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A data-informed system to manage scarce blood product allocation in a randomized controlled trial of convalescent plasma
Li N, Zeller MP, Shih AW, Heddle NM, St John M, Bégin P, Callum J, Arnold DM, Akbari-Moghaddam M, Down DG, et al
Transfusion. 2022
Abstract
BACKGROUND Equitable allocation of scarce blood products needed for a randomized controlled trial (RCT) is a complex decision-making process within the blood supply chain. Strategies to improve resource allocation in this setting are lacking. METHODS We designed a custom-made, computerized system to manage the inventory and allocation of COVID-19 convalescent plasma (CCP) in a multi-site RCT, CONCOR-1. A hub-and-spoke distribution model enabled real-time inventory monitoring and assignment for randomization. A live CCP inventory system using REDCap was programmed for spoke sites to reserve, assign, and order CCP from hospital hubs. A data-driven mixed-integer programming model with supply and demand forecasting was developed to guide the equitable allocation of CCP at hubs across Canada (excluding Québec). RESULTS 18/38 hospital study sites were hubs with a median of 2 spoke sites per hub. A total of 394.5 500-ml doses of CCP were distributed; 349.5 (88.6%) doses were transfused; 9.5 (2.4%) were wasted due to mechanical damage sustained to the blood bags; 35.5 (9.0%) were unused at the end of the trial. Due to supply shortages, 53/394.5 (13.4%) doses were imported from Héma-Québec to Canadian Blood Services (CBS), and 125 (31.7%) were transferred between CBS regional distribution centers to meet demand. 137/349.5 (39.2%) and 212.5 (60.8%) doses were transfused at hubs and spoke sites, respectively. The mean percentages of total unmet demand were similar across the hubs, indicating equitable allocation, using our model. CONCLUSION Computerized tools can provide efficient and immediate solutions for equitable allocation decisions of scarce blood products in RCTs.
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Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial
Bégin P, Callum J, Jamula E, Cook R, Heddle NM, Tinmouth A, Zeller MP, Beaudoin-Bussières G, Amorim L, Bazin R, et al
Nature Medicine. 2021
Abstract
The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.
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Prolonged Blood Storage and Risk of Posttransfusion Acute Kidney Injury
Adegboye J, Sapatnekar S, Mascha EJ, Shah K, Lioudis M, Essber H, Cohen B, Rivas E, Heddle NM, Eikelboom JW, et al
Anesthesiology. 2021
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Editor's Choice
Abstract
BACKGROUND Erythrocyte transfusions are independently associated with acute kidney injury. Kidney injury may be consequent to the progressive hematologic changes that develop during storage. This study therefore tested the hypothesis that prolonged erythrocyte storage increases posttransfusion acute kidney injury. METHODS The Informing Fresh versus Old Red Cell Management (INFORM) trial randomized 31,497 patients to receive either the freshest or oldest available matching erythrocyte units and showed comparable mortality with both. This a priori substudy compared the incidence of posttransfusion acute kidney injury in the randomized groups. Acute kidney injury was defined by the creatinine component of the Kidney Disease: Improving Global Outcomes criteria. RESULTS The 14,461 patients included in this substudy received 40,077 erythrocyte units. For patients who received more than one unit, the mean age of the blood units was used as the exposure. The median of the mean age of blood units transfused per patient was 11 days [interquartile range, 8, 15] in the freshest available blood group and 23 days [interquartile range, 17, 30] in the oldest available blood group. In the primary analysis, posttransfusion acute kidney injury was observed in 688 of 4,777 (14.4%) patients given the freshest available blood and 1,487 of 9,684 (15.4%) patients given the oldest available blood, with an estimated relative risk (95% CI) of 0.94 (0.86 to 1.02; P = 0.132). The secondary analysis treated blood age as a continuous variable (defined as duration of storage in days), with an estimated relative risk (95% CI) of 1.00 (0.96 to 1.04; P = 0.978) for a 10-day increase in the mean age of erythrocyte units. CONCLUSIONS In a population of patients without severely impaired baseline renal function receiving fewer than 10 erythrocyte units, duration of blood storage had no effect on the incidence of posttransfusion acute kidney injury.
PICO Summary
Population
Hospitalized patients enrolled across four countries in the Informing Fresh versus Old Red Cell Management (INFORM) trial (n= 14,461).
Intervention
Transfusion with freshest available erythrocyte units (n= 4,777).
Comparison
Transfusion with oldest available erythrocyte units (n= 9,684).
Outcome
The median of the mean age of blood units transfused per patient was 11 days in the freshest available blood group and 23 days in the oldest available blood group. In the primary analysis, post-transfusion acute kidney injury was observed in 688 of 4,777 (14.4%) patients given the freshest available blood and 1,487 of 9,684 (15.4%) patients given the oldest available blood, with an estimated relative risk of 0.94.
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Red blood cell storage and in-hospital mortality: a secondary analysis of the INFORM randomised controlled trial
Cook RJ, Heddle NM, Lee KA, Arnold DM, Crowther MA, Devereaux PJ, Ellis M, Figueroa P, Kurz A, Roxby D, et al
The Lancet. Haematology. 2017;4((11):):e544-e552. e544
Abstract
BACKGROUND No randomised trials have addressed whether exposure to red blood cells (RBCs) stored longer than 35 days is associated with harm in patients. We aimed to assess the risk of in-hospital mortality associated with transfusing blood stored longer than 35 days. METHODS We did a secondary analysis of the INforming Fresh versus Old Red cell Management (INFORM) trial, a pragmatic, multicentre, randomised controlled trial of patients (≥18 years) admitted to one of six hospitals in Australia, Canada, Israel, and the USA and expected to need RBC transfusions. Patients were randomly assigned (2:1) to receive blood in inventory stored for the longest time (standard care) or the shortest time, using a random allocation schedule and stratified by centre and patient ABO blood group. The primary objective of the INFORM trial was to assess all-cause in-hospital mortality in patients with blood group A and O who were transfused. For our exploratory secondary analysis, we classified individuals into one of three mutually exclusive exposure categories on the basis of the maximum storage duration of any blood unit patients had received on each day in hospital: exclusively exposed to RBCs stored no longer than 7 days, exposed to at least one unit of RBCs stored 8-35 days, and exposed to least one unit of RBCs stored longer than 35 days. Our primary objective was to determine the effect on risk of in-hospital death of time-dependent exposure to RBCs stored longer than 35 days compared with exclusive exposure to RBCs stored no longer than 7 days, both in patients of blood groups A and O and all patients. The INFORM trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN08118744. FINDINGS Between April 2, 2012, and Oct 21, 2015, 31 497 patients were recruited, and 24 736 patients were eligible for inclusion in this analysis. We excluded nine patients for whom information about the storage duration of transfused blood was missing and one patient whose sex was unknown. 4480 (18%) patients were exposed to RBCs with longest storage, 1392 (6%) patients were exposed exclusively to RBCs with shortest storage, and 18 854 (76%) patients were exposed to RBCs stored 8-35 days. Median follow-up was 11 days (IQR 6-20). Exposure to RBCs stored longer than 35 days was not associated with increased risk of in-hospital death compared with exclusive exposure to the freshest RBC units after adjusting for demographic variables, diagnosis category, and blood product use history (in patients with blood group A or O: hazard ratio 0.94, 95% CI 0.73-1.20, p=0.60; in all patients: 0.91, 0.72-1.14, p=0.40). The risk of in-hospital death also did not differ between patients exposed to blood stored 8-35 days and patients exposed to blood stored 7 days or less (in patients with blood group A or O: 0.92, 0.74-1.15, p=0.48; in all patients: 0.90, 0.73-1.10, p=0.29). INTERPRETATION These data provide evidence that transfusion of blood stored for longer than 35 days has no effect on in-hospital mortality, which suggests that current approaches to blood storage and inventory management are reasonable. FUNDING Canadian Institutes for Health Research, Canadian Blood Services, and Health Canada.
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Analysis of Red Blood Cell Storage Duration and in-Hospital Mortality Using Time Dependent Exposure: Is the Oldest Blood Bad?
Heddle NM, Cook RJ, Lee K-A, Arnold DM, Crowther M, Devereaux P, Ellis M, Figueroa PI, Kurz A, Roxby D, et al
Transfusion. 2017;57((53)):33A.. c26-a02c
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Informing Fresh versus Old Red Cell Management (INFORM) trial: a large international pragmatic randomized trial
Heddle NM, Cook RJ, Barty R Liu Y, Arnold DM, Crowther MA, Devereaux PJ, Ellis M, Figueroa P, Hirsh J, Kurz A, et al
Transfusion. 2016;56((S4)):5A.. p6-030a.
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Effect of short-term vs. long-term blood storage on mortality after transfusion
Heddle NM, Cook RJ, Arnold DM, Liu Y, Barty R, Crowther MA, Devereaux PJ, Hirsh J, Warkentin TE, Webert KE, et al
The New England Journal of Medicine. 2016;375((20):):1937-1945
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Editor's Choice
Abstract
Background Randomized, controlled trials have suggested that the transfusion of blood after prolonged storage does not increase the risk of adverse outcomes among patients, although most of these trials were restricted to high-risk populations and were not powered to detect small but clinically important differences in mortality. We sought to find out whether the duration of blood storage would have an effect on mortality after transfusion in a general population of hospitalized patients. Methods In this pragmatic, randomized, controlled trial conducted at six hospitals in four countries, we randomly assigned patients who required a red-cell transfusion to receive blood that had been stored for the shortest duration (short-term storage group) or the longest duration (long-term storage group) in a 1:2 ratio. Only patients with type A or O blood were included in the primary analysis, since pilot data suggested that our goal of achieving a difference in the mean duration of blood storage of at least 10 days would not be possible with other blood types. Written informed consent was waived because all the patients received treatment consistent with the current standard of care. The primary outcome was in-hospital mortality, which was estimated by means of a logistic-regression model after adjustment for study center and patient blood type. Results From April 2012 through October 2015, a total of 31,497 patients underwent randomization. Of these patients, 6761 who did not meet all the enrollment criteria were excluded after randomization. The primary analysis included 20,858 patients with type A or O blood. Of these patients, 6936 were assigned to the short-term storage group and 13,922 to the long-term storage group. The mean storage duration was 13.0 days in the short-term storage group and 23.6 days in the long-term storage group. There were 634 deaths (9.1%) in the short-term storage group and 1213 (8.7%) in the long-term storage group (odds ratio, 1.05; 95% confidence interval [CI], 0.95 to 1.16; P=0.34). When the analysis was expanded to include the 24,736 patients with any blood type, the results were similar, with rates of death of 9.1% and 8.8%, respectively (odds ratio, 1.04; 95% CI, 0.95 to 1.14; P=0.38). Additional results were consistent in three prespecified high-risk subgroups (patients undergoing cardiovascular surgery, those admitted to intensive care, and those with cancer). Conclusions Among patients in a general hospital population, there was no significant difference in the rate of death among those who underwent transfusion with the freshest available blood and those who underwent transfusion according to the standard practice of transfusing the oldest available blood. (Funded by the Canadian Institutes of Health Research and others; INFORM Current Controlled Trials number, ISRCTN08118744 .).
PICO Summary
Population
Adults with type A or type O blood requiring blood transfusion from six centres in Australia, Canada, Israel and USA (n= 20,858).
Intervention
Blood stored for the shortest duration (short-term storage group, n= 6,936).
Comparison
Blood stored for the longest duration (long-term storage group, n= 13,922).
Outcome
The mean storage duration was 13.0 days in the short-term storage group and 23.6 days in the long-term storage group. There were 634 deaths (9.1%) in the short-term storage group and 1213 (8.7%) in the long-term storage group (odds ratio, 1.05; 95% confidence interval [CI], 0.95 to 1.16). When the analysis was expanded to include the 24,736 patients with any blood type, the results were similar, with rates of death of 9.1% and 8.8%, respectively (odds ratio, 1.04; 95% CI, 0.95 to 1.14). Additional results were consistent in three prespecified high-risk subgroups (patients undergoing cardiovascular surgery, those admitted to intensive care, and those with cancer).
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Clinical efficacy and safety of platelets in additive solution treated with two commercial pathogen reduction technologies
Rebulla P, Vaglio S, Aprili G, Beccaria F, Coluzzi S, Girelli G, Graf M, Isernia P, Marconi M, Olivero B, et al
Transfusion. 2015;55((Suppl. 3)):3A.. Abstract no. P2-030A.
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The effect of blood storage duration on in-hospital mortality: a randomized controlled pilot feasibility trial
Heddle NM, Cook RJ, Arnold DM, Crowther MA, Warkentin TE, Webert KE, Hirsh J, Barty RL, Liu Y, Lester C, et al
Transfusion. 2012;52((6):):1203-12.
Abstract
BACKGROUND Whether the duration of storage of blood has an impact on patient outcomes remains controversial. The objective was to determine feasibility of a comparative effectiveness trial to evaluate duration of storage of blood before transfusion on in-hospital mortality. STUDY DESIGN AND METHODS A single-center randomized controlled trial was performed at an acute care hospital in Canada between June and December 2010, involving consecutive hospitalized patients needing blood transfusion. Patients (n=910) were randomly assigned in a 1:2 ratio to receive freshest available versus standard-issue (oldest available) blood. Four feasibility criteria were measured: proportion of eligible patients randomized, contrast in age of blood between treatment groups, real-time data acquisition, and trial impact on blood outdating. In-hospital mortality was also reported. RESULTS A total of 1075 of 1129 patients (95.2%) were eligible and 910 of 1075 (84.7%) were randomized: 309 received freshest available blood (1157 units), and 601 received standard-age blood (2369 units). Contrast in mean age of the oldest blood transfused between groups was 14.6 days: 12.0 (standard deviation [SD], 6.8) days in the fresh arm and 26.6 (SD, 7.8) days in the standard arm. Weekly recruitment and event reporting were achieved for all patients. The blood outdate rate was 0.10%. In-hospital mortality was 10.5%: 35 deaths (11.3%) in the fresh arm and 61 deaths (10.1%) in the standard arm (odds ratio, 1.13; 95% confidence interval [CI], 0.73, 1.76). CONCLUSION It is feasible to conduct a large comparative effectiveness trial comparing the effect of freshest available versus standard-issue blood on in-hospital mortality. The wide CI around the estimate for in-hospital mortality supports the need for a large trial. 2012 American Association of Blood Banks.
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Can we do a 25,000 patient pragmatic study to address the age of blood and mortality controversy? A pilot to determine feasibility
Heddle NM, Eikelboom JW, Cook RJ, Liu Y, Barty RL, Warkentin TE, Arnold DM, Webert KE, Crowther MA
Transfusion. 2011;51(S3):193A.