Low-dose hydroxyurea therapy may prevent stroke in children with sickle-cell anemia: Lancet

Kano, Nigeria: A new study found that as compared to low-dose hydroxyurea therapy, moderate-dose hydroxyurea therapy showed no change in stroke incidence rate in children with sickle cell anemia. Secondary analyses, however, show that the moderate-dose group may have a reduced incidence rate of all-cause hospitalizations.

The findings, published in The Lancet Haematology, provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for primary stroke prevention in children with sickle cell anemia. 

Standard care for primary stroke prevention in children with sickle cell anemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes in high-income countries but warrant initial monthly blood transfusion. In Africa, regular blood transfusion is not feasible for most children. 

Given the above background, Shehu U Abdullahi and the team conducted the study with the objective to test in children with aberrant transcranial Doppler velocities, starting with moderate-dose hydroxyurea rather than a low-dose reduces the risk of stroke. 

SPRING is a phase 3 study of children aged 5–12 years with sickle cell anemia and aberrant transcranial Doppler velocities that is being done at three teaching hospitals in Nigeria. We employed a permuted block allocation approach with four block sizes, stratified by sex and site, for randomization. Except for the pharmacists and statisticians, the allocation was kept secret. Participants were randomly randomized to receive either low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea once daily, with monthly clinical evaluation and laboratory monitoring. The primary outcome was a centrally assessed first stroke or transient ischemic attack. The secondary outcome was hospitalization for any reason. For data analysis, we employed the intention-to-treat population.

The results of this work stated as follow:

1. Between August 2, 2016, and June 14, 2018, 220 people were assigned at random and tracked for a median of 24 years.

2. All of the participants were Nigerians from the following ethnic groups: 179 persons (82%) identified as Hausa, 25 (11%) as Fulani, and 16 (7%) as another ethnicity.

3. Three (3%) of 109 participants in the low-dose hydroxyurea group had strokes, with an incidence rate of 119 per 100 person-years, while five (5%) of 111 in the moderate-dose hydroxyurea group had strokes, with an incidence rate of 192 per 100 person-years.

4. The incidence rate ratio of hospitalization for any cause was 171, with the low-dose group having greater incidence rates per 100 person-years than the moderate-dose group. No participant's hydroxyurea medication was discontinued due to myelosuppression.

In conclusion, these findings give an evidence-based recommendation for low-dose hydroxyurea treatment in children with sickle cell anemia who are at risk of stroke.

Reference:

Abdullahi, S. U., Jibir, B. W., Bello-Manga, H., Gambo, S., Inuwa, H., Tijjani, A. G., Idris, N., Galadanci, A., Hikima, M. S., Galadanci, N., Borodo, A., Tabari, A. M., Haliru, L., Suleiman, A., Ibrahim, J., Greene, B. C., Ghafuri, D. L., Rodeghier, M., Slaughter, J. C., … DeBaun, M. R. (2022). Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial. In The Lancet Haematology (Vol. 9, Issue 1, pp. e26–e37). Elsevier BV. https://doi.org/10.1016/s2352-3026(21)00368-9