Sickle cell care and implementation science

In this issue of Blood Advances, Nieves et al¹ present findings from SACRED (Stroke Avoidance for Children in República Dominicana; ClinicalTrials.gov identifier: NCT02769845), a prospective single-arm trial evaluating cerebrovascular disease and stroke prevention among children with sickle cell anemia (SCA). Their results highlight the significant burden of cerebrovascular disease in Latin American children with SCA and demonstrate the efficacy of hydroxyurea in reducing conditional transcranial Doppler (TCD) velocities. The study also exemplifies the success of North-South partnerships in capacity building to address critical health care gaps.

Cerebrovascular disease is a leading cause of morbidity and mortality in individuals with SCA. The landmark Stroke Prevention Trial in Sickle Cell Anemia trial (1998) established that TCD screening is essential for primary stroke prevention, demonstrating a 92% reduction in overt strokes through chronic blood transfusion for children with elevated TCD velocities (>200 cm/sec).² The TCD With Transfusions Changing to Hydroxyurea trial (2016) subsequently showed that transitioning to daily oral hydroxyurea after a year of transfusions was equally effective in preventing strokes,³ offering families an alternative to the risks of chronic transfusion, including iron overload, infections, and central line complications.

Despite these advances, TCD screening and stroke prevention remain underutilized, even in high-income countries.⁴ Challenges include low provider awareness, difficulty communicating benefits to families, logistical barriers, and care coordination issues.⁵ The situation is more dire in low- and middle-income countries (LMICs), in which limited funding, resources, and trained personnel exacerbate the lack of access to evidence-based practices.

The SACRED trial underscores this disparity while providing actionable insights. Among hydroxyurea-naïve children, 22% had conditional TCD velocities (170-199 cm/sec), and TCD velocities decreased by an average of 20 cm/sec after 6 months of treatment.¹ This finding builds on evidence supporting the benefits of hydroxyurea for children with elevated TCD velocities and those with conditional velocities. Previous studies have shown conversion rates of 23% (from conditional to elevated TCD velocities) in an untreated North American cohort⁶ and 47% in a halted trial involving the United States, Jamaica, and Brazil,⁷ underscoring the critical need for primary stroke prevention.

Although the efficacy of hydroxyurea is well established, the SACRED trial's broader impact lies in its demonstration of effective cross-regional collaboration. A high-income institution funded salaries for local staff, provided hydroxyurea, and trained 10 local medical graduates in comprehensive sickle cell care and TCD screening. This effort significantly bolstered the capacity in the Dominican Republic, benefiting local children with SCA.

However, SACRED represents only a foundational step. Expanding clinical trials for SCA in LMICs is essential for advancing the science and improving global care. Partnerships with high-income collaborators are vital for conducting complex, resource-intensive studies, such as those investigating genetic modifiers or novel therapies in larger and more diverse populations.

Addressing the translational gap through implementation science is equally critical. Delivering evidence-based care to the estimated 7 to 8 million individuals with SCA, most of whom are in LMICs, remains a significant challenge.⁸ Future research must focus on identifying and overcoming barriers to care delivery by applying implementation science principles to design sustainable and scalable solutions. Open-access dissemination of training materials, documentation of successful policy advocacy, and lessons learned from partnerships such as SACRED and similar studies conducted in LMICs^9,10 can help reduce barriers to future initiatives. Engaging governments to support access to essential medicines, including hydroxyurea, will be pivotal in improving the quality of life for individuals living with sickle cell disease.

Finally, the sustainability of interventions in LMICs, including access to medications, TCD technology, and training programs, must be prioritized. Designing evidence-based, locally adaptable interventions that ensure both dissemination and sustainability is critical. Governments, as key stakeholders, must be involved early for the success of these interventions. Given our role as a global health community, we have a responsibility to drive these efforts and contribute to lasting solutions.

Conflict-of-interest disclosure: The authors declare no competing financial interests.