Low- Versus Moderate-Dose Hydroxyurea for Secondary Stroke Prevention in Children with Sickle Cell Disease in Sub-Saharan Africa: Final Results of a Randomized Controlled Trial, Sprint Trial

Abstract

Introduction Strokes are a preventable cause of neurological morbidity and premature death, particularly in children with sickle cell anemia (SCA) living in low-resource countries. If untreated, 50% of children with SCA their first overt ischemic stroke will have a recurrent stroke within two years of the event. In high-income countries, ASH 2020 guidelines recommend indefinite regular blood transfusion therapy for secondary stroke prevention (Blood Adv. 2020). Unfortunately, regular blood transfusion therapy is not a feasible option for children with SCA in sub-Saharan Africa due to the high cost of monthly blood transfusion, limited blood supply, and unsafe transfusion practices. Also, children who receive regular blood transfusions will ultimately require daily iron chelation at a cost that is prohibitive to most families in low-income settings. One randomized controlled trial provided evidence that HU therapy may be an effective therapy for secondary prevention of strokes when compared to no therapy (Blood. 2012;119(17):3925-3932). In the SWiTCH trial, the incidence rate of stroke recurrence in the group randomly allocated to receive maximum tolerated dose HU therapy was significantly higher than the group randomly assigned to receive blood transfusion therapy (5.6 and 0 events per 100 person-years, respectively, but considerably lower when compared to children not treated with any treatment, approximately 28 events per 100 person-years (Niger Postgrad Med J. 2013;20(3):181-187). Given the practical limitations for regular blood transfusion therapy, we tested the hypothesis that for secondary stroke prevention among children with SCA and acute overt ischemic stroke, fixed moderated dose HU therapy (~20 mg/kg/day) results in 80% relative risk reduction when compared to fixed low-dose HU therapy (10 mg/kg/day) in a randomized controlled trial (SPRINT Trial; NCT02675790). Methodology In phase III controlled trial, partially blind d controlled trial, we randomly assigned children 1 - 16 years of age with SCA and a new-onset of ischemic stroke (within 1 month) to receive fixed moderate-dose HU therapy at 20 mg/kg/day or fixed-low dose HU therapy at 10 mg/kg/day) with a monthly follow-up for at least 36 months. The primary endpoint was a recurrence of overt stroke or transient ischemic attack. Myelosuppression was assessed with monthly CBCs. Adherence to hydroxyurea was based on an increase in MCV from baseline and monthly pill count return, as a percent of dispensed pills. Results A total of 101 children with SCA were randomly assigned to fixed low- (~10 mg/kg/day) or moderate- (~20 mg/kg/day) dose hydroxyurea. The mean age was 6.6 years; 55.4% were males, and the median follow up was 1.6 years (IQR 1.0 - 2.3). The DSMB stopped the trial early due to the futility of the primary endpoint. In the fixed low- and moderate-dose groups, the incidence rates of recurrent strokes per 100 person-years were 7.1 and 6.0, respectively, incidence rate ratio of 0.85 (95% CI: 0.20 - 3.34), p=0.999. The incidence rates of mortality per 100 person-years in the fixed low dose and moderate- fixed-dose groups were 2.38 and 3.63, respectively, with an incidence rate ratio of 1.53 (95% CI: 0.18 - 18.30), p=0.98. No participant had hydroxyurea therapy stopped because of myelosuppression. As a measure of adherence, MCV from baseline to endpoint increased 6.2 fl and 13.3 fl in the fixed low- and moderate-dose groups, respectively, p=0.025; returned pills during the trial were 3.3% and 3.5% in the fixed low- and moderate-dose groups, respectively, p= 0.76. Conclusion For secondary stroke prevention, in a randomized controlled trial in children with SCA and new onset of ischemic strokes, fixed low-dose, when compared to fixed moderate-dose hydroxyurea therapy, demonstrated no difference in the incidence rate of stroke recurrence. Fixed low-dose hydroxyurea for secondary prevention of strokes in Nigeria provided similar stroke recurrence rate, when compared to the SWiTCH Trial (Blood. 2012;119(17):3925-3932) with the maximum tolerated dose of hydroxyurea of 7.0 and 5.7 events per 100 person-years, respectively. For secondary stroke prevention, in low-income settings without access to indefinite regular blood transfusion therapy, fixed low-dose hydroxyurea of at least 10 mg/kg/day with biannual CBC is a new evidence-based strategy to prevent strokes and minimize unnecessary laboratory testing. Disclosures DeBaun: Global Blood Therapeutics (GBT): Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: fixed low and moderate dose hydroxyurea for primary stroke prevention in sickle cell

Evidence-based interventions for reducing sickle cell disease-associated morbidity and mortality in sub-Saharan Africa: A scoping review

“…We excluded 129 articles for the following reasons: no empirical evaluation of the effectiveness of the intervention ( n = 42), non-SSA countries ( n = 40), non-English language studies ( n = 12), non-evidenced-based studies ( n = 10), study protocols ( n = 5), abstracts ( n = 5) and adults population only ( n = 15). Finally, 36 articles were included in this study 7 , 27 – 60 – Figure 1 .…”

“…62,67 Our study provides evidence that hydroxyurea doses as low as 10 mg/kg/day significantly reduces stroke incidence and can be used to prevent stroke recurrence in children with SCD where blood transfusion concerns exist. 54,55,59 Unfortunately, HU is expensive and inaccessible in most countries in Africa. 68 Our review suggests pharmacy compounding of the medicine at the primary care pharmacy could alleviate the unavailability and unaffordability of HU -a routine medication for a life-long illness.…”

“…Hydroxyurea (HU) therapy effectively reduced SCD-related adverse events among children, especially stroke incidence and VOC. 29,31,[33][34][35][54][55][56][57][58][59][60][61] In addition, HU therapy showed favourable haematological indices and led to a decline in mortality among children who received it. 61 Furthermore, HU therapy showed low risk of haematological harm.…”

“…31 Studies by Abdullahi et al further posited that low-dose hydroxyurea therapy also reduces both stroke incidence and recurrence and has no significant difference when compared to moderate dose. 54,55,59 NBS, comprehensive primary health screening and economic evaluation Moreover, NBS and comprehensive care was associated with reduced mortality. 62 Furthermore, Kuznick et al demonstrated that the average cost per disability-adjusted-lifeyears (DALY) was lower than the gross domestic product (GDP) in 34 SSA countries.…”

American Society of Hematology 2020 Podcast Collection: Sickle Cell Anaemia

“…In this regard, it is interesting to highlight the contribution of two posters, both by Abdullahi and other colleagues, on the use of hydroxyurea in children in Nigeria both in low and moderate dose... in primary prevention and secondary prevention of stroke [5,6]. And they report that the use of hydroxyurea is effective in lowering the incidence of stroke.…”