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Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind,
Shehu U Abdullahi1, Binta W Jibir2, Halima Bello-Manga3
1Department of Pediatrics, Bayero University/Aminu Kano Teaching Hospital, Kano, Nigeria.
Insights
Moderate-dose hydroxyurea did not reduce stroke incidence in children with sickle cell anaemia compared to low-dose therapy. However, it may lower all-cause hospitalizations, offering a potential guideline for stroke risk management.
Area of Science:
- Pediatric Hematology
- Neurology
- Clinical Trials
Background:
- Sickle cell anaemia poses a high stroke risk in children, particularly in Africa where transfusions are challenging.
- Standard stroke prevention via monthly transfusions is effective but often infeasible in resource-limited settings.
- Hydroxyurea is explored as an alternative for primary stroke prevention in pediatric sickle cell anaemia.
Purpose of the Study:
- To compare the efficacy of moderate-dose versus low-dose hydroxyurea in preventing strokes in children with sickle cell anaemia and abnormal transcranial Doppler (TCD) velocities.
- To assess the impact of different hydroxyurea doses on all-cause hospitalizations in this pediatric population.
Main Methods:
- A phase 3, double-blind, randomized controlled trial (SPRING trial) involving 220 children aged 5-12 years in Nigeria.
- Participants received either low-dose (10 mg/kg/day) or moderate-dose (20 mg/kg/day) oral hydroxyurea.
- The primary outcome was stroke or transient ischemic attack, with secondary outcome of all-cause hospitalization, followed for a median of 2.4 years.
Main Results:
- No significant difference in stroke incidence between the low-dose (3%) and moderate-dose (5%) hydroxyurea groups (Incidence Rate Ratio 0.62; p=0.77).
- Moderate-dose hydroxyurea showed a significantly lower incidence rate of all-cause hospitalizations compared to the low-dose group (16.08 vs 27.43 per 100 person-years; p=0.0071).
- No treatment discontinuations due to myelosuppression were reported.
Conclusions:
- Moderate-dose hydroxyurea does not offer a significant advantage over low-dose therapy in reducing stroke incidence in children with sickle cell anaemia and abnormal TCD velocities.
- Moderate-dose hydroxyurea may be beneficial in reducing all-cause hospitalizations, suggesting a potential role in managing overall morbidity.
- Low-dose hydroxyurea therapy is supported as an evidence-based guideline for children with sickle cell anaemia at risk of stroke, considering feasibility and outcomes.
Background:
In high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. In Africa, where regular blood transfusion is not feasible for most children, we tested the hypothesis that initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities.
Methods:
SPRING is a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5-12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, we used a permuted block allocation scheme with block sizes of four, stratified by sex and site. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 1:1 ratio to low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea taken once daily with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. The secondary outcome was all-cause hospitalisation. We used the intention-to-treat population for data analysis. The trial was stopped early for futility after a planned minimum follow-up of 3·0 years to follow-up for participants. This trial was registered with ClinicalTrials.gov, number NCT02560935.
Findings:
Between Aug 2, 2016, and June 14, 2018, 220 participants (median age 7·2 years [IQR 5·5-8·9]; 114 [52%] female) were randomly allocated and followed for a median of 2·4 years (IQR 2·0-2·8). All participants were Nigerian and were from the following ethnic groups: 179 (82%) people were Hausa, 25 (11%) were Fulani, and 16 (7%) identified as another ethnicity. In the low-dose hydroxyurea group, three (3%) of 109 participants had strokes, with an incidence rate of 1·19 per 100 person-years and in the moderate-dose hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1·92 per 100 person-years (incidence rate ratio 0·62 [95% CI 0·10-3·20], p=0·77). The incidence rate ratio of hospitalisation for any reason was 1·71 (95% CI 1·15-2·57, p=0·0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27·43 vs 16·08). No participant had hydroxyurea treatment stopped for myelosuppression.
Interpretation:
Compared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke.
Funding:
National Institute of Neurological Disorders and Stroke.
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