Guideline-directed care may reduce sickle cell-related cerebrovascular disease

SAN DIEGO — Guideline-directed use of hydroxyurea may reduce cerebrovascular disease among individuals with sickle cell disease, according to single-center study results.

However, further research with a larger cohort and adjustments for clinical covariates is needed to better understand the impact, researchers concluded.

“In addition to hydroxyurea’s known effects of preventing pain, preventing acute chest syndrome and prolonging life, these findings show it may prevent the very earliest manifestations of cerebrovascular disease,” Aleksandra S. Dain, MD, attending physician in the division of hematology at Children’s Hospital of Philadelphia, told Healio. “As people with sickle cell disease are living longer, it’s important to think not just about how we can help them live longer. We also need to think about things like neurocognitive development. If we can prevent abnormalities from early childhood on, that would have a tremendous impact.”

Background

Cerebrovascular disease is a common cause of morbidity among people with sickle cell disease.

More than one-third of pediatric patients experience silent cerebral infarcts by age 14 years, elevating risk for stroke and neurocognitive impairment, according to study background. One prior trial showed 2.9% of patients had abnormal cerebral blood flow as measured by transcranial Doppler (TCD) ultrasound.

Hydroxyurea protects against stroke and cerebrovascular disease progression among individuals who already have TCD-detected abnormalities.

“However, we really don’t know what hydroxyurea does for patients who are very young — like infants — who probably don’t have any brain manifestations of their sickle cell disease,” Dain said.

In September 2014, NHLBI issued guidelines recommending hydroxyurea for all patients with sickle cell disease-SS and sickle cell disease-S-beta0 starting at age 9 months.

The NHLBI guidelines led to near-universal early hydroxyurea in real-word practice; however, the effect of the recommendation on cerebral vascular disease — including silent cerebral infarcts — had not been established.

Dain and colleagues conducted a single-center retrospective study to assess whether the guidelines led to guideline-directed care resulted in greater hydroxyurea use. Researchers also examined the impact on development of cerebrovascular disease.

Methods

Dain and colleagues used an institutional registry to identify patients with sickle cell disease-SS and sickle cell disease-S-beta0 who began hematology care at CHOP between 2009 and 2023.

Exclusion criteria included known cerebrovascular disease before treatment initiation, prematurity less than 28 weeks of gestational age, non-sickle cell disease neurologic disease or hydroxyurea use prior to cohort entry.

Investigators followed patients from their first hematology visit until censoring — defined as bone marrow transplant, transition of care or loss to follow-up — or the outcome of interest.

Outcomes included hydroxyurea use and incident cerebrovascular disease, a composite outcome of first documentation of abnormal TCD, brain MRI with silent infarct or overt ischemic stroke.

Researchers also performed a survival analysis with time-varying exposure.

The analysis included 446 patients (median age at baseline, 2.4 months; 51% male), nearly all (96%) of whom had sickle cell disease-SS.

Median follow-up duration was 5 years (interquartile range, 2.3-8.7).

Results

The percentage of patients prescribed hydroxyurea increased from 29% in the pre-guideline period to 72% in the post-guideline period (HR = 3.4; 95% CI, 2.5-4.63). Median age at first hydroxyurea declined from 4 years (interquartile range, 2.5-7.7) in the pre-guideline period to 2.9 years (interquartile range, 1.1-5.8) in the post-guideline period (P = .002)

During 2,395 person-years of follow-up, researchers reported a 14.8% cumulative incidence of incident cerebrovascular disease events. The 66 events included 53 silent cerebral infarcts, 10 abnormal TCD and three overt ischemic strokes.

Analyses showed improved cerebrovascular disease-free survival in the post-guideline period compared with the pre-guideline period (HR = 0.58; 95% CI, 0.32-1.05). However, the difference did not reach statistical significance. The small study sample and an overrepresentation of patients from the post-guideline period may have contributed to this, according to researchers.

Next steps and implications

Analyses will continue with an expanded cohort, with Dain hoping to include data from 1,000 patients.

“This is still a very large effect size with a hazard ratio of 0.58, so I’m excited for what’s to come,” Dain said. “Hopefully as we analyze additional data with an expanded cohort, we will be able to show a statistically significant difference.”

That could change how clinicians counsel people with sickle cell disease — including families of younger patients — at a time when hydroxyurea uptake and adherence are lower than desired.

“Many infants may have high hemoglobin-S when they are younger than 1 year of age,” Dain told Healio. “They may not have manifestations of sickle cell disease, so parents may want to wait to start hydroxyurea until they see their child developing sickle cell disease symptoms. If we are able to show starting hydroxyurea earlier will prevent problems in the brain that are potentially irreversible, that might help us in our conversations about why to start them on a daily medication even when they are doing well.”

Even with FDA approval of two gene therapies for sickle cell disease, hydroxyurea will continue to have a role in treatment, Dain said.

“it is very exciting to see so many advances that hopefully will improve the duration and quality of life for these patients,” Dain told Healio. “We have more curative therapies for sickle cell disease, but we certainly will not eradicate it in the next few years. We know [the newly approved gene therapies] will not be able to reach many patients, so it’s very important to keep studying other treatments. Even when we’re hearing about a potential cure, research like ours is still very relevant.”