Hydroxyurea Effectiveness in Children and Adolescents with Sickle Cell Anemia: A Large Retrospective, Population-Based Cohort Study
Authors: Quarmyne Maa-Ohui , Dong Wei , Barry Vaughn , Theodore Rodney , Adisa Olufolake A. , Buchanan Iris , Bost James , Brown Robert Clark , Joiner Clinton H. , Lane Peter A. 
Published: October 2019

Abstract
Background: The clinical efficacy of hydroxyurea (HU) in patients with sickle cell anemia (SCA) is well established. In clinical trials, HU has been demonstrated to alter the clinical course of SCA; HU decreases rates of pain, dactylitis, acute chest syndrome (ACS), transfusions, hospitalizations and improves hemoglobin levels. Other studies have shown that HU improves quality of life and decreases mortality. While evidence of efficacy has been well demonstrated, published data about clinical effectiveness is limited. Additionally, attempts to compare outcomes of patients taking HU to those not taking HU have been limited by the inherent selection bias for greater disease severity in patients on HU. We sought to examine the clinical effectiveness of HU in the large population of patients with sickle cell disease (SCD) at Children's Healthcare of Atlanta (CHOA). The program provides comprehensive care to >1,700 active patients; because they include about 95% of all children and adolescents with SCD in the greater Atlanta Metropolitan Area, the program provides a population-based sample. Currently 57% of the 922 children ≥ 1 yr of age with SCA (SS and Sβ0 thalassemia) who are not on chronic transfusions are receiving HU.
Methods: Using a retrospective cohort, pre-post treatment study design to control for disease severity selection bias we evaluated the clinical effectiveness of HU in patients with SCA who received care at CHOA and who first initiated HU in 2009-2011. Children on chronic transfusions, or children with inadequate follow up data and/or who ever took HU in the 3 years prior were excluded. Clinical guidelines for dosing HU have been standardized locally and recommend initial dosage of 20mg/kg/day, followed by dose escalation every 2 months to maximum tolerated dose. For each patient, healthcare utilization, laboratory values and clinical outcomes for the 2-year period prior to HU initiation were compared to those for two years after initiation. Medians were compared using the Wilcoxon Signed Rank test and means using T test. Rate ratios were computed using unadjusted Poisson regression. Interactions testing whether the effect of HU varied by age, sex, or insurance status, were assessed using multivariable Poisson regression.
Results: Of 211 children with SCA who initiated HU in 2009-2011, 134 met eligibility criteria. After initiation of HU, the rate of hospitalization was 0.53 the rate before HU, a 47% reduction (Table). The number of inpatient days, emergency room (ER) visits, pain encounters, episodes of acute chest syndrome (ACS), and transfusions were also significantly reduced (Table). The hemoglobin level (mean +/- SD) pre- and post-HU initiation was 7.3+/-2.7 g /dl and 8.1+/- 2.9 respectively; an increase of 0.8+/-1.1, p<0.0001. Similarly, pre-HU mean corpuscular volume increased from 82.9+/-7.5 fl pre-HU to 95.7+/-10.7 post-HU; an increase of 12.8+/-7.2, p <0.0001. There was a statistically significant interaction between the effect of HU and age of initiation of the drug on hospitalization rates; patients < 7 years of age had a greater reduction in hospitalizations than older children (58% vs 33%, p=0.03). The effect of HU on hospitalizations did not vary by sex or insurance type.
Table 1. Effect of HU initiation on clinical outcomes using Poisson Regression Rate Ratio (Confidence Limits) P Value Hospitalizations 0.53 (0.43 - 0.66) <0.0001 Inpatient Days 0.50 (0.40 - 0.63) <0.0001 ER visits 0.57 (0.49 - 0.67) <0.0001 Pain Encounters 0.64 (0.51 - 0.81) 0.0001 ACS 0.57 (0.39 - 0.83) 0.0036 Blood Exposure 0.43 (0.29 - 0.64) <0.0001
Conclusions: HU is clinically effective in children and adolescents with SCA. HU decreased hospitalizations, ER visits, pain encounters, ACS, use of transfusions and improved hemoglobin levels. HU effectiveness was similar across gender, insurance types and age, although there was a slightly greater reduction in hospitalizations in younger patients. These results are important as they parallel results obtained from HU efficacy studies, thus demonstrating that in 'real life' settings, even without the additional monitoring and adherence incentives of clinical trials, HU improves short-term outcomes in pediatric SCA.

Disclosures
Off Label Use: Hydroxyurea use as disease modifying therapy in pediatric patients with sickle cell disease.