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Hydroxyurea: Pediatric Use in Sickle Cell Anemia

Hydroxyurea: Pediatric Use in Sickle Cell Anemia


This retrospective cohort study aimed to investigate the relationship between adherence to hydroxyurea treatment and clinical outcomes in children and adolescents with sickle cell anemia (SCA). The study utilized Medicaid data spanning from 2005 to 2012 across several U.S. states, focusing on children aged 1 to 17 years with SCA who were enrolled in Medicaid for a minimum of three years.

Hydroxyurea is known to reduce the incidence of vaso-occlusive pain crises (VOC) and acute chest syndrome (ACS) in individuals with SCA. To assess adherence, the researchers calculated the medication possession ratio (MPR), representing the proportion of days covered by hydroxyurea. Clinical outcomes were evaluated six months after the initiation of hydroxyurea and throughout the study period, specifically looking at the number of VOC-related inpatient admissions, emergency department visits, and encounters for ACS.

The study included 515 children who had initiated hydroxyurea treatment. The median MPR was found to be 0.53, with considerable variability. The annual median number of visits for clinical outcomes were as follows: zero for ACS visits, 1.3 for VOC-related emergency department visits, and 1.4 for VOC-related hospital admissions on an in-patient basis. The analysis revealed that the highest quartile of MPR, indicating the highest level of adherence (>75%), was associated with the lowest predicted counts of clinical outcomes. This difference was statistically significant, particularly for ACS visits, when compared to the lowest quartile of MPR.

In conclusion, this study underscores the importance of high levels of adherence to hydroxyurea treatment (exceeding 75%) in achieving a lower incidence of common negative clinical outcomes in children and adolescents with SCA. It also suggests that moderate and severe nonadherence to hydroxyurea may be more prevalent among this population than previously recognized. The findings emphasize the need for innovative strategies to improve adherence to this essential therapy among individuals with SCA.


Sickle cell disease is a significant health concern affecting over 100,000 Americans, with a particularly high incidence of one in 365 African American births. Among its various subtypes, sickle cell anemia (SCA) stands out as the most common and severe form of the disease. Children living with SCA often face substantial morbidity, including painful vaso-occlusive crises (VOC) and the threat of acute chest syndrome (ACS). These health challenges result in increased healthcare utilization, considerable costs, and a diminished quality of life.

Clinical trials have demonstrated the efficacy of hydroxyurea in reducing the frequency of VOC and ACS episodes in individuals with SCA. For instance, the Phase 3 randomized clinical trial known as BABY HUG showed that highly adherent children with SCA who received hydroxyurea experienced fewer VOC and ACS episodes, as well as reduced hospitalizations, compared to those who received a placebo. These benefits were observed even among children who did not initially exhibit symptoms.

However, real-world observational studies have produced conflicting findings regarding the association between hydroxyurea use and acute care utilization among children with SCA. This discrepancy suggests that the impact of hydroxyurea on clinical outcomes may be influenced by varying levels of adherence to the medication outside the controlled environment of clinical trials. While it is generally accepted that an adherence rate of 80% is necessary to achieve positive clinical outcomes, the appropriateness of this threshold can differ depending on the specific medical condition under consideration.

Given this context, the objective of this study was to investigate the relationship between different levels of adherence to hydroxyurea and clinical outcomes among children and adolescents with SCA, using a dataset comprising children covered by Medicaid in six U.S. states. This research aimed to provide valuable insights into the impact of real-world medication adherence on the health outcomes of this vulnerable population.


This retrospective cohort study utilized data from the Medicaid Analytic eXtract, encompassing individual-level information on Medicaid enrollees and their healthcare service utilization. The study spanned the years 2005 to 2012 and included data from Medicaid programs in six U.S. states: Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. These states were selected due to their moderate to high prevalence of sickle cell disease and the availability of accurate and comprehensive data.

The study focused on children aged 1 to 17 years diagnosed with sickle cell anemia (SCA) who were continuously enrolled in Medicaid for three consecutive years within the specified time frame. SCA was identified through validated criteria involving at least three SCA-related claims, ensuring a high level of diagnostic accuracy. Medicaid enrollees with any overlapping health insurance coverage during their enrollment periods (e.g., private insurance) were excluded to ensure the comprehensive capture of all healthcare services paid for by Medicaid during the study period.

For eligible children with an initiation pattern of hydroxyurea use, data for each 3-year period of consecutive Medicaid enrollment were analyzed. An initiation pattern was defined as the absence of hydroxyurea prescription claims in the first year, followed by the filling of at least a 30-day supply of hydroxyurea in the second year. Time intervals with any other medication usage patterns were excluded from further analysis. Each child was allowed to contribute data for one 3-year interval, with preference given to the earliest interval to reflect a true initiation pattern. All exposures and outcomes were annualized for consistency.


The main exposure of interest in this study was hydroxyurea adherence, measured using the medication possession ratio (MPR). To assess MPR, filled prescriptions for hydroxyurea were identified using National Drug Codes, validated with RxNorm and other reference sources. The MPR was calculated as the total days’ supply of hydroxyurea from filled prescriptions, divided by the total number of days from initiation to the end of the study period, minus the days spent as inpatients during the same period. MPR was examined both as a continuous variable and categorized into quartiles (Q1 to Q4) to facilitate clinical interpretation.

The study’s primary clinical outcomes were related to vaso-occlusive crises (VOC) and acute chest syndrome (ACS). For VOC, the outcomes considered were inpatient admissions and emergency department visits with a VOC diagnosis. ACS outcomes encompassed any inpatient admission, emergency department visit, or outpatient visit with an ACS diagnosis. These outcomes have previously demonstrated responsiveness to hydroxyurea treatment in clinical trials. The study’s assessment of these outcomes began 6 months after hydroxyurea initiation and continued throughout the 3-year periods, with the total occurrences of each outcome annualized.

Additional covariates included demographic factors (such as sex, age, state, and calendar year) and prior healthcare utilization. Previous healthcare utilization was included to address potential confounding, as it could be associated with both hydroxyurea adherence and pain-related healthcare encounters, particularly considering that hydroxyurea was primarily recommended for children with severe SCA during the study period. Prior utilization was defined by the annualized number of inpatient admissions, emergency department visits, and outpatient visits from the beginning of the study period to the hydroxyurea initiation date.

Statistical Analysis

In this section of the study, several analytical steps were undertaken to investigate the relationship between hydroxyurea adherence, measured as the medication possession ratio (MPR), and various clinical outcomes among children with sickle cell anemia (SCA) enrolled in Medicaid.

Firstly, summary statistics were calculated for key variables, including sex, age (as of January 1 of year 1), state of residence, year of entry into the study, and prior healthcare utilization.

The study then proceeded to examine the relationship between each clinical outcome (specifically, VOC-related inpatient admissions, VOC-related emergency department visits, and encounters for ACS) and continuously measured MPR through scatterplots. This initial visual exploration helped assess the patterns and trends between MPR and clinical outcomes.

Following the visual examination, separate simple Poisson regression models were employed to investigate the simple associations between the continuously measured MPR and the clinical outcomes. These analyses aimed to determine the initial associations between MPR and each clinical outcome.

Subsequently, the study conducted separate multivariable Poisson regression models for each of the three clinical outcomes, predicting them based on quartiles of MPR, with quartile 1 (MPR 0 to <0.25) as the reference category. The use of quartiles allowed for easier interpretation by healthcare providers, researchers, and clinical trial developers, particularly those focused on addressing issues related to poor adherence. These multivariable models were adjusted for counts of previous healthcare utilization, state of residence, and age (treated as a continuous variable). The modeling process produced incidence rate ratios and predicted counts for each clinical outcome within different MPR quartiles.

All statistical analyses were conducted at a 95% confidence level, and the software SAS 9.4 was used for the computations. It’s important to note that this study received ethical approval from the University of Michigan Institutional Review Board (IRB), ensuring that it adhered to ethical and regulatory standards for research involving human subjects.


In this part of the study, a cohort of 2,747 children with sickle cell anemia (SCA) enrolled in Medicaid was analyzed. Among them, 515 children (about 18.7%) exhibited a hydroxyurea initiation pattern and were included in the study population.


The demographic characteristics of these children with SCA were as follows:

– Gender: Roughly an equal distribution between females (50.3%) and males (49.7%).

– Age at study entry: Predominantly aged 11–15 years (41.4%), followed by 6–10 years (32.4%), and 1–5 years (26.2%).

– State of residence: Most commonly from Florida (31.5%) and least commonly from South Carolina (5.2%), with representation from other states like Illinois, Louisiana, Michigan, and Texas.

– Year entered the study: Entries ranged from 2005 (13.0%) to 2010 (21.8%).

– Prior healthcare utilization: The children had varying levels of previous healthcare utilization, with an average of 3.0 inpatient visits, 5.6 emergency department visits, and 51.0 outpatient visits. The median values for these visits were 2.6 (inpatient), 4.6 (emergency department), and 44.4 (outpatient).


The study observed a median medication possession ratio (MPR) of 0.53 (with an interquartile range of 0.3–0.8) among these children. Additionally, the median counts for clinical outcomes were 1.36 for VOC-related inpatient admissions, 1.33 for VOC-related emergency department visits, and 0.00 for ACS-related visits. The children were categorized into quartiles based on MPR, with 98 children in the first quartile (MPR 0 to <0.25), 137 in the second quartile (MPR 0.25 to <0.50), 143 in the third quartile (MPR 0.50 to <0.75), and 137 in the fourth quartile (MPR 0.75–1). The analysis indicated that as MPR quartile increased, there was a significant decreasing trend in the number of visits for all clinical outcomes.


Poisson regression models were employed to assess the relationships between MPR quartile and each clinical outcome while adjusting for state, age, and previous healthcare utilization. The findings revealed varying associations:

– For VOC-related inpatient admissions, the highest predicted counts were observed in the second and third quartiles of MPR, while the lowest counts were in the fourth quartile.

– Similar trends were observed for VOC-related emergency department visits, with the third quartile showing the highest predicted counts.

– Conversely, for ACS visits, there was a consistent decrease in predicted counts with each increase in MPR quartile.


These results provide insights into the complex relationship between hydroxyurea adherence, as measured by MPR, and clinical outcomes among children with SCA in the Medicaid population.


This study highlights the significance of hydroxyurea in reducing vaso-occlusive pain crises (VOC) and acute chest syndrome (ACS) among children and adolescents with sickle cell anemia (SCA). The research emphasizes the crucial role of adherence to hydroxyurea medication in achieving positive clinical outcomes.


Key findings from the study include:


  1. Adherence Threshold: The study underscores that a high level of adherence, exceeding 75%, is essential to significantly lower the incidence of negative clinical outcomes associated with SCA. This emphasizes the importance of consistent adherence to hydroxyurea treatment.


  1. Prevalence of Nonadherence: The study suggests that moderate and severe nonadherence to hydroxyurea may be more prevalent among children and adolescents with SCA than previously recognized. This highlights the need for innovative strategies to enhance medication adherence in this patient population.


  1. Impact on ACS: Even moderate adherence (above 25%) to hydroxyurea was associated with reduced negative clinical outcomes related to ACS. Notably, a significant decrease in acute care outcomes (hospitalizations and emergency department visits) was observed between the third and fourth quartiles of adherence.


  1. Challenges and Considerations: The study discusses potential explanations for the observed patterns, including the possibility that patients with more severe symptoms may be more likely to adhere to hydroxyurea. It also suggests that specific adherence patterns may be ineffective at reducing clinical outcomes or that exceptionally high adherence levels may be necessary for certain complications.


  1. Importance of Research: The study underscores the need for further research to understand the relationship between moderate levels of hydroxyurea adherence, acute care utilization, and how this relationship may vary with age.


  1. Impact on Quality of Life: Vaso-occlusive pain is a significant concern for children with SCA, leading to lower quality of life, school absences, depression, and impaired social relationships. The study highlights that sustained adherence to hydroxyurea is essential to improving VOC and ACS outcomes.


  1. Addressing Adherence Barriers: The study discusses various interventions aimed at improving hydroxyurea adherence, including patient-focused strategies and potential systematic barriers, such as pharmacy-related challenges. It suggests the involvement of clinical pharmacists as part of the care team and leveraging outpatient encounters as potential intervention targets.


  1. Study Strengths and Limitations: The study’s strengths include considering the lag time between hydroxyurea initiation and clinical outcomes, reducing temporal ambiguity. However, it acknowledges limitations related to administrative data, historical data, confounding factors, and social determinants of health.


In conclusion, this study underscores the critical role of hydroxyurea adherence in improving clinical outcomes for children and adolescents with SCA. It emphasizes the importance of developing comprehensive strategies involving various stakeholders to enhance medication adherence and, subsequently, the quality of life for individuals living with SCA.

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