OBJECTIVE:Iron deficiency anemia (IDA) is a common cause of perioperative morbidity among women and individuals with a uterus undergoing gynecologic surgery, particularly those with abnormal uterine bleeding (AUB). Although intravenous (IV) iron is a safe and effective alternative to red blood cell (RBC) transfusion, IDA often remains underrecognized and undertreated. The Impact of Iron Supplementation on Transfusion in Women Undergoing Gynecologic Procedures (STRONG) pilot study evaluated the feasibility of implementing a multidisciplinary IV iron pathway for patients with IDA awaiting gynecologic surgery. METHODS:This prospective, single-centre cohort study was conducted between June 2022 and March 2025. Eligible patients were adults with laboratory-confirmed IDA (ferritin <30 μg/L or transferrin saturation <20%; and hemoglobin <120 g/L) scheduled for elective gynecologic surgery at least 4 weeks after diagnosis who had failed or were intolerant of oral iron. A multidisciplinary pathway integrating patient blood management (PBM) principles was developed for identifying and managing preoperative IDA. Primary outcomes were recruitment feasibility and pathway implementation feasibility, assessed by protocol adherence and IV iron delivery. Exploratory clinical measures included patient demographics, laboratory values, surgical details, transfusion rates, and perioperative outcomes. RESULTS:Twenty patients consented to study participation. Protocol adherence and IV iron delivery were 100%. Median hemoglobin increased from 93 g/L to 121 g/L preoperatively. Six patients (30%) required perioperative transfusion. CONCLUSION:Implementation of a multidisciplinary IV iron pathway for the detection and management of preoperative IDA in gynecologic surgery was feasible, supporting the integration of PBM strategies into routine perioperative care.

BACKGROUND:Red blood cell (RBC) transfusions are part of essential supportive therapy in patients with acute leukemia, where patients often present with anemia and thrombocytopenia. Together these cytopenias increase bleeding risk; however, optimal hemoglobin (Hb) thresholds for RBC transfusion remain undefined, and current recommendations for restrictive strategies (<7 g/dL) are based on low-certainty, indirect evidence. STUDY DESIGN AND METHODS:A national web-based survey was distributed to 43 physicians (24 centers, Canada) to assess current RBC transfusion practice in patients with acute leukemia, perceptions of a liberal threshold (11 g/dL) in the context of a clinical trial, and feasibility considerations. The survey included categorical responses and open-text fields. RESULTS:Of 38 eligible physicians, 34 responded (89%). For stable, non-bleeding patients receiving induction chemotherapy, 27/34 (79%) used a Hb threshold of 7 g/dL, 6/34 (18%) used 8 g/dL, and 1/34 (3%) used 9 g/dL. Fourteen (14/34, 41%) respondents indicated that a Hb threshold of 11 g/dL was reasonable for the liberal arm of a clinical trial, while 20/34 (59%) did not. For such a trial, 32/34 (94%) would consider enrolling patients in the trial and 2/34 (6%) would not. DISCUSSION:A Hb threshold of 7 g/dL was most reported as standard-of-care. Most respondents supported enrolling their patients in a clinical trial comparing a liberal RBC transfusion strategy of 11 g/dL with standard-of-care. The feasibility of 11 g/dL should be tested with clear justification, appropriate study outcomes, and attention to safety risks and resource demands.

Excessive bleeding is a common and prognostically important complication of cardiac surgery. For bleeding related to coagulation factor deficiency, frozen plasma is the most used therapy. Preliminary trials indicate that 4-factor prothrombin complex concentrate (PCC) may be a suitable alternative. To compare the efficacy and safety of PCC with frozen plasma in patients undergoing cardiac surgery with coagulopathic bleeding. Unblinded randomized noninferiority controlled clinical trial at 12 hospitals in Canada and the US involving adults (≥18 years) who had developed bleeding related to coagulation factor deficiency after termination of cardiopulmonary bypass during surgery (November 30, 2022, to May 28, 2024). Final 30-day follow-up visit was completed on June 28, 2024. A total of 265 patients were randomized to receive PCC (1500 IU ≤60 kg; 2000 IU >60 kg) and 263, frozen plasma (3 U ≤60 kg; 4 U >60 kg) in the operating room. A second dose was allowed over the next 24 hours if indicated; thereafter, only frozen plasma could be used. The primary outcome was hemostatic response (effective if no hemostatic interventions occurred from 60 minutes to 24 hours after treatment initiation). The noninferiority of PCC vs frozen plasma was assessed using a 10% margin and a 1-sided α of .025, with subsequent testing for superiority if noninferiority was demonstrated. Secondary outcomes included allogeneic blood transfusions and adverse events. Patients were followed up until postoperative day 30. Of 538 enrolled patients, 420 patients (median age, 66 years [IQR, 57-73 years]; 74%, male; 10%, Asian; 1%, Black; and 65%, White) were included in the primary analysis; of those, 296 (70%) underwent complex surgeries. Compared with the 207 patients in the frozen plasma group, the 213 patients in the PCC group had higher hemostatic effectiveness (166 [77.9%] vs 125 [60.4%]; difference, 17.6%; 95% CI, 8.7%-26.4%; P < .001 for noninferiority and superiority) and had received fewer transfusions including red blood cells, platelets, and noninvestigational frozen plasma units (mean, 6.6 units; 95% CI, 5.7-7.7 vs 9.3 units; 95% CI, 8.0-10.8; difference, 2.7; 95% CI, 1.0-4.4; P = .002). Seventy-seven patients (36.2%) in the PCC group vs 98 (47.3%) in the frozen plasma group experienced serious adverse events (relative risk [RR], 0.76; 95% CI, 0.61-0.96; P = .02). Twenty-two patients (10.3%) in the PCC group and 39 (18.8%) in the frozen plasma group had acute kidney injury (RR, 0.55; 95% CI, 0.34-0.89; P = .02). In this unblinded randomized clinical trial, PCC had superior hemostatic efficacy and safety advantages to frozen plasma among patients requiring coagulation factor replacement for bleeding during cardiac surgery. ClinicalTrials.gov Identifier: NCT05523297.

Introduction Red blood cell (RBC) transfusion guidelines for patients with acute leukemia are lacking and transfusion practices are based on recommendations for other populations. Patients with acute leukemia often experience the combination of severe anemia and thrombocytopenia, placing them at heightened risk of bleeding. Given that red blood cell (RBC) rheology may enhance platelet function, patients with acute leukemia may benefit from more aggressive correction of anemia. To inform the design of a future randomized clinical trial (RCT) evaluating a liberal RBC transfusion strategy in patients with acute leukemia, we conducted a national survey in Canada to understand current RBC transfusion practices and physician perspectives on the feasibility of a clinical trial. Methods We developed a web-based survey using an electronic data capture platform (REDCap). The survey adopted Dillman's tailored design method, which entailed personalized communication, reminders, and a user-friendly interface. Experts in qualitative research, transfusion medicine, and acute leukemia care reviewed the survey questionnaire. The target sample was members of the MYELO-CAN network, a group of leukemia-treating physicians engaged in leukemia research in Canada. Participants received a personalized secure survey link via email. We collected data on current hemoglobin thresholds for RBC transfusion in clinical practice and attitudes regarding participation in, and feasibility of an RCT evaluating a liberal (Hg = 110 g/L) RBC transfusion threshold. Results Of 43 leukemia physicians from the MYELO-CAN network, 5 were excluded (4 did not treat leukemia and one could not be contacted) and 34 completed the survey (response rate = 89%). Respondents were from 7 Canadian provinces. Most (94%) practiced in academic hospitals and 2 (6%) in community hospitals. For stable, non-bleeding patients undergoing induction chemotherapy for acute leukemia, 27/34 (79%) used a RBC transfusion threshold of 70 g/L; 6/34 (18%) used 80 g/L; and 1/34 (3%) used 90 g/L in current practice. Of 34 respondents, 11 (32%) were willing to participate in a future RCT evaluating a liberal threshold (110 g/L); 21 (62%) were possibly willing; and 2 (6%) were unwilling to participate. The most frequent concern was the investigational hemoglobin threshold of 110 g/L (n=10) and several respondents favored a lower threshold (e.g., 90–100 g/L). Feasibility concerns raised by respondents were: 1) the ability to achieve and maintain the high hemoglobin level (n=7, 21%); 2) the potential impact of the trial on blood bank inventory (n= 5, 15%); 3) justification for the high hemoglobin target (n= 5, 15%); and 4) the rarity of major bleeding as the primary outcome. Three respondents (9%) raised concerns about the risk of transfusion reactions, particularly transfusion-associated circulatory overload (TACO) in older patients. Conclusion This survey identified variation and uncertainty in RBC transfusion practice among physicians treating patients with acute leukemia. There is equipoise for an RCT to examine a liberal RBC transfusion strategy on bleeding outcomes. A hemoglobin target of 100 g/L is likely reasonable for the intervention; the impact on blood bank inventory should be anticipated; and the rarity of severe bleeding will require a large sample size.

Introduction: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare, life-threatening thrombotic disorder that was reported worldwide after vaccination with adenoviral vector-based COVID-19 vaccines in 2021. Initial studies have explored the clinical and laboratory aspects of VITT; however, there is limited data on the long-term outcomes related to quality of life and mental health. In this study, we described physical, cognitive and psychiatric outcomes of patients with VITT in Canada after prolonged follow up. Methods: We identified patients with VITT in Canada based on samples tested in the McMaster Platelet Immunology Laboratory, the national reference laboratory for VITT testing. Consenting patients were contacted for telephone visits on 2 occasions approximately once per year. At the first follow up, patients answered a series of questions about their general physical and mental health. At the second follow-up, patients provided responses to 4 standardized questionnaires by telephone: the Generalized Anxiety Disorder-7 tool, the Patient Health Questionnaire, the Post Traumatic Stress Disorder (PTSD) Checklist, and the EuroQol-5 Dimensions-5 Levels tool. All patients signed informed consent and the study was approved by the Hamilton Integrated Research Ethics Board. Results: We identified 46 patients with VITT in Canada. Of those, 19 patients from 5 provinces consented to participate. Median age at VITT diagnosis was 50 years (IQR, 49 - 61 years) and 58% were female. Patients were followed for a median of 38 months (IQR, 34.1 - 38.5 months). All patients experienced one or more thrombotic event during their initial VITT presentation including pulmonary embolism (n=7), cerebral venous sinus thrombosis (n=6), portal vein thrombosis (n=4), arterial thrombosis (n=3), deep vein thrombosis (n=2), splanchnic vein thrombosis (n=1), renal vein thrombosis (n=1) and acute coronary syndrome (n=1). At the first follow-up (median 17.1 months, IQR 15.4 - 24.2 months), all 19 (100%) patients reported physical symptoms including weight loss, fatigue, visual disturbances, headaches, dizziness, breathing difficulties, body aches, exhaustion with minimal exertion and numbness. 12 (63.2%) patients reported neurocognitive or psychiatric symptoms including brain fog, memory loss, anxiety, panic attacks, PTSD and depression. At the second follow-up (median 38 months, IQR 34.1 - 38.5 months) since initial presentation), 15 (78.9%) patients reported persistent physical symptoms, 10 (52.6%) patients reported neurocognitive or psychiatric symptoms. Based on standardized questionnaires, at the end of follow up, 14 (73.7%) patients had minimal to mild anxiety; 13 (68.4%) patients had minimal to moderate depression; and 2 patients (10.5%) had evidence of PTSD. Conclusion: After 3 years of follow up, patients with VITT experienced physical, neurocognitive and psychiatric impairments. Persistent symptoms consistent with anxiety, depression and PTSD were common in this cohort.

Introduction. Immune thrombocytopenia (ITP) is an autoimmune condition that causes an increase in the risk of bleeding. Bleeding is a patient-important outcome; however, timely and complete assessments of bleeding are time- and labour-intensive. ITP bleeding measurements may be simplified with patient self-assessments. We designed this study to compare the agreement of bleeding assessments done by ITP patients and by trained research staff. Methods. All patients were identified from the McMaster ITP Registry, a longitudinal registry study of consecutive adult patients with thrombocytopenia followed at the McMaster University Medical Centre, a tertiary referral clinic. A modified version of the ITP Bleeding Scale was used for all bleeding assessments, which captured the patients' worst bleeding event at each of 9 anatomical sites - skin, mouth, epistaxis, gastrointestinal, genitourinary, gynecological, pulmonary, ocular or intracranial - graded from 0 (no bleeding) to 2 (severe bleeding) from the time of the last assessment (typically 6 months prior). Patients were provided with instructions on how to use the scale and asked to complete bleeding self-assessments using an online tool. Once the patients completed their self-assessments, a trained research staff member contacted the patient to repeat the bleeding assessment by telephone. Chance-corrected interrater agreement was determined using the kappa statistic for 2-way agreement (Grade 2 vs. Grade 0 or 1 bleeding) and for 3-way agreement (Grade 0 vs. Grade 1 vs. Grade 2). Chance-independent 2-way agreement was also measured using the phi statistic. The primary analysis was the 2-way kappa, since the detection of Grade 2 bleeds is clinically important. Results. We enrolled 108 consecutive patients with ITP from the McMaster ITP Registry who had duplicate bleeding assessments done. The median time between assessments was 3 days (IQR, 2-5). Median age of patients in the study was 53 years (IQR, 38-64), 64% were female. The worst bleeding events, as determined by research staff, were Grade 0 (n=22, 20.4%), Grade 1 (n=34, 31.5%) or Grade 2 (n=52, 48.1%). There was perfect agreement for bleeding assessments at all anatomical sites for 44 patients (40.7%). There were no intracranial hemorrhages and no Grade 2 genitourinary or pulmonary bleeds were reported. Chance-corrected 2-way agreement was excellent for gynecological (k=0.86, 95% CI 0.71-1.02), gastrointestinal (k=1), genitourinary (k=1), pulmonary (k=1) and intracranial (k=1) bleeds ( Table). Agreement was good for skin (k=0.68, 95% CI, 0.54-0.82), oral (k=0.76, 95% CI, 0.53-0.98) and ocular (k=0.66, 95% CI, 0.04-1.28) bleeds, and moderate for epistaxis (k=0.58, 95% CI, 0.21-0.95). Results of chance-independent agreement and 3-way agreement were similar. Conclusions. Bleeding self-assessments by ITP patients yielded comparable results to trained research staff. Agreement for skin and epistaxis was lower than for other sites, suggesting that additional instructions or prompts may be needed for these categories. Bleeding self-assessments could simplify data collection in research and in clinical practice.

Introduction Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. After corticosteroids with or without intravenous immune globulin (first-line treatment), second-line treatment options include rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RAs), and fostamatinib. In Canada, the choice of second-line therapy is influenced by access to medications. The goals of this narrative review are to 1) summarize the evidence for the use of TPO-RAs and other second-line therapies in ITP and 2) highlight differences in public funding criteria for TPO-RAs across provinces and territories in Canada. Methods We conducted a literature review of second-line therapies for ITP. We solicited information on public funding programs for TPO-RAs in Canada from health care providers, pharmacists, and provincial ministries of health. Results Head-to-head trials involving TPO-RAs, rituximab, splenectomy, and fostamatinib are lacking. There is substantial evidence of effect for TPO-RAs in improving platelet count levels, health-related quality of life, bleeding, and fatigue from placebo-controlled trials and observational studies; however, access to TPO-RAs through provincial funding programs in Canada is variable. Splenectomy failure is a prerequisite for the funding of TPO-RAs in Ontario, Manitoba, and Saskatchewan, but not in Alberta or Quebec. Other provinces either do not have access to public funding or funding is provided on a case-by-case basis. Discussion TPO-RAs are effective second-line therapies for the treatment of ITP; however, access is variable across Canada, which results in health disparities and poor uptake of international treatment guidelines.

BACKGROUND:The CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1) trial was a multicenter randomized controlled trial assessing convalescent plasma in hospitalized COVID-19 patients. This study evaluates the cost-effectiveness of convalescent plasma and its impact on quality-of-life to provide insight into its potential as an alternative treatment in resource-constrained settings. METHODS:Individual patient data on health outcomes and resource utilization from the CONCOR-1 trial were used to conduct the analysis from the Canadian public payer's perspective with a time horizon of 30 days post-randomization. Baseline and 30-day EQ-5D-5L were measured to calculate quality-adjusted survival. All costs are presented in 2021 Canadian dollars. The base case assessed the EQ-5D-5L scores of hospitalized inpatients reporting at both timepoints, and a utility score of 0 was assigned for patients who died within 30 days. Costs for all patients enrolled were used. The sensitivity analysis utilizes EQ-5D-5L scores from the same population but only uses costs from this population. RESULTS:940 patients were randomized: 627 received CCP and 313 received standard care. The total costs were $28,716 (standard deviation, $25,380) and $24,258 ($22,939) for the convalescent plasma and standard care arms respectively. EQ-5D-5L scores were 0.61 in both arms (p = .85) at baseline. At 30 days, EQ-5D-5L scores were 0.63 and 0.64 for patients in the convalescent plasma and standard care arms, respectively (p = .46). The incremental cost was $4458 and the incremental quality-adjusted life day was -0.078. DISCUSSION:Convalescent plasma was less effective and more costly than standard care in treating hospitalized COVID-19.

BACKGROUND:The optimal hemoglobin (Hb) threshold for red blood cell transfusions in adult patients with myelodysplastic syndromes (MDS) has not been defined. STUDY DESIGN AND METHODS:We conducted a pilot randomized multi-center study of two transfusion algorithms (liberal, to maintain Hb 110-120 g/L, transfuse 2 units if Hb < 105 g/L and 1 unit if Hb 105-110 g/L vs. restrictive, 85-105 g/L, transfuse 2 units when Hgb < 85 g/L). Primary objectives were 70% compliance in maintaining the q2 week hemoglobin within the targeted range and the achievement of a 15 g/L difference in pre-transfusion Hb. Secondary outcomes included measures of quality of life (QOL), iron studies and safety. RESULTS:Twenty-eight patients were randomized between February 2015-2020, 13 to the restrictive arm and 15 to the liberal arm in three tertiary care centers. The compliance was 66% and 45% and the mean pre-transfusion Hb thresholds were 86 (standard deviation [SD] 8) and 98 g/L (SD 10) in the restrictive and liberal arms, (mean difference 11.8 g/L, p < .0001), respectively. Patients in the liberal arm experienced a mean of 3.4 (SD 2.6) more transfusion visits and received a mean of 5.3 (SD 5.5) more units of blood during the 12-week study. Ferritin increased by 1043 (SD 1516) IU/L and 148 (SD 1319) IU/L in the liberal and restrictive arms, respectively. Selected QOL scores were superior pre-transfusion and more patients achieved clinically important improvements in the liberal arm compared with the restrictive arm for selected symptoms and function domains. CONCLUSION:The results establish that policies for transfusion support can be delivered in practice at multiple hospitals, but further research is required to understand the full clinical effects and safety of liberal transfusion policies in MDS outpatients.

Abstract Background The CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1) trial was a multicenter randomized controlled trial assessing convalescent plasma in hospitalized COVID-19 patients. Though stopped early due to the lack of treatment benefit, the cost-effectiveness of convalescent plasma provides insight into its potential as an alternative treatment option in resource constrained settings.Methods Individual patient data on health outcomes and healthcare resource utilization from the CONCOR-1 trial were used to conduct the analysis from the Canadian public payer’s perspective with a time horizon of 30 days post-randomization. Baseline and 30-day EQ-5D-5L was measured to calculate quality-adjusted survival. All costs are presented in 2021 Canadian dollars. The base case assessed the EQ-5D-5L scores of patients reporting at both timepoints, and a utility score of 0 was assigned for patients who died within 30 days. Costs for all patients enrolled in the study were used. The sensitivity analysis utilizes EQ-5D-5L scores from the same population but only uses the costs from this population.Results 940 patients were randomized: 627 received CCP and 313 received standard care. The total costs were $28,716 (standard deviation, $25,380) and $24,258 ($22,939) for the convalescent plasma and standard care arms respectively. EQ-5D-5L scores were 0.61 both arms (p = 0.85) at baseline. At 30 days, EQ-5D-5L scores were 0.63 and 0.64 for patients in the convalescent plasma and standard care arms respectively (p = 0.46). The incremental cost was $4,458 and incremental quality-adjusted life day was − 0.078.Conclusion These results indicate that convalescent plasma was less effective and more costly than standard care in treating hospitalized patients with COVID-19. The sensitivity analysis yielded similar results to the base case analysis.

Faced with an evolving pandemic and a lack of clarity of the role of convalescent plasma for patients with COVID-19, the CONCOR-1 trial was launched. In 14 months the trial was designed, launched, completed, and submitted for publication. In total, 72 sites in three countries served by four blood suppliers randomised 940 patients. Many enablers facilitated the trial including: three study principal investigators to distribute the trial workload, diverse steering committee members, an international data safety monitoring committee, multiple statisticians and methodologists, virtual meeting platforms, REDCap data platform, pausing of non-COVID-19 trials, rapid approval pathways for institutional review boards and regulators, centralised institutional review boards in many locations, restriction of use of convalescent plasma to trial participants and the incredible dedication by research personnel. In future pandemics, we need to be prepared for rapid launch of trials. The protocols, consent forms, data collection tools, and procedures need to be in draft form ready for use at all times. We were well-prepared for blood shortages but should have anticipated the need to conduct trials with convalescent plasma. In this short article, we detail our lessons learned to inform researchers faced with the next pandemic pathogen.

The associations between RBC transfusion dependence (TD) in patients with myelodysplastic syndromes (MDS) and lower survival, quality of life (QOL), iron overload and cardiac morbidity were recently summarized in a systematic review.1 However, red blood cell (RBC) TD remains the reality for many patients with MDS with a paucity of data to inform optimal transfusion policy for these patients. With only inpatient data2 or expert opinion to guide decisions,3 transfusion thresholds are heterogeneous4, 5 ranging from hemoglobin (Hb) 70 to 90 g/L and 26% of patients wishing they were transfused at higher thresholds.5 Two parallel blinded randomized feasibility trials of similar design comparing liberal with restrictive transfusion thresholds were conducted in the United Kingdom/Australia/New Zealand (REDDS)6 and Canada (RBC-Enhance) (in press, Transfusion). We combined our data sets in a secondary analysis to better evaluate feasibility, explore the impact of higher Hb transfusion thresholds on QOL, and obtain insights in improving the design of future trials. Methods have been previously published.6 Patients with MDS and MDS/MPN including chronic myelomonocytic leukemia (CMML) with a life expectancy of more than 6 months who were stably transfusion dependent (minimum of 1 unit in 8 weeks) were randomized 1:1 using computerized block randomization to a liberal (maintain Hb 110–125 g/L) or restrictive (maintain Hb 85–100 g/L) transfusion strategy with minor differences summarized in Table S1. The transfusion strategy was applied for 12 weeks. The schedule and number of transfusions were dictated by the transfusion algorithms created for the trials (Table S1). Upon enrollment, patient and disease characteristics were captured including WHO classification, risk scores, iron status, transfusions, and treatment. REDDS and RBC-ENHANCE recorded QOL using EQ-5D-3L7 and EORTC-QLQ-C308 at baseline, pre-transfusion, 5–7 days later, and monthly. The primary outcome for both studies was feasibility. For the combined analysis, feasibility outcomes were defined as (1) more than 70% compliance of the pre-transfusion Hb being below the target range of the assigned transfusion threshold; and (2) achievement of at least a 20 g/L (REDDS) or 15 g/L (RBC-ENHANCE) difference between the mean pre-transfusion Hb in the liberal and restrictive strategy groups. Secondary outcomes included enrollment rates, transfusion utilization and visits, adverse events (transfusion reactions and iron assessment), completion of QOL questionnaires, and magnitude of changes in QOL. The statistical considerations, CONSORT diagrams, definitions of clinically significant differences in QOL scores are summarized in the Supplement. Both trials received ethics committee approval at participating institutions. All patients provided informed consent and studies were registered in clinical trial registries (ISRCTN26088319 and NCT02099669). After screening 252 patients in both studies, 66 patients (n = 33 restrictive and n = 33 liberal) were randomized between January 2015 and February 2020. The enrollment rate was 0.46–1 patients/month. There were no significant differences in baseline characteristics between the two transfusion arms (Table S2). Of the 66 randomized patients, 61 received transfusions while on study. The mean (SD) pre-transfusion Hb for the restrictive and liberal arms were significantly different at 85.9 ± 9 and 98.8 ± 9 g/L, respectively, with a mean difference of 12.9 g/L (95% confidence interval [CI] 11.2–14.6; p < .0001) as was the mean Hb of all measured Hb values according to transfusion strategy (liberal 100.4 ± 4.6 vs. restrictive 89.9 ± 6.8 g/L; Figure S1a). There was a significant difference in Hb over time (p = .0025) with a net positive slope in the liberal (slope = 0.49) and a net negative slope for the restrictive arm (slope = −0.32). In the restrictive arm, the percentage of pre-transfusion Hb falling below the allocated transfusion target range (85–100 g/L) was 58%. In the liberal arm, the percentage of pre-transfusion Hb falling below the allocated transfusion target range was 81%. In a post-hoc sum of squares analysis, we found that the mean individual amplitude of variation in Hb was 42% higher in the restrictive versus the liberal arm at 74 ± 59 and 43 ± 31, respectively. In total, 232 and 471 units of RBC were transfused in the restrictive and liberal arms, respectively. Patients in the liberal arm had more CBCs (13.8 vs. 10.3, p = .001), a mean of 3.1 ± 2.9 more transfusion visits, and a mean of 6.3 ± 5.9 extra units of blood during the 12-week study. The mean number of days between transfusions was 18.9 ± 9.9 in restrictive and 13.0 ± 7.5 in liberal arms, respectively (Table 1). There was one episode of allo-immunization and one febrile non-hemolytic transfusion reaction in the liberal arm. Mean ferritin was similarly elevated at baseline but increased by 926 μg/L (95% CI 1446–2095) and 28 μg/L (95% CI −864 to 922) above baseline in the liberal and restrictive arms, respectively (Figure S2). Rates of QOL completion were high: pre- (91%) and post-transfusion (89%). There appeared to be greater stability in the EQ-5D health utility scores for patients in the liberal arm (Figure S1b). The QOL scores measured immediately pre- and 5–7 days post-transfusion were compared between both arms. The pre-transfusion EQ5D health utility scores (0.77 vs. 0.7, p = .003), visual analog scores (71.4 vs. 62.7, p = .001), EORTC QLQ-C30 emotional functioning (84.3 vs. 75.1, p = .002), fatigue (35.7 vs. 43.1, p = .01), nausea/vomiting (3.3 vs. 6.8, p = .01), and appetite loss (12.3 vs. 20.0, p = .02) scores were superior for patients in the liberal arm. Post-transfusion, EQ-5D health utility (0.77 vs. 0.71, p = .01), visual analog scores (72.2 vs. 66.6, p = .03), emotional functioning (84.7 vs. 77.8, p = .01), and constipation scores (17.2 vs. 22.4, p = .03) remained superior in the liberal arm. Pre-transfusion, a higher percentage of patients treated in the liberal arm experienced improvement in physical and social functioning, fatigue, dyspnea, and insomnia while a higher percentage of patients in the restrictive arm experienced improvement in emotional functioning, and financial problems compared with baseline (Figure S3a). Post-transfusion, some but not all of these differences were maintained (Figure S3b). Individual changes in patient mean pre-transfusion QOL scores compared with baseline are presented in waterfall plots for EQ5D health utility, EQ-5D visual analog, physical functioning, social functioning, global QOL, fatigue, and dyspnea (Figure S4a–g). While there were more patients in the liberal arms experiencing benefit (above the x-axis), there were patients who had stability or decrements in selected symptoms and function domains in both treatment arms. We present a combined analysis of two feasibility trials of similar design, providing data on 66 RBC TD patients with MDS randomized to restrictive versus liberal transfusion thresholds. We found a mean pre-transfusion Hb difference of 12.9 g/L between liberal and restrictive arms. Maintaining this mean Hgb difference for 12 weeks required the transfusion of 6.3 extra units of blood over 3.1 extra transfusion visits. This differs from the findings of a small Nordic group study in which the achievement and maintenance of a Hb >120 g/L did not confer a higher transfusion rate once the hemoglobin target was reached.9 Overall, we observed less variability in Hgb levels in the liberal arm with patients reporting clinically important improvements pre- and post-transfusion (compared with baseline) in selected symptom and functional domains. However, many patients in both transfusion arms experienced stability or declines in their scores. This underscores the complex interplay of factors that contribute to QOL in MDS patients such as frailty, comorbidity, disability, and disease-related inflammation. Further research into the impact of transfusions on functional outcomes in sufficiently large cohorts of patients is needed. We thank all participating sites and investigators in RBC-ENHANCE, REDDS, and the NHSBT CTU. We also acknowledge the agreement of the sponsor (NHSBT) to share REDDS trial data. REDDS was funded by NHSBT R&D, the Australian and New Zealand Society of Blood Transfusions (ANZSBT), and the Wellington Division of New Zealand Cancer Society. RBC-ENHANCE was funded by Canadian Cancer Society Research Institute Grant QOLL-14 and MOSPI Fund 2014. All of this research is original and has not been published elsewhere. No medical writers were used to compose this manuscript. The authors declare no conflicts of interest. The data that supports the findings of this study are available from the corresponding author upon reasonable request. Data S1: Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Eltrombopag has been shown to be noninferior to intravenous immunoglobulin (IVIG) for improving perioperative platelet counts in patients with immune thrombocytopenia (ITP) in a randomized trial; thus, cost is an important factor for treatment and policy decisions. We used patient-level data from the trial to conduct a cost-effectiveness analysis comparing perioperative eltrombopag 50 mg daily starting dose, with IVIG 1 or 2 g/kg (according to local practice) from a Canadian public health care payer's perspective over the observation period, from preoperative day 21 to postoperative day 28. Resource utilization data were obtained from the trial data (eltrombopag, n = 38; IVIG, n = 36), and unit costs were collected from the Ontario Schedule of Benefits, Ontario Drug Formulary, and secondary sources. All costs were adjusted to 2020 Canadian dollars. We calculated the incremental cost per patient for all patients randomized. Uncertainty was addressed using nonparametric bootstrapping. The use of perioperative eltrombopag for patients with ITP resulted in a cost-saving of $413 Canadian per patient. Compared with IVIG, the probability of eltrombopag being cost effective was 70% even with no willingness to pay. In a sensitivity analysis based on IVIG dose, we found that with the higher dose of IVIG (2 g/kg), eltrombopag saved $2,714 per patient, whereas with the lower dose of IVIG (1 g/kg), eltrombopag had a higher mean cost of $562 per patient. In summary, based on data from the randomized trial that demonstrated noninferiority, the use of eltrombopag for the management of ITP in the perioperative setting was less costly than IVIG.

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.

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.

Background Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection. Methods CONCOR-1 is an open-label, multicentre, randomized trial. Inclusion criteria include the following: patients > 16 years, admitted to hospital with COVID-19 infection, receiving supplemental oxygen for respiratory complications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset of respiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, and previous severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day 30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α = 0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment ( n = 600). Discussion This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres and neutralization assays for donor qualification. Trial registration Clinicaltrials.gov NCT04348656 . Registered on 16 April 2020.