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1129 Impact of the 2014 NHLBI Hydroxyurea Guidelines on Cerebrovascular Events in Sickle Cell Disease

Program: Oral and Poster Abstracts
Session: 114. Sickle cell Disease, Sickle Cell Trait and Other Hemoglobinopathies, Excluding Thalassemias: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Sickle Cell Disease, epidemiology, Non-Biological therapies, Clinical Research, health outcomes research, Hemoglobinopathies, pediatric, Diseases, Therapies, real-world evidence, young adult , Human, Study Population
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Aleksandra S Dain, MD1, Yimei Li, PhD2,3*, Sahal Master, MPH4*, Shri Karthikeyan1*, Leslie Raffini, MD1,5, Kelly D. Getz, PhD3,5* and Janet L. Kwiatkowski, MD, MSCE1,5

1Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
2Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
3Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
4Children's Hospital of Philadelphia, Philadelphia, PA
5Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA

Background: Cerebrovascular disease (CVD) is a common cause of morbidity in patients with sickle cell disease (SCD). An estimated 37% of children with SCD have silent cerebral infarcts (SCI) by age 14, leading to increased stroke risk and neurocognitive impairment. In the DISPLACE trial (Kanter et al, 2021), 2.9% of patients had abnormal cerebral blood flow as measured on transcranial Doppler ultrasound (TCD). The 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend hydroxyurea (HU) for all patients with SCD-SS and SCD-Sβ0 starting at age 9 months, a significant shift from prior practice. In patients who have already developed TCD abnormalities, HU is protective against stroke and CVD progression. The real-world impact of universal early HU on the development of CVD, particularly on SCI, is not well defined. We hypothesize that the 2014 guidelines led to an increase in HU use and a reduction in the initial development of CVD.

Methods: We performed a single center, retrospective cohort study investigating trends in HU prescriptions and CVD before and after the publication of the 2014 NHLBI guidelines. Patients with SCD-SS and SCD-Sβ0 who initiated hematology care at the Children’s Hospital of Philadelphia between 2009 and 2023 were identified using an institutional registry. Incident HU was defined as the first outpatient HU prescription in patients with a minimum of two orders. Incident CVD was defined as a composite outcome consisting of the first documentation of: abnormal TCD, brain magnetic resonance imaging (MRI) with silent infarct, or overt ischemic stroke. Patients with known CVD before care initiation, prematurity < 28 weeks gestational age, or non-SCD neurologic disease were excluded. For time-to-HU analysis, patients with HU prescriptions before enrollment at our center also were excluded. Patients were followed from their first hematology visit until the outcome of interest or censoring. Censoring criteria included loss to follow up, transition of care, or bone marrow transplant. All brain MRI and TCD reports were manually reviewed. Ages at HU initiation pre- and post- guideline were compared using the Wilcoxon rank-sum test. Times to 1) HU and 2) CVD were summarized using Kaplan-Meier estimators, with the guideline publication date of September 1, 2014 incorporated as a time-varying exposure. Unadjusted associations were calculated using a Cox proportional hazard regression.

Results: A total of 446 patients met inclusion criteria and contributed to analyses. Median age at baseline was 2.4 months, and median duration of follow-up was 5.0 years (IQR: 2.3-8.7). Most patients (430/446, 96%) had SCD SS, and 51% were male.

The proportion of patients ever prescribed HU increased with time (Fig 1), with a peak prevalence of 82% in 2022. Of 385 patients not exposed to HU at baseline, 277 (72%) were prescribed HU during study follow-up. Incident HU prescriptions significantly increased after NHLBI guideline publication (HR 3.40, CI: 2.50 to 4.63, p < 0.001) with an older age at HU initiation before (median 4.0 y, IQR 2.5-7.7) than after (median 2.9 y, IQR 1.1-5.8) publication of the guideline (p = 0.002).

Over a total of 2,395 person-years of follow-up, 66 incident CVD outcomes occurred in this longitudinal cohort, corresponding to a cumulative incidence of 14.8%. These events included 53 SCI, 10 abnormal TCD, and 3 overt ischemic strokes. CVD outcome occurrence was lower after guideline publication than before (HR 0.58, CI: 0.32-1.05), though the association did not reach statistical significance (p = 0.071, Fig. 2).

Discussion: After the NHLBI guideline publication, HU prescriptions increased significantly at our center. Our data suggest that the 2014 guideline-directed care may have led to a greater than 40% reduction in CVD, though this reduction was not statistically significant in our small sample size. Despite guideline recommendations and strong evidence for the role of HU in reducing pain and acute chest syndrome, few patients across the United States are prescribed HU therapy. Adherence and care continuity challenges further lessen the number of patients benefitting from HU. Evidence of efficacy of early and universal HU in CVD prevention would strengthen guideline recommendations and improve clinical care in patients with SCD. Ongoing analysis includes an expanded cohort and adjustment for clinical covariates to better examine the direct impact of early HU on CVD.

Disclosures: Raffini: Genetech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Boeringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Kwiatkowski: BioMarin Pharmaceutical: Consultancy; Forma Therapeutics: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Vertex Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Consultancy, Research Funding; Chiesi Farmaceutici: Consultancy; Regeneron Pharmaceuticals: Consultancy; Bluebird Bio: Research Funding; Editas Medicine: Research Funding; Pfizer: Research Funding.

*signifies non-member of ASH