A systematic review of advances and challenges in stroke prevention in sickle cell disease since the STOP trials

Abstract

Abstract Background Stroke is among the most disabling complications of sickle cell disease (SCD). The STOP trials established transcranial Doppler (TCD) screening with chronic transfusion as the basis of primary stroke prevention. Implementation remains uneven, however, and evidence for adults and for newer agents is limited. Objectives To synthesise evidence on stroke prevention in SCD since the STOP era, covering advances in diagnosis and therapy, barriers to implementation in sub-Saharan Africa, and research priorities. Methods Systematic review reported according to PRISMA 2020. PubMed/MEDLINE, CENTRAL, Global Index Medicus, Google Scholar and trial registries were searched from January 1998 to 17 September 2026. Randomised, cohort and cross-sectional studies of primary or secondary stroke prevention in children or adults with SCD were eligible. Two reviewers screened records, extracted data and assessed risk of bias using RoB 2, ROBINS-I and the JBI checklists. Findings were synthesised narratively because of heterogeneity. Results Of 1793 records screened, 63 reports describing 58 studies were included. In children with abnormal TCD velocities, chronic transfusion reduced first stroke by about 90%, and stopping transfusion led to reversion to abnormal velocities and stroke. Hydroxyurea was non-inferior to transfusion for maintaining TCD velocities after at least one year of transfusion. For secondary prevention, hydroxyurea with phlebotomy was inferior to transfusion with chelation. Matched-sibling transplantation improved long-term cerebrovascular outcomes. No newer pharmacological agent has been tested against a stroke endpoint Stroke prevalence in African cohorts ranged from 0.85% to 8.5%. Access to screening and safe transfusion was the main constraint in the region. Conclusions The interventions established by the STOP trials remain the cornerstone of primary stroke prevention in SCD, but their benefit is unevenly realised. Stroke rates have risen again where screening adherence has declined, and in much of sub-Saharan Africa, where the burden is greatest, access to TCD screening and safe transfusion is still limited. The main barrier has therefore shifted from knowledge to delivery. Priorities are to scale up screening and hydroxyurea programmes in low-resource settings and to generate stronger evidence for adults. Trial registration OSF Registries, Doi: https://doi.org/10.17605/OSF.IO/2DMCQ , registered 4 September 2026 (retrospective registration; see Sect. 2.2).