Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial

Abdullahi, Shehu U.; Jibir, Binta W.; Bello‐Manga, Halima; Gambo, Safiya; Inuwa, Hauwa; Tijjani, Aliyu; Idris, Nura; Galadanci, Aisha Amal; Hikima, Mustapha Shuaibu; Galadanci, Najibah A.; Borodo, Awwal Musa; Tabari, AM; Haliru, Lawal; Suleiman, Aisha; Ibrahim, Jamila; Greene, Brittany Covert; Ghafuri, Djamila Labib; Rodeghier, Mark; Slaughter, James C.; Kirkham, Fenella J.; Neville, Kathleen; Kassim, Adetola A.; Trevathan, Edwin; Jordan, Lori C.; Aliyu, Muktar H.; DeBaun, Michael R.

doi:10.1016/s2352-3026(21)00368-9

Cited by 46 publications

(45 citation statements)

References 32 publications

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“…Another consideration in HU primary prophylaxis is dosage. HU dosage in SCD treatment has been recently explored in Abdullahi’s [ 19 ] clinical trial conducted in Nigeria, where they demonstrated that low-dose (10 mg/kg/day) and moderate-dose (20 mg/kg/day) HU treatment resulted in comparable stroke risk, but the moderate-dose group had decreased all-cause hospitalizations. Our study did not assess the effects of HU dosage on MCA TAMX scores.…”

Section: Discussionmentioning

confidence: 99%

“…A recently published randomized clinical trial compared the efficacy of moderate-dose (20 mg/kg/day) and low-dose (10 mg/kg/day) HU in primary stroke prevention among children with SCD [ 19 ]. Conducted in Nigeria, where regular blood transfusions cannot be feasibly done, this study demonstrated that stroke risk between moderate-dose and low-dose HU treatment was not significantly different.…”

Section: Introductionmentioning

confidence: 99%

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Prophylactic Hydroxyurea Treatment Is Associated with Improved Cerebral Hemodynamics as a Surrogate Marker of Stroke Risk in Sickle Cell Disease: A Retrospective Comparative Analysis

Peine

Callaghan

et al. 2022

JCM

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Sickle cell disease (SCD) increases the incidence of childhood stroke eighty-fold. Stroke risk can be estimated by measurement of the blood velocity through the middle cerebral artery (MCA) using transcranial doppler ultrasound (TCD). A high MCA blood velocity indicates increased stroke risk due to cerebral vasculopathy, and first-line treatment to prevent primary or recurrent strokes in high-risk children with SCD has classically been chronic blood transfusions. Research has more recently shown that many of these patients may safely transition from transfusions to oral hydroxyurea (HU) treatment while maintaining a decreased risk of stroke. However, the effect on stroke risk of truly prophylactic HU treatment beginning in infancy, prior to the onset of cerebral vasculopathy, is less well understood. Our retrospective study aimed to document the long-term effects of HU treatment compared with no HU treatment in children with SCD, using TCD measurements as our primary outcome and a surrogate marker of stroke risk. Our results showed that when accounting for age-related variability and duration of treatment, prophylactic HU treatment was independently associated with lower TCD MCA velocities compared with no HU treatment, providing further evidence supporting its early initiation for patients with SCD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prophylactic Hydroxyurea Treatment Is Associated with Improved Cerebral Hemodynamics as a Surrogate Marker of Stroke Risk in Sickle Cell Disease: A Retrospective Comparative Analysis

Peine

Callaghan

et al. 2022

JCM

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“…A systematic review identified three RCTs that demonstrated the efficacy of transfusion in children with SCA and abnormal TCD velocities 30–33. One RCT of hydroxyurea therapy in children with SCA in Nigeria demonstrated efficacy of both low-dose and moderate-dose hydroxyurea therapy in lowering stroke incidence 34…”

Section: Early Diagnosis and Managementmentioning

confidence: 99%

Sickle cell disease in children: an update of the evidence in low- and middle-income settings

Odame

2022

Arch Dis Child

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Sickle cell disease (SCD), one of the most common monogenetic diseases in the world, is associated with multisystemic complications that begin in childhood. Most of the babies homozygous for the sickle haemoglobin gene are born in sub-Saharan Africa. Over the years, progress has been made with early diagnosis through newborn screening, penicillin prophylaxis, pneumococcal immunisation, transcranial Doppler (TCD) screening, hydroxyurea therapy and chronic blood transfusions with remarkably improved survival and quality of life of children with SCD. However, wide disparities in outcomes exist between high-income countries (HICs) where over 90% survive to adulthood, and low-income and middle-income countries (LMICs) where less than half achieve that milestone. Even in HICs, racial inequities pose barriers to accessing specialised care and receiving treatment for acute pain episodes. Better understanding of SCD pathophysiology is being exploited to develop new disease-modifying drugs and gene therapy approaches to further improve outcomes. Bone marrow transplantation is established as a curative treatment for SCD, but it is largely unavailable in LMICs. To bridge the disparity and inequity gaps, innovative approaches are needed in LMICs. Validated and more affordable, easy-to-use point-of-care tests offer opportunities to link early diagnosis with immunisation programmes and healthcare encounters. Widespread use of hydroxyurea therapy—a relatively affordable and effective disease-modifying drug—in LMICs would help improve survival and quality of life. Integration of SCD treatment into primary care linked to district level/provincial hospitals that are supported with evidence-based guidelines will help extend needed interventions to many more patients living in LMICs.

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“…Further, a multicenter trial (SPRING [Primary Stroke Prevention in Nigeria]: NCT02560935) was completed in 3 centers in 2 states, Kano and Kaduna in northern Nigeria, to answer a critical question on the optimal dose of HU (20 mg/kg vs. 10 mg/kg) for primary stroke prevention. Results demonstrated that in low-income settings without access to indefinite regular blood transfusion therapy, fixed low-dose HU of at least 10 mg/kg/day is effective for primary stroke prevention [ 10 ]. More recently, the 2020 American Society of Hematology guidelines on central nervous system complications in sickle cell disease (SCD) recommend that children with SCD and abnormal TCD measurements living in low- and middle-income countries where regular blood transfusions are not readily available receive at least moderate dose (20 mg/kg/day) of HU [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Primary Prevention of Stroke in Children With Sickle Cell Anemia in Nigeria: Protocol for a Mixed Methods Implementation Study in a Community Hospital

Bello‐Manga¹,

Haliru²,

Ahmed³

et al. 2022

JMIR Res Protoc

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Background In Nigeria, approximately 150,000 children with sickle cell anemia (SCA) are born annually, accounting for more than half of all SCA births worldwide. Without intervention, about 11% of children with SCA will develop a stroke before their 20th birthday. Evidence-based practices for primary stroke prevention include screening for abnormal transcranial Doppler (TCD) measurements coupled with regular blood transfusion therapy for at least one year, followed by hydroxyurea (HU) therapy indefinitely. In high-resource countries, this strategy contributes to a 92% decrease in stroke incidence rates. In 2016, as part of a capacity building objective of the Stroke Prevention Trial in Nigeria (1R01NS094041: SPRING), TCD screening was adopted as standard care at Barau Dikko Teaching Hospital in Kaduna. However, with just 70 radiologists and only 3 certified in TCD screening in the state, just 5.49% (1101/20,040) of eligible children with SCA were screened. Thus, there is a need to explore alternate implementation strategies to ensure children with SCA receive standard care TCD screening to decrease stroke incidence. Objective This protocol describes a study to create a stroke prevention program in a community hospital in Kaduna through task shifting TCD screening to nurses and training medical officers to initiate and monitor HU utilization for stroke prevention. Methods This study will be conducted at 2 sites (teaching hospital and community hospital) over a period of 3 years (November 2020 to November 2023), in 3 phases using both quasi-experimental and effectiveness-implementation study designs. In the needs assessment phase, focus groups and structured interviews will be conducted with health care providers and hospital administrators to identify barriers and facilitators to evidence-based stroke prevention practices. Results from the needs assessment will inform intervention strategies and a process plan to fit the needs of the community hospital. In the capacity building phase, nurses and medical officers at the community hospital will be trained on TCD screening and HU initiation and monitoring. In the implementation phase, children with SCA aged 2-16 years will be recruited into a nonrandomized single-arm prospective trial to determine the feasibility of initiating a task-shifted stroke prevention program by recording recruitment, retention, and adherence rates. The Reach and Effectiveness components of the RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) framework will be used to evaluate implementation outcomes between the community and teaching hospitals. Results The needs assessment phase of the study was completed in February 2021. Manuscript on findings is currently in preparation. Capacity building is ongoing with TCD training and sickle cell disease and stroke education sessions for nurses and doctors in the community hospital. Recruitment for the implementation trial is expected to commence in July 2022. Conclusions This study proposes a structured, theory-driven approach to create a stroke prevention program in a community hospital in Kaduna, Nigeria, to decrease stroke incidence among children with SCA. Results will provide preliminary data for a definitive randomized clinical trial in implementation science. International Registered Report Identifier (IRRID) PRR1-10.2196/37927

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Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial

Cited by 46 publications

References 32 publications

Prophylactic Hydroxyurea Treatment Is Associated with Improved Cerebral Hemodynamics as a Surrogate Marker of Stroke Risk in Sickle Cell Disease: A Retrospective Comparative Analysis

Prophylactic Hydroxyurea Treatment Is Associated with Improved Cerebral Hemodynamics as a Surrogate Marker of Stroke Risk in Sickle Cell Disease: A Retrospective Comparative Analysis

Sickle cell disease in children: an update of the evidence in low- and middle-income settings

Primary Prevention of Stroke in Children With Sickle Cell Anemia in Nigeria: Protocol for a Mixed Methods Implementation Study in a Community Hospital

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