Stroke Avoidance for Children in REpública Dominicana (SACRED): Protocol for a Prospective Study of Stroke Risk and Hydroxyurea Treatment in Sickle Cell Anemia

Abstract

BackgroundIn the Dominican Republic, where the burden of sickle cell anemia (SCA) is high, many children lack access to routine screening and preventative care. Children with SCA are at risk for stroke, an event that leads to significant morbidity and mortality. In the United States, screening via transcranial Doppler (TCD) identifies children with SCA at highest stroke risk, allowing early intervention with blood transfusions. The need for indefinite transfusions for primary stroke prevention limits their practicality in limited-resource countries. Hydroxyurea has been shown to lower TCD velocities and to prevent conversion from conditional (170 to 199 cm/sec) to abnormal (greater than or equal to 200 cm/sec) velocities. In resource-limited settings, implementation of a TCD screening program, coupled with hydroxyurea therapy, could reduce the burden of SCA and stroke.ObjectiveThe aims of the Stroke Avoidance for Children in REpública Dominicana (SACRED) trial are (1) to screen children with SCA for stroke risk using TCD and to determine the prevalence of elevated velocities in a cross-sectional sample; (2) to identify clinical and laboratory correlates of elevated velocities; and (3) to obtain longitudinal data on the natural history of TCD velocities and to measure therapeutic effects of hydroxyurea.MethodsThis prospective trial, designed and conducted by Cincinnati Children’s Hospital Medical Center (CCHMC) and Hospital Infantil Robert Reid Cabral (HIRRC) with Centro de Obstetricia y Ginecología, includes a baseline cross-sectional epidemiological survey of the distribution of TCD velocities across a large cohort of children with SCA in the Dominican Republic. Children with conditional velocities are eligible to begin protocol-directed hydroxyurea if laboratory criteria are met. The treatment schedule begins with a fixed-dose of approximately 20 mg/kg/day for 6 months, after which it escalates to maximum tolerated dose (MTD). All participants undergo longitudinal annual TCD evaluation, while those on hydroxyurea have semi-annual evaluations during the 3-year study period. Data are collected using an Internet-based Research Electronic Data Capture (REDCap) system with forms translated into Spanish; both remote and on-site monitoring are used.ResultsTo date, 122 children with SCA have enrolled in SACRED including 85 (69.7%, 85/122) with normal, 29 (23.8%, 29/122) with conditional, 5 (4.1%, 5/122) with abnormal, and 3 (2.5%, 3/122) with inadequate TCD velocities. Of the 29 children with conditional TCD velocities, 17 (59%, 17/29) have initiated hydroxyurea per protocol, with plans for escalation to MTD.ConclusionsThe SACRED trial will provide novel epidemiologic data about the prevalence of children with SCA and increased stroke risk in the Dominican Republic. The study also includes an investigation of the impact of hydroxyurea at MTD on elevated TCD velocities, as well as clinical and laboratory parameters. The design and implementation of SACRED reflect a successful international institutional partnership, one...

Current and Future Therapeutics for Treating Patients with Sickle Cell Disease

“…HU's effectiveness will be determined by comparing the baseline and potentially reduced TCD velocities. Preliminary study results from the SACRED study identified a higher prevalence of conditional TCD and lower abnormal TCD, which the investigators suggest could be attributed to differences in baseline status, prior treatment effects, or genetics [27]. The Stroke in Young Adults with Sickle Cell Anemia (SPIYA) study is currently investigating HU's effectiveness in preventing stroke in Nigerian adolescents and young adults with sickle cell anemia.…”

Transcranial Doppler Ultrasonography-Related Research in the Caribbean Region

“…The trial underscored the significance of implementing a TCD screening program in conjunction with hydroxyurea therapy to decrease the impact of SCD and strokes in resource-constrained settings [ 13 , 14 ]. The study was conducted in partnership with the Cincinnati Children's Hospital Medical Center, which also collaborated with researchers from the Dominican Republic on a similar clinical trial, Stroke Avoidance for Children in REpública Dominicana (SACRED), on the efficacy of hydroxyurea in reducing TCD velocities [ 15 ]. Hematopoietic SCT offers the potential for stopping transfusion therapy, but its benefits have not been established.…”