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Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria
Wong RSM, Navarro-Cabrera JR, Comia NS, Goh YT, Idrobo H, Kongkabpan D, Gómez-Almaguer D, Al-Adhami M, Ajayi T, Alvarenga P, et al
Blood advances. 2023
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Editor's Choice
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for adults with PNH (United States), adults with PNH with inadequate response to or intolerance of a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for 3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate efficacy and safety of pegcetacoplan versus control (supportive care only; eg, blood transfusions, corticosteroids, and supplements) in complement inhibitor-naive patients with PNH. Eligible adults receiving supportive care only for PNH were randomized and stratified based on their number of transfusions (<4, ≥4) 12 months before screening. Patients received pegcetacoplan 1080 mg subcutaneously twice weekly or continued supportive care (control) for 26 weeks. Coprimary endpoints were hemoglobin stabilization (avoidance of >1-g/dL decrease in hemoglobin levels without transfusions) from baseline through week 26 and lactate dehydrogenase (LDH) change at week 26. Overall, 53 patients received pegcetacoplan (n=35) or control (n=18). Pegcetacoplan was superior to control for hemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1% [95% CI: 57.2, 89.0]; P <0.0001) and change from baseline in LDH (least-square mean change: pegcetacoplan, -1870.5 U/L; control -400.1 U/L; difference, -1470.4 U/L [95% CI: -2113.4, -827.3]; P <0.0001). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals observed. Pegcetacoplan rapidly and significantly stabilized hemoglobin and reduced LDH in complement inhibitor-naive patients and had a favorable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT04085601.
PICO Summary
Population
Adult patients with paroxysmal nocturnal haemoglobinuria enrolled in the PRINCE trial conducted in 22 centres in Hong Kong, Malaysia, Philippines, Singapore, Thailand, Colombia, Mexico and Peru (n= 53).
Intervention
Subcutaneous infusions of pegcetacoplan (pegcetacoplan group, n= 35).
Comparison
Supportive care including transfusions, anticoagulants, corticosteroids, and supplements (control group, n= 18).
Outcome
Pegcetacoplan was superior to control for haemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1%, 95% CI [57.2, 89.0]) and change from baseline in lactate dehydrogenase, (least-square mean change: pegcetacoplan, -1870.5 U/L; control -400.1 U/L; difference, -1470.4 U/L, 95% CI [-2113.4, -827.3]). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals were observed.
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Effect of red blood cell storage time in pediatric cardiac surgery patients: A subgroup analysis of a randomized controlled trial
Martin, S. M., Tucci, M., Spinella, P. C., Ducruet, T., Fergusson, D. A., Freed, D. H., Lacroix, J., Poirier, N., Sivarajan, V. B., Steiner, M. E., et al
JTCVS open. 2023;15:454-467
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Editor's Choice
Abstract
OBJECTIVE This study aimed to determine whether or not transfusion of fresh red blood cells (RBCs) reduced the incidence of new or progressive multiple organ dysfunction syndrome compared with standard-issue RBCs in pediatric patients undergoing cardiac surgery. METHODS Preplanned secondary analysis of the Age of Blood in Children in Pediatric Intensive Care Unit study, an international randomized controlled trial. This study included children enrolled in the Age of Blood in Children in Pediatric Intensive Care Unit trial and admitted to a pediatric intensive care unit after cardiac surgery with cardiopulmonary bypass. Patients were randomized to receive either fresh (stored ≤7 days) or standard-issue RBCs. The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured up to 28 days postrandomization or at pediatric intensive care unit discharge, or death. RESULTS One hundred seventy-eight patients (median age, 0.6 years; interquartile range, 0.3-2.6 years) were included with 89 patients randomized to the fresh RBCs group (median length of storage, 5 days; interquartile range, 4-6 days) and 89 to the standard-issue RBCs group (median length of storage, 18 days; interquartile range, 13-22 days). There were no statistically significant differences in new or progressive multiple organ dysfunction syndrome between fresh (43 out of 89 [48.3%]) and standard-issue RBCs groups (38 out of 88 [43.2%]), with a relative risk of 1.12 (95% CI, 0.81 to 1.54; P = .49) and an unadjusted absolute risk difference of 5.1% (95% CI, -9.5% to 19.8%; P = .49). CONCLUSIONS In neonates and children undergoing cardiac surgery with cardiopulmonary bypass, the use of fresh RBCs did not reduce the incidence of new or progressive multiple organ dysfunction syndrome compared with the standard-issue RBCs. A larger trial is needed to confirm these results.
PICO Summary
Population
Children admitted to a paediatric intensive care unit after cardiac surgery with cardiopulmonary bypass, enrolled in the Age of Blood in Children in Pediatric Intensive Care Unit trial (ABC-PICU), (n= 178).
Intervention
Fresh (stored ≤7 days) red blood cells (RBCs), (n= 89).
Comparison
Standard-issue RBCs (n= 89).
Outcome
The authors performed a preplanned subgroup analysis of the ABC-PICU trial. The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured up to 28 days post-randomization or at paediatric intensive care unit discharge, or death. There were no statistically significant differences in new or progressive multiple organ dysfunction syndrome between fresh (43 out of 89 [48.3%]) and standard-issue RBCs groups (38 out of 88 [43.2%]), with a relative risk of 1.12; 95% CI [0.81, 1.54] and an unadjusted absolute risk difference of 5.1%; 95% CI [-9.5%, 19.8%].
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A comparative study of stored arterial versus venous blood collected using the acute normovolemic hemodilution method in coronary artery bypass grafting patients in Iran
Mansouri, M., Yazdani, A., Masoumi, G., Mirmohammadsadeghi, M., Mirmohammadsadeghi, A.
Acute and critical care. 2023
Abstract
BACKGROUND In the present study, arterial and venous blood was collected from patients who were candidates for elective coronary artery bypass grafting (CABG); the blood was stored for 28 days and cellular, biomechanical, and hematological changes in blood were compared to determine whether stored arterial blood is superior to stored venous blood. METHODS The present follow-up comparative study included 60 patients >18 years of age, with hemoglobin >14 mg/dl and ejection fraction >40% who were candidates for CABG. After induction of anesthesia, 250 ml of arterial or venous blood was drawn from patients (arterial blood group and venous blood group). Laboratory blood samples were taken at specified times from the collected blood and re-injected into the patients after CABG. RESULTS Significant differences were observed in pH, partial pressure of carbon dioxide (PCO2), partial pressure of oxygen (PO2), bicarbonate (HCO3), and glucose values at several time points between the groups. Other parameters such as urea and creatinine did not show any significant differences between the groups. CONCLUSIONS Twenty-eight days of storage can have a negative effect on some of the cellular, biochemical, and hematological components of arterial and venous blood; however, the quality of stored arterial blood and venous blood does not differ significantly.
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A Comparative Preliminary Randomized Clinical Study to Evaluate Heavy Bupivacaine Dextrose Prolotherapy (HDP) and Autologous Blood Injection (ABI) for Symptomatic Temporomandibular Joint Hypermobility Disorder
Bhargava D, Sivakumar B, Bhargava PG
Journal of maxillofacial and oral surgery. 2023;22(1):110-118
Abstract
PURPOSE Temporomandibular joint (TMJ) sub-luxation can have a significant psycho-social impact on a patients' well-being. Several treatment modalities have been described in the literature for the same. The present study was undertaken to investigate the efficacy of heavy bupivacaine-dextrose prolotherapy (HDP) for the peri-articular tissues, superior joint space and the retro-discal area in the patients with symptomatic chronic sub-luxation. MATERIALS AND METHODS A preliminary clinical study was conducted among 60 patients diagnosed with chronic painful sub-luxation of the TMJ. Patients were divided into control group (CG), n = 30, where autologous blood was injected in the superior joint space, peri-capsular tissues and retro-discal area bilaterally as per the predetermined protocol; and the study group (SG), n = 30 patients were administered heavy bupivacaine-dextrose injection bilaterally in the peri-articular tissues, superior joint space and retro-discal area. The efficacy of the treatment was evaluated by assessing pain, maximum inter-incisal opening (MIO), changes in computed tomography scan, magnetic resonance imaging study, number and need for subsequent injections in both the groups. RESULT Among the 60 patients, majority of the patients exhibited successful outcome after both the interventions, ABI and HDP. There was statistically significant reduction in recorded pain score with reduced MIO post-treatment. No morphological changes were noted in the condyle in both the groups. No complications were recorded among the study population. CONCLUSION HDP is a safe and simple modality for treating symptomatic sub-luxation with predictable clinical outcome. Heavy bupivacaine-dextrose can be considered as a prolotherapeutic agent for symptomatic chronic temporomandibular joint sub-luxation with the pharmacological benefit of local anaesthesia and proliferent delivery through the same injection.
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Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants: A Secondary Near-Infrared Spectroscopy Study of the Transfusion of Prematures Randomized Clinical Trial (TOP NIRS)
Chock, V. Y., Kirpalani, H., Bell, E. F., Tan, S., Hintz, S. R., Ball, M. B., Smith, E., Das, A., Loggins, Y. C., Sood, B. G., et al
JAMA network open. 2023;6(9):e2334889
Abstract
IMPORTANCE Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. OBJECTIVE To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. DESIGN, SETTING, AND PARTICIPANTS This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. INTERVENTIONS Near-infrared spectroscopy monitoring of Csat and Msat. MAIN OUTCOMES AND MEASURES Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. RESULTS A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower-hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher-hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs -0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03). CONCLUSIONS AND RELEVANCE In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01702805.
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An Individualized Red Blood Cell Transfusion Strategy Using Pediatric Perioperative-Transfusion-Trigger Score Reduced Perioperative Blood Exposure for Children: A Randomized Controlled Clinical Trial
Luo Z, Li Y, Li X, Liao R
Therapeutics and clinical risk management. 2023;19:229-237
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Editor's Choice
Abstract
OBJECTIVE The optimal red blood cell transfusion strategy for children remains unclear. We developed an individualized red blood cell transfusion strategy for children and tested the hypothesis that transfusion guided by this strategy could reduce blood exposure, without increasing perioperative complications in children. METHODS In this randomized controlled clinical trial, 99 children undergoing noncardiac surgeries who had blood loss of more than 20% total blood volume were randomly assigned to an individualized-strategy group using Pediatric Perioperative-Transfusion-Trigger Score or a control group. The amount of transfused red blood cell was counted, and patients were followed up for postoperative complications within 30 days. RESULTS Twenty-six children (53.1%) in the individualized-strategy group received transfusion perioperatively, as compared with 37 children (74%) in the control group (p < 0.05). During surgery, children in the individualized-strategy group were exposed to fewer transfusions than in the control group (0.87±1.03 vs 1.33±1.20 Red-Blood-Cell units per patient, p = 0.02). The incidence of severe complications in the individualized-strategy group had a lower trend compared to the control group (8.2% vs 18%, p = 0.160). No significant difference was found in the other outcomes. CONCLUSION This trial proved that red blood cell transfusion guided by the individualized strategy reduced perioperative blood exposure in children, without increasing the incidence of severe complications. This conclusion needs to be reaffirmed by larger-scale, multicenter clinical trials.
PICO Summary
Population
Children undergoing non-cardiac surgery who had blood loss of more than 20% total blood volume (n= 99).
Intervention
Individualized red blood cell (RBC) transfusion strategy using Pediatric Perioperative-Transfusion-Trigger Score (individualized-strategy group, n= 49).
Comparison
RBC transfusion initiated when the patient’s haemoglobin concentration was lower than 8g per deciliter, or lower than 10g per deciliter for newborns (control group, n= 50).
Outcome
Twenty-six children (53.1%) in the individualized-strategy group received transfusion perioperatively, as compared with 37 children (74%) in the control group. During surgery, children in the individualized-strategy group were exposed to fewer transfusions than in the control group (0.87±1.03 vs. 1.33±1.20 red blood cell units per patient). The incidence of severe complications in the individualized-strategy group had a lower trend compared to the control group (8.2% vs. 18%). No significant difference was found in the other outcomes.
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Autologous versus allogeneic blood transfusion: A comparative study of the peri-operative outcomes in a tertiary care hospital in South India amidst the COVID-19 pandemic
Sam, A. M., Gupta, D., Radhakrishnan, A., Sethuraman, M., Dash, P. K., Pitchai, S., Kesavapisharady, K.
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2023;:103753
Abstract
Autologous blood transfusion is known to have advantages over allogeneic transfusion. The COVID-19 pandemic intensified the already existing shortage of allogeneic blood supply. We carried out a study during this period with the aim to elicit the effects of autologous blood collection and transfusion, to compare the peri-operative outcomes of autologous and allogeneic transfusion practices and also to assess the influence of the autologous transfusion programme in the Blood Centre inventory. It was prospective observational comparative study among neurosurgical and vascular surgical patients in a tertiary care centre in South India. 141 patients were allocated into Group I (n = 71) who received autologous transfusion and those who received conventional allogeneic transfusion were clustered as Group II (n = 72) for analysis. We employed Acute Normovolemic Hemodilution (ANH), Pre-deposit Autologous Donation (PAD) and Intra-operative Cell Salvage (ICS) as various modalities for autologous blood collection. In our study, 43 (60.6%) from Group I received exclusive autologous blood transfusion, whereas 28 (39.4%) required additional allogeneic transfusion. No significant difference in hemoglobin, hematocrit, platelet count and INR were observed between the groups post transfusion. Significant difference was observed in the thoracoabdominal aortic aneurysm (TAAA) patients with respect to duration of ICU stay (2.7 ± 1.1 days in Group I and 6.2 ± 0.8 days in Group II; p = 0.002) and re-exploration due to bleeding (16.7% in Group I and 40% in Group II; p = 0.048). Autologous blood transfusion is safe and effective. It can be employed as routine practice and also during any acute shortage or pandemic.
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Informative cluster size in cluster-randomised trials: A case study from the TRIGGER trial
Kahan, B. C., Li, F., Blette, B., Jairath, V., Copas, A., Harhay, M.
Clinical trials (London, England). 2023;:17407745231186094
Abstract
BACKGROUND Recent work has shown that cluster-randomised trials can estimate two distinct estimands: the participant-average and cluster-average treatment effects. These can differ when participant outcomes or the treatment effect depends on the cluster size (termed informative cluster size). In this case, estimators that target one estimand (such as the analysis of unweighted cluster-level summaries, which targets the cluster-average effect) may be biased for the other. Furthermore, commonly used estimators such as mixed-effects models or generalised estimating equations with an exchangeable correlation structure can be biased for both estimands. However, there has been little empirical research into whether informative cluster size is likely to occur in practice. METHOD We re-analysed a cluster-randomised trial comparing two different thresholds for red blood cell transfusion in patients with acute upper gastrointestinal bleeding to explore whether estimates for the participant- and cluster-average effects differed, to provide empirical evidence for whether informative cluster size may be present. For each outcome, we first estimated a participant-average effect using independence estimating equations, which are unbiased under informative cluster size. We then compared this to two further methods: (1) a cluster-average effect estimated using either weighted independence estimating equations or unweighted cluster-level summaries, and (2) estimates from a mixed-effects model or generalised estimating equations with an exchangeable correlation structure. We then performed a small simulation study to evaluate whether observed differences between cluster- and participant-average estimates were likely to occur even if no informative cluster size was present. RESULTS For most outcomes, treatment effect estimates from different methods were similar. However, differences of >10% occurred between participant- and cluster-average estimates for 5 of 17 outcomes (29%). We also observed several notable differences between estimates from mixed-effects models or generalised estimating equations with an exchangeable correlation structure and those based on independence estimating equations. For example, for the EQ-5D VAS score, the independence estimating equation estimate of the participant-average difference was 4.15 (95% confidence interval: -3.37 to 11.66), compared with 2.84 (95% confidence interval: -7.37 to 13.04) for the cluster-average independence estimating equation estimate, and 3.23 (95% confidence interval: -6.70 to 13.16) from a mixed-effects model. Similarly, for thromboembolic/ischaemic events, the independence estimating equation estimate for the participant-average odds ratio was 0.43 (95% confidence interval: 0.07 to 2.48), compared with 0.33 (95% confidence interval: 0.06 to 1.77) from the cluster-average estimator. CONCLUSION In this re-analysis, we found that estimates from the various approaches could differ, which may be due to the presence of informative cluster size. Careful consideration of the estimand and the plausibility of assumptions underpinning each estimator can help ensure an appropriate analysis methods are used. Independence estimating equations and the analysis of cluster-level summaries (with appropriate weighting for each to correspond to either the participant-average or cluster-average treatment effect) are a desirable choice when informative cluster size is deemed possible, due to their unbiasedness in this setting.
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Refraining from Packed Red Blood Cells in Cardiopulmonary Bypass Priming as a Method of Neuroprotection in Pediatric Cardiac Surgery
Ivkin AA, Grigoriev E, Sinitskaya AV
Journal of clinical medicine. 2023;12(4)
Abstract
Congenital heart defect (CHD) surgeries are performed with cardiopulmonary bypass (CPB) and are complicated by several factors that affect the child's brain. However, to date, the number of studies on brain protection in cardiac surgery remains small. The aim of this study was to assess the impact of refraining from using packed red blood cells (PRBCs) in priming solutions in children with congenital defects (CHDs) who require surgical interventions using CPB to prevent brain injury in the postoperative period. MATERIAL AND METHODS This study included 40 children, and the mean age was 14 (12-22.5) months and the mean weight was 8.8 (7.25-11) kg. All patients underwent CHD closure using CPB. The patients were divided into two groups depending on the use of PRBCs in the priming solution. Brain injury was assessed using three specific blood serum markers, namely S100 calcium-binding protein β (S100β), neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP) before surgery, after the completion of CPB and 16 h after surgery (first, second and third control points). Markers of systemic inflammatory response were also analyzed, including interleukin-1, -6, -10 and tumor necrosis factor alpha (TNF-α). A clinical assessment of brain injury was carried out using a valid, rapid, observational tool for screening delirium in children of this age group, i.e., "Cornell Assessment of Pediatric Delirium". RESULTS Factors of the intra- and postoperative period were analyzed, such as hemoglobin levels, oxygen delivery (cerebral tissue oxygenation, blood lactate level and venous oxygen saturation) and indicators of organ dysfunction (creatinine, urea, bilirubin levels, duration of CPB and length of stay in the ICU). Following the procedure, there were no significant differences between the groups and all indicators were within the reference values, thus demonstrating the safety of CHD closure without transfusion. Moreover, the highest level of specific markers of brain injury were noted immediately after the completion of CPB in both groups. The concentration of all three markers was significantly higher in the group with transfusion after the completion of CPB. Moreover, GFAP levels were higher in the transfusion group and 16 h after surgery. CONCLUSIONS The results of the study show the safety and effectiveness of brain injury prevention strategies that consist of not conducting PRBC transfusion.
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A pilot randomized study for optimal red cell transfusion in acute myeloid leukemia patients with intensive chemotherapy
Byun JM, Park W, Shin DY, Koh Y, Kim I, Yoon SS, Park JH, Kim H, Hong J
Blood transfusion = Trasfusione del sangue. 2023
Abstract
BACKGROUND Although blood transfusion is fundamental throughout the course of hematologic malignancies, acute myeloid leukemia (AML) patients requiring intensive chemotherapy are left at the edges of patient blood management programs because current guidelines do not have established recommendations for red blood cell (RBC) transfusion threshold in patients treated for hematological disorders with anemia and accompanied severe thrombocytopenia. To provide answers for the trigger and doses of ideal RBC transfusion in such situation, we conducted this prospective randomized trial. MATERIALS AND METHODS Newly diagnosed non-acute promyelocytic AML patients undergoing chemotherapy were considered eligible for enrollment. Patients were randomized into 4 groups using a 2 by 2 factorial design, according to the RBC transfusion trigger (hemoglobin [Hb], 7 vs 8 g/dL) and the number of units per transfusion episode (quantity, single vs double-unit). RESULTS Initially 91 patients were randomized into 4 groups, but the protocol adherence rate was 90.1%. Hb trigger did not affect the amount of RBC transfusion required during treatment. Patients receiving RBC transfusion at Hb <7 g/dL used a median of 4 units of RBC (range 0-12), and those receiving transfusion at Hb <8 g/dL also used a median of 4 units of RBC (range 0-24) (p=0.305). The number of RBC units per transfusion did not affect the total amount of RBC transfusion required during treatment. AML treatment outcomes and bleeding events did not differ across the 4 groups. DISCUSSION This study demonstrated the feasibility for restrictive RBC transfusion (Hb <7 g/dL, RBC 1 unit) in AML patients undergoing chemotherapy, regardless of chemotherapy intensity.