Serial prophylactic exchange blood transfusion in pregnant women with sickle cell disease (TAPS-2): statistical and qualitative analysis plan for a randomised controlled feasibility trial
BACKGROUND There are significant knowledge gaps regarding the effectiveness of serial prophylactic exchange blood transfusion (SPEBT) for pregnant women with sickle cell disease (SCD). The protocol for the randomised feasibility trial assessing SPEBT versus usual care in women with SCD (TAPS2 trial) has previously been published. This publication outlines the statistical and qualitative analysis plan for the study. METHODS AND DESIGN TAPS2 is a randomised two-arm phase 2 feasibility trial with a nested qualitative study and health economic evaluation. Up to 50 pregnant women with SCD and a singleton pregnancy will be recruited and individually randomised to either SPEBT approximately every 6-10 weeks until delivery (intervention arm) or to usual care (control arm). Information will be collected on a range of feasibility and clinical outcomes. RESULTS Due to the impact of COVID-19 on study recruitment, the initial study period of 24 months was extended to 48 months. Other protocol updates designed to mitigate the impact of COVID-19-related disruption included allowing for remote consent and conducting all qualitative interviews by telephone. The primary outcome for the trial is the overall recruitment rate. The number of women screened, eligible, consented, randomised and withdrawn will be summarised as a CONSORT flow diagram. Differences in clinical outcomes will additionally be presented as an initial assessment of efficacy and to inform sample size calculations for a future definitive trial. Qualitative interviews with trial participants and clinicians will be analysed using reflexive thematic analysis; data from interviews with participants who declined to participate in the trial will be extracted and incorporated into summary tables to report key findings. The health economic analysis plan is not covered by this update. CONCLUSION The publication of this analysis plan is designed to aid transparency and to reduce the potential for reporting bias. TRIAL REGISTRATION NIH registry ( www. CLINICALTRIALS gov ), registration number NCT03975894 (registered 05/06/19); ISRCTN ( www.isrctn.com ), registration number ISRCTN52684446 (retrospectively registered 02/08/19).
Comparative evaluation of efficacy and safety of automated versus manual red cell exchange in sickle cell disease: A systematic review and meta-analysis
Vox sanguinis. 2022
BACKGROUND AND OBJECTIVES Exchange transfusion is a valuable treatment option in sickle cell disease (SCD) and is preferred over simple transfusion as it removes abnormal haemoglobin S (HbS) levels and reduces complications. This meta-analysis aims to evaluate the efficacy and safety profile of automated red cell exchange (aRBX) procedure over manual red cell exchange transfusion (MET) in SCD patients. MATERIALS AND METHODS A standard meta-analysis protocol was developed, and after performing a comprehensive literature search in PubMed/MEDLINE, Cochrane and International Clinical Trial Registry Platform (ICTRP), reviewers assessed eligibility and extracted data from nine relevant studies. A random effects model was used to estimate the pooled effect size calculated from the mean difference in HbS percentage, serum ferritin level and risk ratio for the adverse events. Quality assessment was done using the risk-of-bias assessment tool, and a summary of observations was prepared using standard Cochrane methodology with GradePro GDT. RESULTS The random-model analysis revealed a mean difference of 4.10 (95% CI: -3.29-11.49; Z = 1.09; p = 0.28) for HbS percentage, mean difference of 435.29 (95% CI: -73.74-944.32; Z = 1.68; p = 0.09) for serum ferritin and pooled risk ratio of 1.35 (95% CI: 0.63-2.87; Z = 0.77; p = 0.44) for adverse events. CONCLUSION This meta-analysis did not reveal any significant benefit of aRBX in reducing HbS percentage and attenuating the serum ferritin level when compared with MET. There was also no significant increased risk of adverse events detected in association with aRBX.
Erythrocytapheresis versus phlebotomy in the maintenance treatment of HFE hemochromatosis patients: results from a randomized crossover trial
BACKGROUND Phlebotomy is standard maintenance treatment of patients with hereditary hemochromatosis (HH). Erythrocytapheresis, which selectively removes red blood cells, provides a new, potentially more effective treatment option. Our aim was to evaluate the effectiveness of erythrocytapheresis over phlebotomy for maintenance therapy in patients with HH. STUDY DESIGN AND METHODS We conducted a two-treatment-arms, randomized, crossover clinical trial, involving 46 patients, treated for 1 year with either erythrocytapheresis or phlebotomy to keep the ferritin level at not more than 50 µg/L. After 1 year, patients were switched to the other treatment modality. Primary endpoint was the number of treatment procedures per treatment year. Secondary endpoints were intertreatment intervals, several aspects of health-related quality of life, costs, and patient discomfort as well as preference for one of both treatments. RESULTS The mean number of required treatment procedures per treatment year was significantly higher using phlebotomy versus erythrocytapheresis (3.3 vs. 1.9; mean difference, 1.4; 95% confidence interval, 1.1-1.7). The median intertreatment time was 2.3 times longer for erythrocytapheresis. There was no significant difference in overall health assessed by SF-36 and EQ-5D, respectively, between both treatments arms. The number of self-reported swollen joints was significantly higher during phlebotomy treatment. The mean treatment costs of one treatment year were 235€ for phlebotomy versus 511€ for erythrocytapheresis. Eighty percent of patients preferred erythrocytapheresis as treatment method. CONCLUSION Erythrocytapheresis significantly reduced the number of treatment procedures per treatment year, although the mean treatment costs per year are higher in our health care system. It is the preferred treatment for the majority of patients.
Preoperative transfusion in patients with sickle cell disease to prevent perioperative complications: A systematic review and meta-analysis
Background Sickle cell disease (SCD) is associated with perioperative vascular (SCD-related) and non-vascular complications. To minimize perioperative complications during elective surgery, either exchange blood transfusion or simple blood transfusion can be used. We systematically reviewed the literature and meta-analyzed randomized and observational trials comparing exchange transfusion to simple transfusion, as well as studies comparing preoperative transfusion to no transfusion to assess the relative risk (RR) and benefit of each strategy in sickle cell patients undergoing surgery. Methods Medline, Embase, and the Cochrane-controlled trial register were searched to identify studies that evaluated exchange transfusion to simple transfusion, as well as studies comparing any form of blood transfusion with no transfusion. Studies were evaluated according to a priori inclusion criteria and critically appraised using established internal validity criteria. Pooled RR was estimated using a random effects model. Results Three randomized trials and seven observational studies were included. We found there was no difference between exchange transfusion and simple transfusion for perioperative mortality, vascular, or non-vascular perioperative complications. However, transfusion-related complications (RR 2.41, 95% confidence interval (CI): 1.49-3.91) and the amount of blood transfused (mean difference 2.03, 95% CI: 1.23-2.83) were higher in those treated with exchange transfusion versus simple transfusion. Similarly, there was no difference in perioperative mortality, vascular, or non-vascular perioperative complications between those treated with preoperative transfusion strategy and no transfusion strategy. Conclusion Based on the current literature, neither preoperative exchange transfusion nor simple transfusion reduces perioperative complications in patients with SCD who are undergoing surgery; however, available studies were underpowered to detect a treatment effect.
Erythrocytapheresis compared with whole blood phlebotomy for the treatment of hereditary haemochromatosis
Blood Transfusion = Trasfusione Del Sangue. 2014;12(Suppl 1):s84-9
BACKGROUND Hereditary haemochromatosis may result in severe organ damage which can be prevented by therapy. We studied the possible advantages and disadvantages of erythrocytapheresis as compared with phlebotomy in patients with hereditary haemochromatosis. MATERIALS AND METHODS In a prospective, randomised, open-label study, patients with hereditary haemochromatosis were randomised to bi-weekly apheresis or weekly whole blood phlebotomy. Primary end-points were decrease in ferritin levels and transferrin saturation. Secondary endpoints were decrease in haemoglobin levels, discomfort during the therapeutic procedure, costs and technicians' working time. RESULTS Sixty-two patients were included. Thirty patients were randomised to apheresis and 32 to whole blood phlebotomy. Initially, ferritin levels declined more rapidly in the apheresis group, and the difference became statistically highly significant at 11 weeks; however, time to normalisation of ferritin level was equal in the two groups. We observed no significant differences in decline of transferrin saturation, haemoglobin levels or discomfort. The mean cumulative technician time consumption until the ferritin level reached 50 μg/L was longer in the apheresis group, but the difference was not statistically significant. The cumulative costs for materials until achievement of the desired ferritin levels were three-fold higher in the apheresis group. CONCLUSION Treatment of hereditary haemochromatosis with erythrocytapheresis instead of whole blood phlebotomy results in a more rapid initial decline in ferritin levels and a reduced number of procedures per patient, but not in earlier achievement of target ferritin level. The frequency of discomfort was equally low with the two methods. The costs and, probably, technician time consumption were higher in the apheresis group.
Comparison of intra-procedural pain between a novel continuous arteriovenous exchange and conventional pull-push techniques of partial exchange transfusion in neonates: a randomized controlled trial
Journal of Perinatology. 2014;34((9):):693-7.
OBJECTIVE We compared intra-procedural neonatal pain, agitation and sedation scale (N-PASS) scores between a novel 'continuous arteriovenous exchange' (CAVE) and conventional pull-push (PP) techniques of partial exchange transfusion (PET) among neonates with polycythemia. STUDY DESIGN Neonates >32-0/7 weeks gestation, requiring PET for polycythemia, were randomized to PP or CAVE techniques. The procedure was video-recorded and edited to mask the technique. Intra-procedural N-PASS scores assigned by two trained and masked neonatal fellows were compared. RESULT Twenty-two neonates were randomized to CAVE (n=12) or PP (n=10) method. The area under curve for cumulative N-PASS scores was significantly lesser in CAVE group (mean difference-11.9 (95% CI=-4.2, -19.6), P=0.005)). Decrease in hematocrit and complications of PET were comparable. Time for PET was longer with CAVE technique (16 (9, 29) min vs 10 (6, 12) min, P=0.016). CONCLUSION CAVE technique of PET was associated with lesser procedure-related pain (N-PASS scores) as compared with PP technique among neonates >32 weeks gestation.
Two-stage single-volume exchange transfusion in severe hemolytic disease of the newborn
Journal of Maternal-Fetal & Neonatal Medicine. 2012;25((7):):1080-3.
OBJECTIVE Evaluation of two-stage single-volume exchange transfusion (TSSV-ET) in decreasing the post-exchange rebound increase in serum bilirubin level, with subsequent reduction of the need for repeated exchange transfusions. METHODS The study included 104 neonates with hyperbilirubinemia needing exchange transfusion. They were randomly enrolled into two equal groups, each group comprised 52 neonates. TSSV-ET was performed for the 52 neonates and the traditional single-stage double-volume exchange transfusion (SSDV-ET) was performed to 52 neonates. RESULTS TSSV-ET significantly lowered rebound serum bilirubin level (12.7 +/- 1.1 mg/dL), compared to SSDV-ET (17.3 +/- 1.7 mg/dL), p < 0.001. Need for repeated exchange transfusions was significantly lower in TSSV-ET group (13.5%), compared to 32.7% in SSDV-ET group, p < 0.05. No significant difference was found between the two groups as regards the morbidity (11.5% and 9.6%, respectively) and the mortality (1.9% for both groups). CONCLUSION Two-stage single-volume exchange transfusion proved to be more effective in reducing rebound serum bilirubin level post-exchange and in decreasing the need for repeated exchange transfusions.
Exchange transfusion therapy and its effects on real-time microcirculation in pediatric sickle cell anemia patients: an intravital microscopy study
Journal of Pediatric Hematology/Oncology. 2012;34((3):):169-74.
Periodic blood exchange transfusion is a treatment modality commonly used to manage pediatric sickle cell anemia at the University of California Davis Medical Center. The goal of exchange transfusion therapy is to ameliorate vasoocclusion and improve tissue perfusion by removing sickled red blood cells and introducing normal red blood cells. Using computer-assisted intravital microscopy, pretransfusion and posttransfusion microvascular characteristics were analyzed. In this study, the bulbar conjunctiva exhibited a "blanched" avascular appearance in all 6 pediatric sickle cell anemia patients before transfusion, indicative of tissue hypoperfusion and ischemia. Immediately after transfusion, substantial improvement in vascularization and tissue perfusion resulted, reflected by the enhanced appearance of capillaries and arterioles. In addition, a decrease in red cell velocity was observed. These observations provide evidence that exchange transfusion therapy is beneficial in ameliorating vasoocclusion and improving tissue perfusion. However, with the paradoxical posttransfusion decrease in red cell velocity presumably due to induced hyperviscosity from the large transfusion volume, blood flow is still impaired. This decreased velocity may thwart efforts to improve oxygen delivery through transfusion and may, to some extent, promote vasoocclusion instead. This paradoxical result warrants further investigation on the effects of transfusion volume and viscosity in the exchange transfusion process.
Therapeutic erythrocytapheresis, a new treatment for naive patients with hereditary hemochromatosis
Vox Sanguinis. 2010;99((Suppl S1):):414-415.. Abstract No. P-0885.
Effect of partial exchange transfusion in asymptomatic polycythemic LBW babies
Indian Pediatrics. 2004;41((4):):366-72.
This randomized controlled trial was conducted to determine the effect of partial exchange transfusion in polycythemic babies. Forty five asymptomatic polycythemic babies with birth weight < or = 2000 g were included and randomly assigned to undergo either partial exchange transfusion using isotonic saline within 4 hours of screening or routine medical management. Outcome measures were neonatal morbidity (especially hypoglycemia and neurological alterations) and mortality; developmental delays using DDST-II, neurological deficits, tone and DTR abnormalities over 18 months follow up period. The overall neonatal morbidity in this study was low and comparable in the two groups. Some of the polycythemic babies in the non-exchanged group found initially at 3 months age with suspected developmentgrew out of their developmental delay at 18 months of age or later while those who underwent exchange transfusion and with retarded development at 3 months of age remained so even at 18 months of age.