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

Abstract

We tested the hypothesis that fixed oral moderate-dose hydroxyurea (20 mg/kg/day) for initial treatment of secondary stroke prevention results in an 80% relative risk reduction of stroke or death when compared to fixed oral low-dose hydroxyurea (10 mg/kg/day) in a phase III, double-blind, parallel-group, randomized controlled trial in children with sickle cell anemia (SCA) living in Nigeria. 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 versus 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% CI 0.32 - 3.00), P=0.97. The trial was stopped early due 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=0.74. As a measure of adherence to the oral hydroxyurea therapy, the median percent of returned pills were 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. The ID number assigned to the study is NCT02675790

Hydroxyurea for children with sickle cell disease in sub‐Saharan Africa: A summary of the evidence, opportunities, and challenges

“…Again, similar to the SPIN trial, no participant stopped treatment for myelosuppression in either group despite monthly laboratory monitoring for a minimum follow‐up of 3 years, further supporting the limited need for frequent laboratory monitoring with either low or moderate hydroxyurea dosing strategies. In a similar study design investigating the role of hydroxyurea for secondary stroke prevention, the phase III SPRINT trial found similar efficacy in secondary stroke prevention for fixed low‐dose hydroxyurea (10 mg/kg/day) compared to fixed moderate dose (20 mg/kg/day) in 101 Nigerian children with SCA who had previously suffered a stroke 26 . As a direct outcome of these studies, three states in Nigeria (Kano, Kaduna, Katsina) have acted to ensure government purchase of hydroxyurea to support local stroke prevention programming 54 .…”

“…If health care providers cannot perform a CBC, there is the belief that hydroxyurea cannot be administered at all due to safety concerns. We have seen from the studies discussed above that hematologic toxicity is rare (<5% of CBCs with hematologic toxicity) and often not associated with any clinical signs or symptoms 26,27,31,49,50 . The requirement for laboratory monitoring is still not clear, but it appears quite safe to perform laboratory monitoring only every 3–6 months, though there is a question as to whether that is even necessary.…”

“…Reduction in inflammatory markers (white blood cell count, platelet count) Brain Improved neurocognitive function 22,23 Reduced transcranial Doppler (TCD) velocities 24,25 Reduction in stroke and stroke risk 26,27 Heart Reduction in myocardial fibrosis 28 Reverse cardiac remodeling and improvement in cardiomyopathy 29 Lungs Improved pulmonary hypertension 30 Reduced acute chest syndrome 11,19,31 Kidneys Improved urinary concentrating ability and less renal enlargement 32 Reduced proteinuria 33 Immune system Reduction in malaria for children in Africa 34 Improved splenic function 17 Mortality Reduced mortality for adults in the MSH Study (US) 14 Reduced mortality for children in Brazil 35 Reduced mortality for children in Belguim 36 Reduced mortality for children in sub-Saharan Africa…”

“…In a similar study design investigating the role of hydroxyurea for secondary stroke prevention, the phase III SPRINT trial found similar efficacy in secondary stroke prevention for fixed low-dose hydroxyurea (10 mg/kg/day) compared to fixed moderate dose (20 mg/kg/day) in 101 Nigerian children with SCA who had previously suffered a stroke. 26 As a direct outcome of these studies, three states in Nigeria (Kano, Kaduna, Katsina) have acted to ensure government purchase of hydroxyurea to support local stroke prevention programming. 54 .…”

Stroke in the young

“…Not all patients with sickle cell and stroke have arteriopathy and, consequently, providers should perform a complete stroke workup to look for other factors that may increase the risk of stroke in these children and young adults [55]. Although chronic transfusion therapy remains an important preventive strategy for children with sickle cell and stroke or with arteriopathy, hydroxyurea is a reasonable lower cost alternative [11]. There are ongoing gene therapy trials for sickle cell disease with initially promising results in eliminating vaso-occlusive crises, though further research is needed to determine optimum timing and how this influences stroke risk [74,75 ▪ ].…”