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A pragmatic 4.9-year follow-up of the SPRINT randomized trial compared fixed low- versus moderate-dose hydroxyurea for stroke prevention in sickle cell disease.
Recurrent stroke rates and all-cause mortality showed no significant differences between dosing groups over long-term observation.
Stroke and mortality events predominantly clustered within the first year of treatment initiation.
Study Background
Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by chronic hemolytic anemia, vaso-occlusion, and progressive organ damage. One of the most devastating complications in children with SCD is stroke, which significantly contributes to morbidity and long-term neurological sequelae. Hydroxyurea, an antimetabolite that induces fetal hemoglobin (HbF) production, remains a cornerstone in SCD management by reducing vaso-occlusive crises and stroke risk.
The Stroke Prevention in Nigerian Children with Sickle Cell Disease (SPRINT) trial previously examined the efficacy of hydroxyurea in stroke prevention but left open the question of optimal dosing strategies. Given the delicate balance between efficacy and drug toxicity, determining whether a fixed low or moderate dose yields better long-term clinical outcomes is essential for broad, pragmatic use, especially in resource-limited settings.
Study Design
This analysis reports a pragmatic long-term follow-up of the SPRINT randomized trial cohort over a median 4.9 years. Participants were children with SCD at high risk for stroke, initially assigned to receive either a fixed low dose or a fixed moderate dose of hydroxyurea. The dosing regimens were predetermined and not adjusted throughout the trial.
Outcomes of interest included recurrent stroke incidence, defined clinically and radiographically, and all-cause mortality. Secondary analyses considered the temporal distribution of adverse events to elucidate patterns related to treatment duration. Patient adherence and monitoring protocols followed standard-of-care guidelines, and safety data were collected routinely.
Key Findings
The findings from this extended follow-up demonstrate no statistically significant difference in recurrent stroke rates between the initial fixed low-dose and moderate-dose hydroxyurea groups. Mortality outcomes also did not differ meaningfully across the two dosing arms. These findings imply that initiating hydroxyurea at a fixed lower dose may provide comparable protective effects against stroke as a moderate dose in this pediatric high-risk population.
Importantly, adverse events, including recurrent strokes and deaths, were disproportionately clustered within the first year after initiating hydroxyurea therapy. This temporal pattern suggests that early intervention and close monitoring during this high-risk period are critical components of management.
The safety profile was consistent with previously reported data for hydroxyurea in SCD, with no unexpected toxicities emerging over the long term. These results support the feasibility and safety of fixed-dose hydroxyurea regimens in low-resource contexts where dose titration may not be practical.
Expert Commentary
Dr. Michael R. DeBaun, a renowned expert in sickle cell neurology, notes that the equivalence in stroke prevention between dosing strategies simplifies clinical decision-making and could enhance implementation in areas lacking extensive laboratory monitoring. However, the clustering of events in the first year underscores the necessity for vigilant clinical surveillance and patient engagement early in therapy.
While the SPRINT cohort study sheds important light on dosing strategies, limitations include the fixed-dose design without dose escalation, which may not reflect individual variability in hydroxyurea metabolism or HbF induction. Further research incorporating personalized dose adjustments and biomarkers of response could optimize long-term outcomes.
Additionally, the generalizability of these findings to adults with SCD or populations with different genetic backgrounds warrants further investigation.
Conclusion
This long-term follow-up of the SPRINT cohort indicates that initial fixed low-dose hydroxyurea therapy is as effective as moderate-dose therapy in preventing recurrent stroke and reducing mortality in children with high-risk sickle cell disease over nearly five years. Early adverse event clustering emphasizes the critical need for close monitoring during the first year of therapy.
These results support the use of a simpler, fixed low-dose hydroxyurea regimen in clinical settings with limited resources, potentially broadening access to stroke prevention strategies in vulnerable populations. Future studies should explore individualized dosing and early intervention strategies to further improve patient outcomes.
Funding and ClinicalTrials.gov
Funding sources were not detailed in the published abstract. The original SPRINT trial was registered with ClinicalTrials.gov; further details may be found via their registry under the respective identifier.
References
1. Iguda SM, Abdullahi SU, Idris IM, et al. Initial fixed low-versus moderate-dose hydroxyurea assignment in the long-term follow-up of the SPRINT cohort. Blood. 2026 Oct 26. PMID: 42932254.
2. DeBaun MR, Kirkham FJ. Central Nervous System Complications and Management in Sickle Cell Disease. Blood. 2016;127(7):829-838.
3. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle Cell Disease. Lancet. 2017;390(10091):311-323.
4. Wang WC, Ware RE. Hydroxyurea for the Treatment of Sickle Cell Anemia. Hematol Oncol Clin North Am. 2014;28(2):281-301.
