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1.
Hydroxyurea for secondary stroke prevention in children with sickle cell anaemia: a systematic review of clinical evidence and outcomes
Aderinto, N., Olatunji, G., Kokori, E., Abdulbasit, M.
Annals of medicine and surgery (2012). 2024;86(2):1042-1047
Abstract
BACKGROUND Stroke remains one of the leading complications of sickle cell anaemia (SCA) in children. Traditionally, SCA treatment focused on symptom relief. However, the high incidence of strokes in children has prompted a reevaluation of treatment, particularly hydroxyurea, for secondary stroke prevention. This study assesses hydroxyurea's effectiveness and safety in preventing secondary strokes in paediatric SCA patients. METHODS This systematic review followed a pre-defined protocol registered with PROSPERO. Comprehensive searches were conducted across PubMed, Embase, Scopus, MEDLINE, Google Scholar, and the Cochrane Library up to August 2023. Studies were included involving paediatric SCA patients at risk of secondary stroke, assessing hydroxyurea as the primary intervention. RESULTS A total of six studies meeting inclusion criteria were included. The effectiveness of hydroxyurea in preventing secondary strokes, with variable responses reported across studies. Adverse effects, including mild neutropenia, are associated with hydroxyurea treatment but with variability in reported toxicity levels. CONCLUSION Hydroxyurea holds promise in preventing recurrent strokes in children with SCA, though its efficacy and safety profiles vary among individuals. Optimal dosages and treatment durations require further investigation, necessitating vigilant monitoring of haematological parameters. Future research should refine dosing strategies, consider individual patient characteristics, assess long-term effects, and explore ancillary benefits beyond stroke prevention.
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2.
Efficacy and safety of deferoxamine, deferasirox and deferiprone triple iron chelator combination therapy for transfusion-dependent β-thalassaemia with very high iron overload: a protocol for randomised controlled clinical trial
Premawardhena, A., Perera, C., Wijethilaka, M. N., Wanasinghe, S. K., Rajakaruna, Rhmg, Samarasinghe, Rankk, Williams, S., Mettananda, S.
BMJ open. 2024;14(2):e077342
Abstract
INTRODUCTION Despite the improvement in medical management, many patients with transfusion-dependent β-thalassaemia die prematurely due to transfusion-related iron overload. As per the current guidelines, the optimal chelation of iron cannot be achieved in many patients, even with two iron chelators at their maximum therapeutic doses. Here, we evaluate the efficacy and safety of triple combination treatment with deferoxamine, deferasirox and deferiprone over dual combination of deferoxamine and deferasirox on iron chelation in patients with transfusion-dependent β-thalassaemia with very high iron overload. METHODS AND ANALYSIS This is a single-centre, open-label, randomised, controlled clinical trial conducted at the Adult and Adolescent Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Patients with haematologically and genetically confirmed transfusion-dependent β-thalassaemia are enrolled and randomised into intervention or control groups. The intervention arm will receive a combination of oral deferasirox, oral deferiprone and subcutaneous deferoxamine for 6 months. The control arm will receive the combination of oral deferasirox and subcutaneous deferoxamine for 6 months. Reduction in iron overload, as measured by a reduction in the serum ferritin after completion of the treatment, will be the primary outcome measure. Reduction in liver and cardiac iron content as measured by T2* MRI and the side effect profile of trial medications are the secondary outcome measures. ETHICS AND DISSEMINATION Ethical approval for the study has been obtained from the Ethics Committee of the Faculty of Medicine, University of Kelaniya (Ref. P/06/02/2023). The trial results will be disseminated in scientific publications in reputed journals. TRIAL REGISTRATION NUMBER The trial is registered in the Sri Lanka Clinical Trials Registry (Ref: SLCTR/2023/010).
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3.
Effect of Benson's relaxation technique versus music intervention on physiological parameters and stress of children with thalassemia during blood transfusions: A randomized controlled trial
Badr, E. A., Ibrahim, H., Saleh, S. E.
Journal of pediatric nursing. 2023
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Editor's Choice
Abstract
BACKGROUND Children with thalassemia are generally dependent on blood transfusions and face a lot of stress and alteration in their physiological parameters through the procedure. AIM: This study aimed to investigate the effect of Benson's relaxation technique versus music intervention on physiological parameters and stress of children with thalassemia during blood transfusions. DESIGN A randomized, controlled trial with three parallel groups. METHODS One hundred and twenty preschool-age children with thalassemia who underwent blood transfusions were randomly assigned to three groups. Children of the control group received only routine hospital care through blood transfusions. Music intervention group children listened to recorded Mozart's music and children of Benson's relaxation group received relaxation intervention before and during the blood transfusions. Outcome measures were physiological parameters and behavioral distress levels. SETTING Hematology outpatient clinic of the Children's University Hospital at El-Shatby in Alexandria from October 2022 to February 2023. RESULTS The mean total score of children's behavioral responses to stress before the blood transfusions procedure was 19.32 ± 4.08, 14.20 ± 0.93, and 16.92 ± 4.74 in the control, music, and Benson groups, respectively. Beyond that, there was a decline in their physiological parameters and behavioral stress response during and after procedure among groups of study (P = 0.005 & <0.001, respectively). CONCLUSION Music and Benson's relaxation interventions had a helpful effect on stabilizing the physiological parameters and reducing behavioral distress levels in children with thalassemia undergoing blood transfusions. PRACTICE IMPLICATIONS This study directs paediatric nurses to apply Benson's relaxation and music interventions for children with thalassemia to enhance their responses.
PICO Summary
Population
Preschool-age children with thalassemia who underwent blood transfusions (n= 120).
Intervention
Benson’s relaxation technique intervention (n= 40).
Comparison
Mozart's music intervention (n= 40); routine hospital care (n= 40).
Outcome
The mean total score of children's behavioral responses to stress before the blood transfusions procedure was 19.32 ± 4.08, 14.20 ± 0.93, and 16.92 ± 4.74 in the control, music, and Benson groups, respectively. Beyond that, there was a decline in their physiological parameters and behavioral stress response during and after procedure among groups of study.
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4.
Preoperative Transfusion in Sickle Cell Disease Children Undergoing Adenotonsillectomy
Kanotra, S., Muller, S. H., Kanotra, J., Gardner, R., Kanotra, S. P.
Indian journal of otolaryngology and head and neck surgery : official publication of the Association of Otolaryngologists of India. 2023;75(2):227-235
Abstract
OBJECTIVE To perform a systematic review and meta-analysis comparing two pre-operative transfusion regimens (conservative versus aggressive) in children with sickle cell disease(SCD) undergoing adenotonsillectomy in terms of post-operative complications, complications related to SCD and transfusion related complications. DATA SOURCES AND REVIEW METHODS A literature review was performed through PubMed, EMBASE, Cochrane, and Ovid databases using the following phrases: (Adenotonsillectomy OR Tonsillectomy) AND (Sickle Cell Disease OR Sickle Cell Trait). Using predetermined inclusion and exclusion criteria, seven articles were selected for systemic review and two control trials were included in meta-analysis. RESULTS Out of a total of 3,146 results, seven articles were selected for review and two controlled trials were included in the meta-analysis. There was no statistically significant difference in the rate of primary and secondary hemorrhage between the aggressive and conservative transfusion regimens (RR = 3.1, CI = 0.84-11.4, p-value = 0.089). The rate of sickle cell disease related complications including vaso-occlusive crisis and acute chest syndrome was also not statistically significant between the two transfusion groups (RR = 1.4, CI = 0.7-2.8, p-value = 0.339). Even though, the transfusion related complications did not reach statistical significance, there was a higher complication rate in the group receiving aggressive blood transfusion. CONCLUSION In SCD children undergoing adenotonsillectomy, an aggressive transfusion regimen that focuses on reducing the Hemoglobin S ratio to below 30% has not been shown to be more effective in reducing post-operative complications when compared to a conservative transfusion regimen. Therefore, it is reasonable to utilize a conservative transfusion regimen, thereby reducing the transfusion-associated risks.
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5.
Compliance and clinical benefit of deferasirox granule and dispersible tablet formulation in pediatric patients with transfusional iron overload: in a randomized, open-label, multicenter, phase II study
Taher, A. T., Wali, Y., Cruz, M. C., Charoenkwan, P., Aydinok, Y., Werner, O., Govindaraju, S., Romen, F., Viprakasit, V.
Haematologica. 2023
Abstract
CALYPSO (NCT02435212), a randomized, open-label, multicenter, phase 2 study evaluated the compliance, clinical benefits, and safety of deferasirox granules and dispersible tablets in pediatric patients with iron overload. Iron chelation therapy-naive and iron chelation therapy-pre-treated patients aged 2 to 0.5 mg/mg; 24.5% and 34.2%), upper respiratory tract infection (28.2% and 29.7%), and pyrexia (26.4% and 23.4%). In iron chelation therapy-naive patients, mean compliance and change from baseline in serum ferritin with both deferasirox formulations were not significantly different. The safety profile was comparable between granule and dispersible tablets formulations, and was consistent with the general safety profile of deferasirox.
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BAY 81-8973 Efficacy and Safety in Previously Untreated and Minimally Treated Children with Severe Hemophilia A: The LEOPOLD Kids Trial
Ljung, R., Chan, A. K. C., Glosli, H., Afonja, O., Becker, B., Tseneklidou-Stoeter, D., Mancuso, M. E., Saulyte-Trakymiene, S., Kenet, G.
Thrombosis and Haemostasis. 2023;123(1):27-39
Abstract
INTRODUCTION BAY 81-8973, a full-length recombinant factor VIII for hemophilia A treatment, has been extensively evaluated in previously treated patients in the LEOPOLD (Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease) clinical trials. AIM: To assess BAY 81-8973 efficacy and safety when used for bleed prophylaxis and treatment in previously untreated/minimally treated patients (PUPs/MTPs). METHODS In this phase III, multicenter, open-label, uncontrolled study, PUPs/MTPs (<6 years old) with severe hemophilia A received BAY 81-8973 (15-50 IU/kg) at least once weekly as prophylaxis. Primary efficacy endpoint was the annualized bleeding rate (ABR) within 48 hours after prophylaxis infusion. Adverse events and immunogenicity were assessed. Patients who developed inhibitors were offered immune tolerance induction (ITI) treatment in an optional extension phase. RESULTS Fifty-two patients were enrolled, with 43 patients (mean age: 13.6 months) treated. Median (interquartile range) ABR for all bleeds within 48 hours of prophylaxis infusion was 0.0 (0.0-1.8) among patients without inhibitors (n = 20) and 0.0 (0.0-2.2) among all patients. As expected, inhibitors were the most frequent treatment-related adverse event (high titer: 17 [39.5%] patients; low titer: 6 [13.9%] patients). Six of 12 patients who underwent ITI treatment in the extension phase (high titer [n = 5], low titer [n = 1]) achieved a negative inhibitor titer. CONCLUSION BAY 81-8973 was effective for bleed prevention and treatment in PUPs/MTPs. The observed inhibitor rate was strongly influenced by a cluster of inhibitor cases, and consequently, slightly higher than in other PUP/MTP studies. Overall, the BAY 81-8973 benefit-risk profile remains unchanged and supported by ongoing safety surveillance. Immune tolerance can be achieved with BAY 81-8973.
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Eltrombopag for Adults and Children with Immune-Refractory Thrombocytopenic Purpura: A Systematic Review
de Barros Torelli, D. F. H., Oliveira, C. B. S., Nai, G. A., Trindade, E. M., Prestes-Carneiro, L. E.
Journal of clinical medicine. 2023;12(12)
Abstract
Eltrombopag is an agonist that binds to the membrane-bound domain of the thrombopoietin receptor used in immune thrombocytopenic purpura (ITP). We conducted a meta-analysis of randomized controlled trials to assess the efficacy and safety of eltrombopag in adults and children with refractory ITP. Adults who received eltrombopag had a significantly better platelet response (relative risk [RR], 3.65; 95% confidence interval [CI], 2.39-5.55), but there were no differences in the incidence of bleeding (RR, 0.8; 95% CI, 0.52-1.22) and adverse effects (RR, 0.99; 95% CI, 0.55-1.78) compared with the placebo. In children, there was no difference between eltrombopag and placebo for a platelet response >50,000/mm(3) (RR, 3.93; 95% CI, 0.56-27.79) and the number of adverse events (RR, 0.99; 95% CI, 0.25-1.49); however, a lower incidence of bleeding was observed (RR, 0.47; 95% CI, 0.27-0.83). Treatment with eltrombopag protected adults and children from severe disease and death.
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8.
Safety Profile of Eltrombopag in Different Age Groups: An Analysis of Real-World Pharmacovigilance and Randomized Clinical Trials
Qu H, Wu J, Ma C, Qiaolongbatu X, Song X, Feng T, Wu Z, Lou Y, Fan G
Clinical pharmacology and therapeutics. 2023
Abstract
Eltrombopag is clinically approved for use in immune thrombocytopenia (ITP), chronic hepatitis C-related thrombocytopenia, and aplastic anemia and suitable for children; however, data on its overall safety profile are scarce. This study aimed to explore the clinical features of adverse drug events (ADEs) associated with eltrombopag in different age groups using ICSRs from the World Health Organization database VigiBase and the US Food and Drug Administration Adverse Event Reporting System database from 2008 to 2022 in combination with a meta-analysis of data from randomized clinical trials in the literature from inception to July 28, 2022. We conducted disproportionality analyses by grouping patients into the following age groups: 0-17 (0-23 months,2-11 years, 12-17 years), 18-64, and ≥65 years. The ADEs about hepatobiliary disorders, thrombosis, skin and subcutaneous tissue disorders, infections and so on were observed more differently in each age group. Meta-analysis results showed differences in the four system organ classes between adults and children with ITP: infections and infestations, general disorders and administration site conditions, skin and subcutaneous tissue disorders, and investigations. The adverse drug reactions in the latest version of instructions were searched in the databases to analyze their post-marketing safety signal strength. We observed signals of elevated alanine aminotransferase, aspartate aminotransferase, and blood bilirubin levels in all age groups. For children, urinary tract infection and back pain, showed signals. Due to the inherent limitations of pharmacovigilance studies, more experiments are needed to assess the risks of eltrombopag in different ages.
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9.
Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial
Young G, Srivastava A, Kavakli K, Ross C, Sathar J, You CW, Tran H, Sun J, Wu R, Poloskey S, et al
Lancet (London, England). 2023
Abstract
BACKGROUND Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors. METHODS This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102. FINDINGS Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5-33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0-2·7]) than in the bypassing agents on-demand group (18·1 [10·6-30·8]), corresponding to a 90·8% (95% CI 80·8-95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported. INTERPRETATION Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia. FUNDING Sanofi.
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10.
Efficacy and safety of pharmacological interventions for managing sickle cell disease in children and adolescents: protocol for a systematic review with network meta-analysis
Tonin, F. S., Ginete, C., Fernandez-Llimos, F., Ferreira, J., Delgadinho, M., Brito, M.
BMJ open. 2023;13(2):e064872
Abstract
INTRODUCTION Sickle cell disease (SCD), an inherited haemoglobinopathy, has important impact on morbidity and mortality, especially in paediatrics. Previous systematic reviews are limited to adult patients or focused only on few therapies. We aim to synthesise the evidence on efficacy and safety of pharmacological interventions for managing SCD in children and adolescents. METHODS AND ANALYSIS This systematic review protocol is available at Open Science Framework (doi:10.17605/OSF.IO/CWAE9). We will follow international recommendations on conduction and report of systematic reviews and meta-analyses. Searches will be conducted in PubMed, Scopus and Web of Science (no language nor time restrictions) (first pilot searches performed in May 2022). We will include randomised controlled trials comparing the effects of disease-modifying agents in patients with SCD under 18 years old. Outcomes of interest will include: vaso-occlusive crisis, haemoglobin levels, chest syndrome, stroke, overall survival and adverse events. We will provide a narrative synthesis of the findings, and whenever possible, results will be pooled by means of pairwise or Bayesian network meta-analyses with surface under the cumulative ranking curve analyses. Different statistical methods and models will be tested. Dichotomous outcomes will be reported as OR, risk ratio or HR, while continuous data will be reported as standard mean differences, both with 95% CI/credibility interval. The methodological quality of the trials will be evaluated using the Risk of Bias 2.0 tool, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION This study refers to a systematic review, so no ethics approval is necessary. We intent to publish our findings in international, peer-reviewed journal. Data will also be presented to peers in scientific events. Additionally, the results obtained in this study may contribute towards the update of therapeutic guidelines and for the development of health policies for SCD. PROSPERO REGISTRATION NUMBER CRD42022328471.