safer Transfusion (BE PMID 28840943
• Zeller MP, Barty R, Dunbar NM, Elahie A, Flanagan P, Garritsen H, Kutner JM, Pagano MB, Poglod R, Rogers TS, Staves J, van Wordragen-Vlaswinkel M, Zwaginga JJ, Murphy MF, Heddle NM, Yazer MH; Biomedical Excellence for Safer Transfusion (BEST) Collaborative. An international investigation into AB plasma administration in hospitals: how many AB plasma units were infused? The HABSWIN study. Transfusi PMID 29030954
• Friede T, Kieser M. Blinded sample size re-estimation in superiority and noninferiority trials: bias versus variance in variance estimation. Pharm Stat. 2013 May-Jun;12(3):141-6. doi: 10.1002/pst.1564. Epub 2013 Mar 19. PMID 23509095
• Leach Bennett J, Blajchman MA, Delage G, Fearon M, Devine D. Proceedings of a consensus conference: Risk-Based Decision Making for Blood Safety. Transfus Med Rev. 2011 Oct;25(4):267-92. doi: 10.1016/j.tmrv.2011.05.002. Epub 2011 Jul 16. PMID 21763103
• Cooper DJ, McQuilten ZK, Nichol A, Ady B, Aubron C, Bailey M, Bellomo R, Gantner D, Irving DO, Kaukonen KM, McArthur C, Murray L, Pettila V, French C; TRANSFUSE Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Age of Red Cells for Transfusion and Outcomes in Critically Ill Adults. N Engl J Med. 2017 Nov 9;377(19):1858-1867. doi: 10.1056/NEJMoa1707572. PMID 28952891
• Hernandez G, Ospina-Tascon GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, Friedman G, Castro R, Alegria L, Teboul JL, Cecconi M, Ferri G, Jibaja M, Pairumani R, Fernandez P, Barahona D, Granda-Luna V, Cavalcanti AB, Bakker J; The ANDROMEDA SHOCK Investigators and the Latin America Intensive Care Network (LIVEN); Hernandez G, Ospina-Tascon G, Petri Damiani L, Estenssoro E, Dubin A, Hurtado J, Fr PMID 30772908

Identifiers

NCT: NCT06840756 · 5080

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗