Chronic blood transfusion guided by transcranial Doppler ultrasound remains the cornerstone of primary stroke prevention in children with sickle cell disease, yet the benefit of that decades-old strategy is still not reaching most of the people who need it, according to a systematic review published in Discover Pediatrics. The review, reported under PRISMA 2020 guidelines, screened 1,793 records and included 63 reports describing 58 studies published between 1998 and 2026, spanning randomised trials, cohort studies and cross-sectional surveys from sub-Saharan Africa, North America, Europe, Latin America and the Middle East.
The review’s authors, a team led by Chanda Kapoma and colleagues, found that the interventions established by the landmark STOP trials have not been superseded. In children with abnormal transcranial Doppler velocities, chronic transfusion reduced first stroke by about 90 percent, and the STOP 2 trial showed that stopping transfusion once velocities normalised led to reversion to abnormal velocities and to stroke. Hydroxyurea escalated to the maximum tolerated dose was non-inferior to continued transfusion for maintaining Doppler velocities in selected children who had completed at least a year of transfusion, but hydroxyurea combined with phlebotomy was inferior to transfusion with chelation for preventing recurrent stroke in children who had already had an overt stroke. Matched-sibling transplantation improved long-term cerebrovascular outcomes. No newer pharmacological agent has been tested against a stroke endpoint.
The trial evidence is more nuanced than a simple ranking of treatments. The TWiTCH trial, often misread as contradicting SWiTCH, addressed a different population: children with abnormal Doppler velocities and no severe vasculopathy on magnetic resonance angiography, who had already completed at least twelve months of transfusion and had never had an overt stroke. In that group, hydroxyurea at maximum tolerated dose was non-inferior to continued transfusion for maintaining velocities at 24 months, and no stroke occurred in either arm. The review stresses that TWiTCH does not support hydroxyurea as a substitute for transfusion after overt stroke, nor transition in children with severe vasculopathy, who were excluded. The Silent Cerebral Infarct Multi-Center Clinical Trial extended the rationale for transfusion further, showing that regular transfusion reduced the recurrence of infarction, whether overt stroke or new silent infarct, by 58 percent in children with magnetic resonance-confirmed silent infarction and normal Doppler velocities.
Perhaps the most striking finding concerns what has happened since those trials succeeded. In a statewide Californian cohort of 7,636 people with sickle cell disease, ischaemic stroke fell by 66 percent in the two years immediately after STOP, but the gain was not sustained. Ischaemic stroke rates in children rose from 165.1 to 234.9 per 100,000 person-years between 1999–2009 and 2010–2019, and rose comparably in adults aged 31 to 50 years, from 303.2 to 431.1 per 100,000 person-years. Proposed explanations include incomplete adoption of screening outside comprehensive sickle cell centres, under-use of hydroxyurea and transfusion, and greater ascertainment through improved neuroimaging. The cumulative incidence of first intracranial haemorrhage in the cohort rose from 0.5 percent by age 20 to 6.8 percent by age 60, while first ischaemic stroke rose from 2.1 percent to 13.5 percent over the same interval.
The review’s authors conclude that the main barrier has shifted from knowledge to delivery. In much of sub-Saharan Africa, where more than 90 percent of people with sickle cell disease live, access to transcranial Doppler screening and safe transfusion remains limited. Reported stroke prevalence in African cohorts ranged from 0.85 percent in a Ghanaian registry of 4,115 patients to 8.5 percent in a Malawian paediatric cohort, but the review cautions that these estimates are uncertain in both directions. Most African estimates derive from facility-based cross-sectional studies without confirmatory brain imaging, so facility-based sampling may over-represent severe disease while absent imaging and pre-hospital mortality lead to under-ascertainment. Genotype composition, which is rarely reported, may also explain part of the between-country variation, since HbSC disease carries lower stroke risk than HbSS or HbSβ⁰-thalassaemia.
Hydroxyurea emerges as the most realistic backbone of prevention at scale across the region, supported by African trial evidence. The REACH study established feasibility and safety across four countries with reductions in clinical events, and NOHARM demonstrated safety in a malaria-endemic setting. In extended follow-up to a median of 93 months, recurrent stroke events were less frequent after escalation to maximum tolerated dose than during a preceding fixed-dose phase, with an incidence rate ratio of 0.27, though the confidence interval of 0.07 to 1.06 crossed unity. The SPRING trial in Nigerian children with abnormal velocities found no difference in stroke incidence between low- and moderate-dose hydroxyurea, and the SPRINT trial found similar recurrent-stroke rates with low- and moderate-dose regimens for secondary prevention, at 7.1 and 6.0 per 100 person-years, though without a transfusion comparator it does not establish equivalence. The review notes that the monitoring burden of dose escalation, requiring frequent blood counts, is the principal obstacle in settings without reliable laboratory access, which explains why fixed low-dose protocols persist despite their smaller expected effect.
The therapeutic pipeline has become more uncertain. Voxelotor was withdrawn worldwide in 2024 due to safety issues, including an imbalance between vaso-occlusive events and deaths, and crizanlizumab did not show a significant reduction in vaso-occlusive events in its confirmatory STAND trial; neither trial regarded stroke as a primary outcome. Pyruvate kinase activators such as mitapivat and etavopivat are described as promising, but their effects on cerebrovascular outcomes have not been established. Gene-based therapies using CRISPR/Cas9 or an anti-sickling β-globin gene require myeloablative conditioning and specialised facilities, carry risks including infertility and, for the lentiviral product, haematological malignancy, and their registration studies did not use cerebrovascular outcomes as major endpoints. The review concludes these should be seen as disease-modifying treatments with unproven cerebrovascular benefits rather than established stroke-prevention strategies.
Haematopoietic stem cell transplantation remains the only established curative option, and the strongest cerebrovascular evidence comes from the French DREPAGREFFE trial, in which donor availability determined allocation. Among 67 children with a history of abnormal velocities, normalisation of Doppler velocities at one year was substantially more frequent after matched-sibling-donor transplantation than with continued transfusion, and ten-year follow-up confirmed superior cerebrovascular outcomes, including greater reduction in arterial stenosis score, alongside benefits in cognitive function and quality of life. Yet fewer than one in five patients has a suitable sibling donor, and across most of sub-Saharan Africa transplantation capacity is effectively absent, the sharpest divergence between the evidence base and the epidemiological burden.
Adults represent the most conspicuous evidence gap. Transcranial Doppler has not been validated as a screening tool in adults, because velocities fall physiologically with age and the 200 cm/s threshold derived in children cannot be transferred, and no adult equivalent has been prospectively validated. No randomised trial has tested primary stroke prevention in adults with sickle cell disease, so practice is extrapolated from paediatric trials, an extrapolation weakened by the shift in predominant stroke subtype from ischaemic to haemorrhagic events with age. Conventional risk factors such as hypertension and hyperlipidaemia become material contributors in adulthood, and blood-pressure control, lipid management and renal protection are plausible and inexpensive targets that have not been formally evaluated in this population.
The review identifies priorities including adult-specific risk-stratification tools, better evidence on conditional Doppler velocities of 170 to 199 cm/s, which are numerically large in African cohorts where screening capacity is scarcest, implementation trials of decentralised screening and task-shifted screening by trained nurses and technicians, and prospective incorporation of cerebrovascular outcomes into trials of emerging therapies. The authors also declare limitations: retrospective trial registration, no pooled effect estimates because of heterogeneity, restricted database access, English-language restriction and facility-based African designs. Their central message is that closing the gap will depend less on new mechanisms than on reliably delivering established ones, extending the evidence base to adults, and generating implementation data in the settings that carry the burden.
Subject of Research: Stroke prevention in sickle cell disease since the STOP trials
Article Title: A systematic review of advances and challenges in stroke prevention in sickle cell disease since the STOP trials
Article References: Kapoma, C., Sichamba, P., Hatwiko, H., Mutalange, M., Mulemena, J. A., Chanda, W., Michelo, M., Hamooya, B. M., Machiko, A., Phiri, C., Munsaka, S. M., & Kamvuma, K. (2026). A systematic review of advances and challenges in stroke prevention in sickle cell disease since the STOP trials. Discover Pediatrics, 1(1), Article 10. https://doi.org/10.1007/s44571-026-00011-7
Image Credits: AI Generated
DOI: 10.1007/s44571-026-00011-7
Keywords: sickle cell disease, stroke prevention, transcranial Doppler, chronic transfusion, hydroxyurea, STOP trials, sub-Saharan Africa, systematic review, silent cerebral infarction, stem cell transplantation, gene therapy, health systems
News Source: Cassandra Pierce. (October 28, 2026). Stroke Prevention in Sickle Cell Disease Still Rests on Decades-Old Trials. Scienmag.
