Tonin, FernandaGinete, CatarinaFerreira, J.Delgadinho, MarianaFernandez-Llimos, FernandoBrito, Miguel2023-08-252023-08-252023-04Tonin FS, Ginete C, Ferreira J, Delgadinho M, Fernandez-Llimos F, Brito M. Comparative efficacy and safety of pharmacological interventions for sickle cell disease in children and adolescents: a network meta-analysis. In: Abstract Book for the 17th Annual Sickle Cell and Thalassaemia Conference. HemaSphere. 2023;7(Suppl 1):46.http://hdl.handle.net/10400.21/16411Background: Sickle cell disease (SCD), an inherited hemoglobinopathy characterized by anemia, severe pain, acute chest syndrome (ACS), and vaso-occlusive crisis (VOC), has an important impact on morbidity and mortality worldwide, especially in the pediatric population (over 50% die before age of 5). Although few treatment options are available, new disease-modifying therapies, intended to prevent or reduce SCD-related complications are under development. Previous systematic reviews are limited to adult patients or focused only on gathering data on a few therapies. Aims: Our aim was to synthetize the evidence on the efficacy and safety profiles of pharmacological interventions for managing SCD in children and adolescents. Methods: A systematic review with searches in PubMed, Scopus, and Web of Science was performed (May-2022). The protocol is registered at PROSPERO CRD42022328471. We included randomized controlled trials comparing any disease-modifying agent used to treat SCD complications in patients under 18 years old. The outcomes of interest included: VOC, ACS, transfusions, hospital admission, discontinuation, and serious adverse events. Data were pooled by means of Bayesian network meta-analyses with the surface under the cumulative ranking curve analyses (SUCRA). Results were reported as odds ratio (OR) with 95% credibility intervals (CrI). Additionally, stochastic multicriteria acceptability analyses (SMAA) were performed. The methodological quality of the trials and certainty of evidence were evaluated through RoB 2.0 tool and the GRADE approach, respectively. Results: Overall, 17 randomized controlled trials (n=1,972 patients) published between 1982-2022, conducted mostly in Africa (41%) and North America (35%) were included for analyses. Around one-third of the trials were restricted to homozygous patients for the SCD allele (SS HMZ); yet when reported, patients with heterozygous S-C combination represented less than 30% of the population. Males accounted for 49.0% of the cases, with ages varying from 1 to 19 years old. Almost all trials (n=15, 88.2%) directly compared active drugs with placebo. The evaluated interventions were: hydroxyurea [n=6 trials], L-arginine [n=3], antiplatelets [n=2], immunotherapy/monoclonal antibodies [n=2], sulfates [n=2], docosahexaenoic acid [n=1], niprisan [n=1] (Figure 1). SUCRA and SMAA revealed that immunotherapy/monoclonal antibodies and hydroxyurea 20 mg/kg are potentially more effective against ACS (17% and 24% probabilities, respectively), VOC (around 29% and 20%, respectively) and needing of transfusions (around 25%), while L-arginine (100-200 mg/kg) and placebo were more associated with these events. Although therapies were overall considered safe, antiplatelet and sulfates may lead to more discontinuations and severe adverse events (uncertainty evidence). Results were similar between age subgroups (<10 years vs. 10-19 years). Summary - Conclusion: The available evidence on the effect of drugs on managing SCD in children and adolescents is still insufficient and weak. No clear definition and reporting criteria for some outcomes exist. Hydroxyurea 20 mg/kg/day may remain the standard of care for these patients, however, long-term, well-designed trials comparing new immunotherapy/monoclonal antibodies should be performed. The use of monotherapies with L-arginine, antiplatelets, or sulfates should be avoided given the poor benefit-risk ratio for this population.engSickle cell diseasePharmacological interventionChildrenAdolescentconference object10.1097/01.HS9.0000928488.59931.31