Characterizing a Population with Severe Manifestations of Sickle Cell Disease Using U.S. Real-World Evidence
Authors: Paramore Clark , Kong Amanda , Minegishi Sachiyo , Shi Weiliang 
Published: October 2019

Abstract
Background
Sickle cell disease (SCD) is a monogenetic disorder, with 300,000 to 400,000 infants born annually with the disease around the world (Kato et al, Nat Rev Dis Primers 2018). SCD is a progressively debilitating and life-threatening disease characterized by hemolytic anemia, painful vaso-occlusive events (VOEs) and persistent vasculopathy that result in significant morbidity, poor quality of life and early mortality. There is significant heterogeneity in clinical manifestations of SCD, given that vaso-occlusion and hemolysis-associated endothelial dysfunction may manifest in any tissue or organ. Severely affected patients may experience a diverse set of complications (Kato et al, Nat Rev Dis Primers 2018). Given the limited research to date in this area, the objectives of this real-world, retrospective study were to 1) identify and describe severely debilitating clinical complications experienced by patients with SCD in the U.S. and 2) examine rates of associated co-morbidities for this cohort.
Methods
A retrospective cohort analysis was undertaken utilizing patient-level, de-identified administrative claims data from the Truven Health U.S. MarketScan® Commercial, Medicare Supplemental, and Medicaid Multi-State Databases, for the period from January 1, 2010 to September 30, 2016. SCD patients were identified based on: ≥ 2 separate dates during study period with a medical claim having a SCD diagnosis (based on set of relevant ICD-9 or ICD-10 CM codes) and included in analyses if they had ≥ 2 years of follow-up with continuous plan enrollment. Treatment approaches and clinical outcomes were defined using a pre-specified list of relevant diagnosis and treatment codes. Commonly identified characteristics of severe SCD were assessed for each patient during their 1st 2 years of continuous enrollment during study period. These included 1): having frequent (i.e. ≥ 4) VOEs [i.e. sickle cell crises either distinct from acute chest syndrome (ACS) or unspecified] that require emergency room care or hospitalization, 2) stroke or history of stroke, 3) receiving chronic red blood cell (RBC) transfusions, or 4) ≥ 1 medical encounters for ACS.
Results
A total of 18,740 patients with SCD (56% Female; 61% from Medicaid database; 75% Black [only reported in Medicaid sample]) met the study criteria. Nearly 60% of the cohort were < 20 years old, 73% < 30 years old and only 9% ≥ 50 years old. Over the 2-year follow-up period, 23% of patients had ≥ 1 prescription for hydroxyurea. Table 1 provides a breakdown of patient comorbidities by age group. The most common comorbidities across all evaluated patients were cardiomegaly (12.6%), depression (11.8%), anxiety (7.8%) and osteonecrosis (7.7%). The prevalence of chronic kidney disease (CKD) increased most markedly as patient age increased, with 20% of 55-64-year-olds experiencing CKD. By the age of 35, over half (53.3%) of the SCD patients had at least one of the 13 listed comorbidities; this increased to 74.2% for a subset with 4 years of follow-up available. Thirty-three percent of patients had ≥ 1 inpatient admission for a VOE. Figure 1 shows patient counts for the selected complications of severe SCD, with rates and overlap among subgroups varying between children and adults. Approximately one-third of patients with SCD with multiple hospitalizations/emergency visits due to VOEs also had an ACS event. There was limited overlap in patients with SCD with history of stroke and those with an ACS event; and as expected there was very little overlap in patients with SCD receiving chronic transfusions and those with ≥4 VOEs or those with ACS (as RBC transfusions are prescribed to certain SCD patients to limit symptom impact).
Conclusions
Based on this contemporary real-world evidence from the U.S. setting, a substantial proportion of patients with SCD experience a diverse set of severely debilitating complications of the disease, as well as other co-morbidities associated with the disease. The high rate of comorbidities across all age groups and overrepresentation of patients younger than 30 years of age (relative to age distribution of general U.S. population) indicate that patients with SCD still experience significant morbidity and early mortality with current standard medical care. Given the notable heterogeneity of the clinical manifestations of SCD, future treatment approaches should address the root cause of the disease.

Disclosures
Paramore: bluebird bio: Employment, Equity Ownership. Kong:bluebird bio: Consultancy, Research Funding. Minegishi:bluebird bio: Employment, Equity Ownership. Shi:bluebird bio: Employment, Equity Ownership.