Hydroxyurea for secondary stroke prevention in children with sickle cell anemia in Nigeria: a randomized controlled trial.

We tested the hypothesis that fixed oral moderate-dose hydroxyurea (20 mg/kg per day) for initial treatment of secondary stroke prevention results in an 80% relative risk reduction of stroke or death when compared with fixed oral low-dose hydroxyurea (10 mg/kg per day) in a phase 3 double-blind, parallel-group, randomized controlled trial in children with sickle cell anemia (SCA) living in Nigeria. A total of 101 participants were randomly allocated to low-dose (n = 49) and moderate-dose (n = 52) hydroxyurea treatment groups. The median participant follow-up was 1.6 years (interquartile range, 1.0-2.3), with a planned minimum follow-up of 3.0 years. A total of 6 recurrent strokes and 2 deaths vs 5 recurrent strokes and 3 deaths occurred in the low- and moderate-dose groups, respectively. The incidence rate ratio (IRR) of the primary outcome measure of stroke or death in the low- and moderate-dose hydroxyurea treatment groups was 0.98 (95% confidence interval [CI], 0.32-3.00; P = .97). The trial was stopped early owing to no clinical difference in the incidence rates of the primary outcome measure. The incidence rates of recurrent strokes were 7.1 and 6.0 per 100 person-years in the low- and moderate-dose groups, respectively, (IRR, 1.18; 95% CI, 0.30-4.88; P = .74). As a measure of adherence to the oral hydroxyurea therapy, the median percent of returned pills was 3.0% and 2.6% in the low- and moderate-dose groups, respectively. No participant had hydroxyurea therapy stopped for myelosuppression. For children with SCA in low-income settings without access to regular blood transfusion therapy, initial low-dose hydroxyurea is a minimum known efficacious dose for secondary stroke prevention.

Primary prevention of stroke in children with sickle cell anemia in sub-Saharan Africa: rationale and design of phase III randomized clinical trial.

Strokes in children with sickle cell anemia (SCA) are associated with significant morbidity and premature death. Primary stroke prevention in children with SCA involves screening for abnormal transcranial Doppler (TCD) velocity coupled with regular blood transfusion therapy for children with abnormal velocities, for at least one year. However, in Africa, where the majority of children with SCA live, regular blood transfusions are not feasible due to inadequate supply of safe blood, cost, and the reluctance of caregivers to accept transfusion therapy for their children. We describe the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria Trial [StrokePreventioninNigeria (SPRING) trial, NCT02560935], a three-center double-blinded randomized controlled Phase III clinical trial to 1) determine the efficacy of moderate fixed-dose (20 mg/kg/day) versus low fixed-dose (10 mg/kg/day) hydroxyurea therapy for primary stroke prevention; 2) determine the efficacy of moderate fixed-dose hydroxyurea for decreasing the incidence of all cause-hospitalization (pain, acute chest syndrome, infection, other) compared to low fixed-dose hydroxyurea. We will test the primary hypothesis that there will be a 66% relative risk reduction of strokes in children with SCA and abnormal TCD measurements, randomly allocated, for a minimum of three years to receive moderate fixed-dose versus low fixed-dose hydroxyurea (total n = 220). The results of this trial will advance the care of children with SCA in sub-Saharan Africa, while improving research capacity for future studies to prevent strokes in children with SCA.

Children with sickle cell anemia with normal transcranial Doppler ultrasounds and without silent infarcts have a low incidence of new strokes.

In a prospective cohort study, we tested the hypothesis that children with sickle cell anemia (SCA) with normal transcranial Doppler ultrasound (TCD) velocities and without silent cerebral infarcts (SCIs) would have a lower incidence rate of new neurological events (strokes, seizures or transient ischemic attacks) compared to children with normal TCD measurements and SCIs, not receiving regular blood transfusions. Nonrandomized participants from the silent cerebral infarct transfusion (SIT) Trial who had screening magnetic resonance imaging (MRI) of the brain and normal TCD measurements were included. Follow-up ended at the time of first neurological event (stroke, seizure or transient ischemic attack), start of regular blood transfusion, or loss to follow-up, whichever came first. The primary endpoint was a new neurological event. Of 421 participants included, 68 had suspected SCIs. Mean follow-up was 3.6 years. Incidence rates of new neurological events in nontransfused participants with normal TCD values with SCIs and without SCIs were 1.71 and 0.47 neurological events per 100 patient-years, respectively, P = .065. The absence of SCI(s) at baseline was associated with a decreased risk of a new neurological event (hazard ratio 0.231, 95% CI 0.062-0.858; P = .029). Local pediatric neurologists examined 67 of 68 participants with suspected SCIs and identified 2 with overt strokes classified as SCIs by local hematologists; subsequently one had a seizure and the other an ischemic stroke. Children with SCA, without SCIs, and normal TCD measurements have a significantly lower rate of new neurological events when compared to those with SCIs and normal TCD measurements. Pediatric neurology assessment may assist risk stratification.