BACKGROUND:

Recent publications should have resulted in increased hydroxyurea usage in children with sickle cell disease (SCD). We hypothesized that hydroxyurea use in children with SCD increased over time and was associated with decreased acute care visits.

METHODS:

This was a secondary analysis of the Truven Health Analytics–IBM Watson Health MarketScan Medicaid database from 2009 to 2015. The multistate, population-based cohort included children 1 to 19 years old with an International Classification of Diseases, Ninth or 10th Revision diagnosis of SCD between 2009 and 2015. Changes in hydroxyurea were measured across study years. The primary outcome was the receipt of hydroxyurea, identified through filled prescription claims. Acute care visits (emergency department visits and hospitalizations) were extracted from billing data.

RESULTS:

A mean of 5138 children each year were included. Hydroxyurea use increased from 14.3% in 2009 to 28.2% in 2015 (P < .001). During the study period, the acute-care-visit rate decreased from 1.20 acute care visits per person-year in 2009 to 1.04 acute care visits per person-year in 2015 (P < .001); however, the drop in acute care visits was exclusively in the youngest and oldest age groups and was not seen when only children enrolled continuously from 2009 to 2015 were analyzed.

CONCLUSIONS:

There was a significant increase in hydroxyurea use in children with SCD between 2009 and 2015. However, in 2015, only ∼1 in 4 children with SCD received hydroxyurea at least once. Increases in hydroxyurea were not associated with consistently decreased acute care visits in this population-based study of children insured by Medicaid.

What’s Known on This Subject:

Recent publications have shown increased benefit of hydroxyurea for sickle cell disease (SCD), expanding its potential use to more children. Controlled studies in academic centers have demonstrated that hydroxyurea use decreases emergency department visits and hospitalizations in SCD.

What This Study Adds:

There has been a small increase in hydroxyurea use but no consistent pattern of decreased emergency department or hospital use, suggesting that the benefits of hydroxyurea for preventing acute pain in SCD are not translating to the community.

Sickle cell disease (SCD) affects ∼90 000 individuals in the United States, including 36 000 children.1,2 SCD is characterized by vasoocclusive crises (VOCs), most commonly episodes of severe pain, resulting in high rates of acute care use, including emergency department (ED) visits and hospitalizations.3,4 SCD ranked fifth among the diagnoses of Medicaid superusers, defined as individuals with 4 or more hospital stays annually.5 

Hydroxyurea decreases leukocytosis and reduces expression of adhesion molecules, thus preventing VOC, acute chest syndrome, and hospitalization in patients with SCD.6,7 In a retrospective, single-center analysis, initiation of hydroxyurea among pediatric patients with SCD reduced rates of hospitalization, VOC, and ED visits by 40%.8 However, hydroxyurea remains underused despite demonstrated effectiveness.9,10 On the basis of these studies and expert opinion, the 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines for the management of SCD recommended hydroxyurea be offered to children aged 9 months or older with sickle cell anemia (hemoglobin [Hb]SS or HbSβ0 thalassemia) regardless of clinical severity and referred for specialist evaluation in other forms of SCD if pain interferes with quality of life.11,12 

These NHLBI guidelines have the potential to increase hydroxyurea use by expanding the age range for children with sickle cell anemia and extending it to patients with other SCD genotypes. Although both well-controlled clinical trials at comprehensive sickle cell centers and single-site, controlled, pre-post studies have demonstrated a decrease in acute care visits, these changes have not been investigated in multisite studies. We hypothesized that hydroxyurea use would increase, and acute care visits would decrease, across a Medicaid-insured sickle cell population.

The Truven Health Analytics–IBM Watson Health MarketScan Medicaid database, a well-established multistate collection of deidentified claims for Medicaid enrollees, including commercially insured Medicaid patients, allows for analyses of combined pharmacy and use at the payer level.13,15 It has been shown that ∼80% of children with SCD are Medicaid insured.16 Individual states are not identified in the database, and the states can change each year. All visits from a state are included, and individuals within a state can be tracked across years if the state is included in multiple years. The database includes an indicator for enrollment months and all hospitalization, ED, and pharmacy claims. The study of deidentified data was determined to be exempt by our institutional review board.

Children 1 to 19 years old with a diagnosis of SCD and enrolled for at least 11 of 12 months in any calendar year between 2009 and 2015 were eligible. The diagnosis of SCD was based on at least 1 inpatient visit or 2 outpatient visits with a primary or secondary diagnosis of SCD, defined by International Classification of Diseases, Ninth Revision (ICD-9) or 10th Revision (ICD-10) code. ICD-9 codes included 282.41, 282.42, 282.6, 282.60, 282.61, 282.62, 282.63, 282.64, 282.68, and 282.69; ICD-10 codes, for year 2015, included D57.1, D57.20, D57.40, and D57.80. Children were excluded for the first year after their birth year to ensure that they were old enough to receive hydroxyurea and, if they were in foster care (2% of the SCD population in this data set), to mitigate the impact of potentially fragmented care.

The primary outcome was the receipt of hydroxyurea as identified through pharmacy claims for a filled prescription. Children were categorized as having received at least 1 hydroxyurea prescription and by the percentage of days covered by hydroxyurea prescriptions. Each prescription included data regarding the number of days dispensed. Percentage of days covered was calculated as the percentage of days of hydroxyurea dispensed between the date of the first receipt of hydroxyurea and the end of the calendar year with a cutoff of 66%. For example, if a child received ten 30-day prescriptions (300 total days) starting January 1 of the calendar year, the child had 300 of 365 days (82%) covered. Alternatively, if a child received two 30-day prescriptions with a gap of 3 months between them, the child would only have 50% of days (2 of 4 months) covered. The percentage of days covered was calculated by year for each year that a child was in the database. We chose 66% as the cutoff for days covered because it fell into the moderate range of previously published work and was the average in a previously reported study of penicillin use in SCD.17,18 The percentage of children who received hydroxyurea at least once and with at least 66% of days covered was calculated in each year.

Acute care visits, defined as ED visits and hospitalizations, were a secondary outcome. The total number of acute care visits for a child per calendar year was extracted; visits were categorized as ED visits or hospitalizations. ED visits resulting in hospitalization were categorized as hospitalizations. Rates of visits were calculated on the basis of the number of visits for a given year divided by the number of children enrolled in that year.

A priori, we decided to analyze by age and sickle cell genotype. Age was determined annually as of December 31. For the genotype analysis, children were analyzed as the SCD group overall, and a subset of children with HbSS was also analyzed. Given that previous literature documented miscoding within administrative data, children were categorized as having HbSS if ≥95% of claims with a diagnosis code for a specific sickle cell genotype were HbSS.19,20 

To evaluate whether changes in hydroxyurea use were indicative of overall changes in SCD guideline–adherent care, we extracted 3 markers of guideline-based care: compliance with penicillin prophylaxis, receipt of transcranial Doppler (TCD) screening, and receipt of influenza vaccine. Adequate penicillin prophylaxis was defined as >66% filled days with penicillin, amoxicillin, and/or erythromycin over the year. The analysis was completed only for children <5 years old on the basis of current standards for antimicrobial prophylaxis. Annual TCD screening was evaluated in children ages 2 through 18 years. TCD screening was identified by using ICD-9 procedure codes (88.71) and Current Procedural Terminology codes (93886 and 93888). Both penicillin compliance and TCD screening were evaluated in children with HbSS disease exclusively. Receipt of a yearly influenza vaccine was determined by using ICD-9 procedure codes (99.52), Current Procedural Terminology codes (90655, 90657, 90661, and 90662), and Healthcare Common Procedure Coding System codes (G0008) and was evaluated for all children regardless of SCD genotype.

Categorical descriptive statistics were summarized by using frequencies and percentages; continuous descriptive statistics were summarized by using medians with interquartile ranges. Data were analyzed cross-sectionally by calendar year between 2009 and 2015. To allow for comparisons across years, age was divided into 4 groups: 1 to 6, 7 to 12, 13 to 16, and 17 to 19 years.

To analyze changes in hydroxyurea use over time, univariate comparisons were made by using a χ2 test for categorical variables and the Kruskal-Wallis test for nonnormal continuous data. Changes in the rate of receipt of hydroxyurea per patient per year were assessed by using a generalized linear mixed model, assuming a negative binomial distribution (to account for overdispersion and the large number of people not receiving hydroxyurea) and natural log link function. The percentage of children with 66% coverage with hydroxyurea was assessed over time by using a generalized linear mixed model, assuming a binomial distribution and a logit link function.

Changes in ED visits, hospitalizations, and total acute care visits (ED visits plus hospitalizations) per person-year were analyzed by using generalized linear modeling, assuming a Poisson distribution.

Because the states in the database changed from year to year, changes in outcomes could be due to state-specific differences. We therefore conducted a sensitivity analysis by repeating the hydroxyurea and acute-care-visit analyses only including children present in the database for all 7 years. As shown in Fig 1, this analysis excludes both the youngest and oldest age groups because no children present in the data set in 2009 could be 1 to 6 years old in 2015, and the oldest age group in 2009 aged out by 2015. All other age groups are still present, albeit at different ages in subsequent study years.

FIGURE 1

Depiction of the study population. For the longitudinal cohort, there would be no children 1 to 6 years old in 2015 who had been eligible in 2009. A child who was 11 years old (dark box) in 2009 would be analyzed as 7 to 12 years old in 2009, 13 to 16 years old in 2013, and 17 to 19 years old in 2015. Children ≥15 years old in 2009 would no longer be in the cohort in 2015.

FIGURE 1

Depiction of the study population. For the longitudinal cohort, there would be no children 1 to 6 years old in 2015 who had been eligible in 2009. A child who was 11 years old (dark box) in 2009 would be analyzed as 7 to 12 years old in 2009, 13 to 16 years old in 2013, and 17 to 19 years old in 2015. Children ≥15 years old in 2009 would no longer be in the cohort in 2015.

Close modal

All analyses were conducted by using SAS version 9.4 (SAS Institute, Inc, Cary, NC). P ≤. 05 was considered statistically significant.

From 2009 to 2015, a mean of 5138 children each year met eligibility criteria. The total number of children with SCD included in the analyses ranged from 4021 to 6528 across the years (Table 1). The number of states varied from 10 to 12. Approximately 50% of the population was of female sex, and 58% had HbSS.

TABLE 1

Demographics of the Study Population

2009201020112012201320142015
Enrollees, N 4406 4106 4021 5458 5051 6528 6395 
No. states represented 12 12 10 10 10 11 12 
Age, y, n (%)        
 1–6 1580 (35.9) 1537 (37.4) 1500 (37.3) 2025 (37.1) 1843 (36.5) 2309 (35.4) 2204 (34.5) 
 7–12 1291 (29.3) 1189 (29.0) 1180 (29.3) 1649 (30.2) 1587 (31.4) 2131 (32.6) 2154 (33.7) 
 13–16 883 (20.0) 791 (19.3) 741 (18.4) 1033 (18.9) 961 (19.0) 1235 (18.9) 1194 (18.7) 
 17–19 652 (14.8) 589 (14.3) 600 (14.9) 751 (13.8) 660 (13.1) 853 (13.1) 843 (13.2) 
Female sex, n (%) 2213 (50.2) 2038 (49.6) 1972 (49.0) 2672 (49.0) 2468 (48.9) 3176 (48.7) 3147 (49.2) 
HbSS, n (%) 2576 (58.5) 2348 (57.2) 2291 (57.0) 3075 (56.3) 2833 (56.1) 3556 (54.5) 3487 (54.5) 
2009201020112012201320142015
Enrollees, N 4406 4106 4021 5458 5051 6528 6395 
No. states represented 12 12 10 10 10 11 12 
Age, y, n (%)        
 1–6 1580 (35.9) 1537 (37.4) 1500 (37.3) 2025 (37.1) 1843 (36.5) 2309 (35.4) 2204 (34.5) 
 7–12 1291 (29.3) 1189 (29.0) 1180 (29.3) 1649 (30.2) 1587 (31.4) 2131 (32.6) 2154 (33.7) 
 13–16 883 (20.0) 791 (19.3) 741 (18.4) 1033 (18.9) 961 (19.0) 1235 (18.9) 1194 (18.7) 
 17–19 652 (14.8) 589 (14.3) 600 (14.9) 751 (13.8) 660 (13.1) 853 (13.1) 843 (13.2) 
Female sex, n (%) 2213 (50.2) 2038 (49.6) 1972 (49.0) 2672 (49.0) 2468 (48.9) 3176 (48.7) 3147 (49.2) 
HbSS, n (%) 2576 (58.5) 2348 (57.2) 2291 (57.0) 3075 (56.3) 2833 (56.1) 3556 (54.5) 3487 (54.5) 

The percentage of children who received hydroxyurea at least once increased from 14.3% in 2009 to 28.2% in 2015 (P < .001; Fig 2). The increase was higher for HbSS compared with non-HbSS; the HbSS group increased from 18.1% to 37.8%, whereas the non-HbSS group increased from 8.9% to 16.6% (P < .001 for all comparisons).

FIGURE 2

Percentage of children who received hydroxyurea at least once, overall and stratified into HbSS and non-HbSS groups. All 3 analyses show significant increases over time (P < .001).

FIGURE 2

Percentage of children who received hydroxyurea at least once, overall and stratified into HbSS and non-HbSS groups. All 3 analyses show significant increases over time (P < .001).

Close modal

Receiving hydroxyurea at least once increased over time in all age groups (Fig 3); the youngest age group increased from 4.9% to 18.6% (P < .001), whereas the oldest age group increased from 26.2% to 37.0% (P < .001).

FIGURE 3

Percentage of children who received hydroxyurea at least once, overall and stratified by age group. All groups show significant increases over time (P < .001).

FIGURE 3

Percentage of children who received hydroxyurea at least once, overall and stratified by age group. All groups show significant increases over time (P < .001).

Close modal

The evaluation of days covered closely followed the results for receiving hydroxyurea. Forty-six percent of those with at least 1 prescription had 66% of days covered, with no change seen across years. The percentage with 66% of days covered was highest for 1- to 6-year-old children (54%) and lowest in 17- to 19-year-old children (31.4%). The percentage with 66% of days covered among those who received hydroxyurea at least once was slightly higher in those with HbSS (48%) compared with non-HbSS (42%). The overall percentage of children with SCD with 66% of days covered increased from 6.7% in 2009 to 12.8% in 2015 (P < .001). This percentage increased in all age groups over the years of the study: 1- to 6-year-olds, 3% were hydroxyurea adherent in 2009 vs 10% in 2015; 7- to 12-year-olds, 9.3% were hydroxyurea adherent in 2009 vs 14.7% in 2015; 13- to 16-year-olds, 8.6% were hydroxyurea adherent in 2009 vs 14.9% in 2015; and 17- to 19-year-olds, 8.3% were hydroxyurea adherent in 2009 vs 11.6% in 2015 (all P < .001).

In the subset of children with HbSS, ∼83% of 1- to 4-year-olds filled at least 1 penicillin prescription in a given year, and 28% of all eligible children had 66% of days covered; neither of these percentages changed over time (both P > .05). TCD screening in the HbSS population had some annual variation, but there was no general trend upward because 60.8% of eligible patients with HbSS received TCD screening in 2009 compared with 60.6% in 2015. Influenza vaccination decreased during the study period from 55.6% in 2009 to 50.9% in 2015 (P < .001).

During the study period, the acute-care-visit rate decreased from 1.20 acute care visits per person-year in 2009 to 1.04 acute care visits per person-year in 2015 (P < .001; Fig 4). The rate of acute care visits varied by age: in 2009, 1- to 6-year-olds had 0.95 visits per person-year, 7- to 12-year-olds had 0.97 visits per person-year, 13- to 16-year-olds had 1.10 visits per person-year, and 17- to 19-year-olds had 2.39 visits per person-year. When changes in acute-care-visit rates were analyzed by age (Fig 5), 1- to 6-year-olds had significant decreases in hospitalization and total acute-care-visit rates but no change in ED-visit rates, and 7- to 12-year-olds had increased ED-visit rates, decreased hospitalization rates, and no overall change in acute-care-visit rates. In the older age groups, 13- to 16-year-olds had increased ED-visit rates, no change in hospitalization rates, and a small increase in overall acute-care-visit rates, and 17- to 19-year-olds had significant decreases in hospitalizations and acute care visits with no change in ED visits.

FIGURE 4

Overall acute care rates by visit type.

FIGURE 4

Overall acute care rates by visit type.

Close modal
FIGURE 5

Acute care rates by age and visit type.

FIGURE 5

Acute care rates by age and visit type.

Close modal

Overall, 2011 children met eligibility criteria and were managed for all years. Receipt of hydroxyurea increased in this cohort as they aged from 13% in 2009 to 32% in 2015 (P < .001). The percentage with 66% of days covered increased from 6.5% to 12.5% (P < .001).

We analyzed receipt of hydroxyurea and acute care use by age group, ensuring that the same age groups in the same states were represented, allowing for analyses of 7- to 12-year-olds and 13- to 16-year-olds. Comparing 2009 to 2015 for both age groups, the receipt of hydroxyurea increased in 7- to 12-year-olds from 16.4% to 26.4% and increased in 13- to 16-year-olds from 23.3% to 36.0% (both P < .001). The percentage with 66% of days covered increased in 7- to 12-year-olds from 8.6% to 12.3% (P = .05) and in 13- to 16-year-olds from 9.5% to 15.2% (P = .024). When analyzing acute care use, despite increased hydroxyurea use in both the 7- to 12-year-old and 13- to 16-year-old age categories, there were no significant declines in overall acute care use (7- to 12-year-olds, 1.04 visits per person-year in 2009 vs 1.03 visits per person-year in 2015 [P > .05]; 13- to 16-year-olds, 1.28 acute care visits per person-year in 2009 compared with 1.31 visits per person-year in 2015 [P > .05]). Among 7- to 12-year-olds, similar use rates were maintained in all 3 categories, whereas 13- to 16-year-olds had an increase in ED use offset by a slight decrease in hospitalization.

Hydroxyurea use in this multistate collection of Medicaid-enrolled children with SCD increased significantly between 2009 and 2015. All childhood age groups had significant increases in both hydroxyurea use and the percentage with 66% of days covered, with twice as many children receiving a hydroxyurea prescription at least once and having 66% of days covered. These increases suggest that dissemination of scientific evidence on the impact and efficacy of hydroxyurea therapy and publication of updated evidence-based guidelines may have affected practice.

Despite these increases in hydroxyurea use, however, almost two-thirds of children with HbSS and three-quarters of children with SCD overall did not fill a single prescription for hydroxyurea in 2015. Although it is difficult to determine the percentage of children with SCD who should receive hydroxyurea, the small increase in the rate of prescribing in our study does not match the increase in evidence of the effectiveness of hydroxyurea. The exact reason for the less-than-expected increase cannot be determined from this study. Previous barriers, including lack of knowledge of effectiveness and safety, may have been overcome in recent years; however, the need for frequent monitoring may require specific targeted interventions to be successful in a Medicaid-insured population with decreased access to care and barriers to completing required appointments.21,23 

There was only a slight decrease in overall acute-care-visit rates across the sickle cell population with no consistent pattern of decreased acute care use across age groups. For both the overall and sensitivity analyses, there was no change in the acute-care-visit rates for 7- to 12-year-olds or 13- to 16-year-olds despite increased hydroxyurea use. The sensitivity analysis was only possible in the middle 2 age groups, and the greatest decreases in acute care visits in the cross-sectional analyses were seen in the youngest and oldest groups. It is possible that the youngest age group, which had the highest relative increase in hydroxyurea use, is benefitting most from the increased hydroxyurea usage, and the decreased acute care visits could be plausibly attributed to the hydroxyurea. However, the oldest age group (17- to 19-year-olds) also had decreased acute care visits despite having the smallest increase in hydroxyurea use. The lack of a consistent pattern of increased hydroxyurea use associated with decreased acute care visits is concerning; however, these findings may have been adversely impacted by the low level of hydroxyurea usage in our study cohort. Ultimately, more research is needed to ensure that Medicaid-enrolled children outside of academic medical centers receive the same benefits from hydroxyurea as those in well-controlled studies.

Given recent publications and the release of the 2014 NHLBI guidelines for the treatment of SCD, we hypothesized that there would be an increase in hydroxyurea use over the study period. We found an increase in the receipt of hydroxyurea. The lack of change in other guideline-based care practices suggests that increased hydroxyurea usage is not the result of a general improvement in guideline-based sickle cell care. The relatively low rate of penicillin prophylaxis, TCD screening, and influenza vaccination for children with SCD from our study is consistent with previous studies.17,24 

This study has several limitations. First, the population was limited to children continuously enrolled in Medicaid and may not apply to children enrolled in commercial insurance or discontinuously enrolled in Medicaid. Previous studies, however, have shown that most children with SCD are Medicaid insured, making the study more generalizable.2 In assessing hydroxyurea usage, we used filled prescriptions as a proxy for actual hydroxyurea prescriptions, but prescriptions could have been written and not filled. However, previous studies have also used filled prescriptions as an appropriate surrogate for usage.17,25 There is no gold standard value for adequate use of hydroxyurea; we used 66% on the basis of previous literature.17,18 We also could not track other potential benefits of hydroxyurea use, including outpatient pain experience, TCD results, and survival, nor do we know why guideline-adherent care for all measures was less than ideal. It is possible that the decrease in influenza vaccine rates were due to changes in the included states or an increase in alternative sources of the vaccine that are not captured in the database. Finally, we focused on population-level estimates of filled prescriptions and acute care use rather than individual-level analyses. It is important to look at population-level hydroxyurea use and usage rates because outside of well-controlled studies, there has been no evidence that increased hydroxyurea use is associated with decreased acute-care-visit rates for children with SCD.

Hydroxyurea use increased in children with SCD between 2009 and 2015. Despite this increase, in 2015, only 1 in 4 children with SCD received hydroxyurea, and only 1 in 8 received hydroxyurea that covered 66% of eligible days. In addition, these increases in hydroxyurea use were not associated with a consistent pattern of decreased acute care visits. These findings illustrate the ongoing barriers to hydroxyurea use in a population-based cohort of Medicaid-enrolled children with SCD and the need to better understand how to translate the benefits to children managed in clinical trials to nonacademic settings.

Drs Brousseau, Richardson, and Arnold conceptualized and designed the study, designed the data instruments, supervised the data analysis, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Hall, Ellison, Shah, Raphael, and Bundy aided in the design of the study and interpretation of data and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

ED

emergency department

ICD-9

International Classification of Diseases, Ninth Revision

ICD-10

International Classification of Diseases, 10th Revision

NHLBI

National Heart, Lung, and Blood Institute

SCD

sickle cell disease

TCD

transcranial Doppler

VOC

vasoocclusive crisis

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.