Introduction
Sickle cell disease (SCD) is a pleiotropic genetic disorder of the hemoglobin with a chronic course of progressive end-organ dysfunction superimposed by recurrent episodes of acute vaso-occlusion (VOC) leading to frequent acute care resource utilization [i.e., visits to the emergency department (ED) and hospitalizations]. Additionally, due to the loss of splenic function early in life, individuals with SCD are at high risk of infections from encapsulated organisms, prompting additional acute hospital visits in the event of fever, which is considered an emergency in SCD [
1].
Childhood survival among patients with SCD has improved in the last decades. In high-income countries (HIC), greater than 95% of children with SCD survive to age 18 years [
2]. In low-and middle- income countries (LMIC), such as Brazil, improvements in survival have also been observed [
3,
4]. Initially recognized as a juvenile disease, SCD is now increasing in prevalence among adults in Brazil as more children and adolescents survive [
5]. As a result, SCD has become a chronic medical disease in Brazil, characterized by a pattern of recurrent episodes of acute events and progressive organ dysfunction as seen in HIC, [
6] collectively leading to increased acute care utilization and financial burden on the health care system [
7]. Therefore, SCD represents a public health challenge for many countries, especially LMIC, where resources are scarcer and decisions about resource allocation are based on competing priorities.
Although there are some data regarding the costs associated with SCD in Europe and the United States, [
8,
9] such data are not yet available for LMICs. The aim of this study was to evaluate the costs associated with acute complications of SCD at a large publicly-funded hematology center in Brazil, over a 6-month period. We hypothesized that there is variability in cost relative to reason for hospital visit, age and exposure to hydroxyurea. Our objectives were to 1) estimate the costs associated with acute care treatment of children and adults with SCD, according to the reason for the hospital visit, and 2) explore the potential cost-savings of hydroxyurea therapy during acute care visits.
Discussion
It is estimated that between 60,000 to 100,000 individuals live with SCD in Brazil today [
3,
15]. In other LMICs the SCD population is also showing improvements in survival, [
16] highlighting the need for better understanding of the costs and resources needed to support continued survival improvements. Clinical guidelines outlining healthcare management of the SCD population specifies early diagnosis, ongoing monitoring, and disease-specific therapies. The optimal delivery of care for hemoglobin disorders, therefore, requires access to highly specialized care centers. As in other LMICs, detailed cost analyses of treatment of SCD complications are not available, precluding appropriate planning of allocation of funds to treatment centers and development of health policies. Further complicating clinical efforts, novel therapeutics to address SCD burden are beginning to enter the marketplace in HIC. Without baseline data on costs, economic evaluation and comparative effectiveness studies to justify LMIC implementation of novel therapeutics are not feasible, thus perpetuating global gaps in outcomes and health disparities.
In our analysis of a single tertiary center in Brazil, over a period of 6 months, approximately one-third of all patients with SCD (52% of children and 48% of adults) at this institution utilized the ED for an acute visit and 33.3% of them were hospitalized for SCD-related acute complications. Although acute care costs per each event for anemia exacerbation were highest among all causes of hospital visits, anemia was a less frequent cause for ED visit or admission, thus, when viewed from the broader health system perspective, VOC was the largest contributor to costs overall. To our knowledge, this is the first report of costs associated to acute care treatment of patients with SCD in Brazil.
The multiple complications seen in SCD contribute to significant morbidity and premature mortality, as well as substantial costs to the healthcare system [
17]. Chronic end-organ damage can significantly increase the costs associated with the treatment in SCD and in our analysis, acute complications of end-organ damage represented the highest costs during hospitalizations. Although conducted in a LMIC country, our results correlate and are corroborated by published data among adults in the United States insured under government Medicaid plans showing high costs associated with end-organ damage [
18]. Furthermore, our microcosting analysis reveals that pharmacy costs, housing, and personnel time accounted for most of the cost related to ED and inpatient visits in our analysis. These findings are also in accord with data from SCD patients insured under the Medicaid government plan in the United States, which showed pharmacy and inpatient costs to be main drivers of high costs in SCD [
19].
Identifying opportunities for cost-savings is a critical secondary output from our analysis. Prior cost-savings with hydroxyurea therapy have been shown in children who participated in the BABYHUG clinical trial study [
20]. However, few studies have investigated the cost-savings of disease-modifying therapies in SCD in real-world settings. Our results suggest a lower acute resource utilization with hydroxyurea, as acute care visits by treated patients were less common than that by untreated ones. Among individuals with higher medication adherence levels, cost-savings with hydroxyurea therapy were also suggested by a reduction in costs, but only among visits by patients with the most severe sickle genotypes (HbSS or HbSβ
0-thalassemia) who were not admitted following an ED visit and during ED visits for anemia exacerbation. Our findings should be interpreted with caution, as adherence was overall low (well below the desired goal of 80%) and our analysis excluded treated patients not seen in the ED during the study period. Our analysis failed to show cost reductions with hydroxyurea during admissions, likely reflecting the limits of a disease-modifying therapy in reducing costs in the face of greater disease severity, where costs are inherently higher. Our findings, however, underscore the importance of interventions to improve hydroxyurea prescribing by providers and adherence by patients. To better understand the potential role of hydroxyurea in reducing care costs in SCD, our future work will investigate the relationship between hydroxyurea adherence and utilization for the entire SCD population (with and without ED utilization) of HEMORIO and will include not only acute care costs, but also ambulatory costs.
Although not included in this analysis, new disease-modifying therapies that can reduce acute SCD complications (crizanlizumab [
21] and L-glutamine [
22]) and reduce anemia (voxelotor [
23]) have recently transitioned to standard of care in HICs and will soon become available in LMICs. As to our knowledge, no cost-benefit or cost-effectiveness analyses have been done based on these new drugs, our study will serve as a critical benchmark against which these new therapies may be compared. Our findings can, for instance, be used in cost-effectiveness analyses to inform policy decisions regarding coverage of new disease-modifying drugs in LMICs, based on their estimated cost-savings potential during acute events from SCD.
Costs associated with admissions for acute VOC among children were generally higher than for adults. Although the reasons are unclear, longer duration of admissions (approximately twice as long) and higher use of blood products among children, as compared with adults, potentially explains these differences. In a retrospective cost analysis in England, children ages 10 to 19 years were also more likely to have longer inpatient lengths of stay compared to other age groups [
24]. Care utilization differences among adults and children in Brazil warrant future evaluations of how implementation of evidence-based practices occur in LMICs among adults.
The two highest hospitalization costs in our analysis were observed in two patients with HbSS who developed multiple complications following an admission for vaso-occlusive pain (sepsis and multi-organ failure), substantially prolonging their lengths of stay. Patients with high frequency of hospitalizations (high utilizers) also incurred in high utilization costs. Further, our overall LOS was high (mean of 2.8 days for adults) contrasting with a study from England that showed that more than half of the adults were discharged within 24 h, [
25] suggesting opportunities to enhance ambulatory preventative services. Collectively, our results highlight a critical need to develop new tools to identify high-risk groups of patients with SCD as a strategy to mitigate the cost burden of SCD impact on the health system.
Although presenting important cost information, our study had limitations. First, we only included data from one center in Brazil, limiting generalizability. However, our data include real costs from vendors and distributors. While practice differences may vary by location, our findings are likely similar to those observed at other Brazilian institutions. Second, our analysis was limited to 6 months of observation but given our large population and no seasonal changes from prior and subsequent months, our data are likely representative of longer periods and different times of the year. The strength of our study lies in its scope in that it covers the most common diagnoses of acute complications from SCD in the ED and inpatient settings and provides a comprehensive description of acute care costs with a detailed account of different types of medical expenses. Additionally, our cost data were not estimated from existing schedule of payment sources or extrapolated from other sources, but rather, used real-world cost data.
In conclusion, our study showed that SCD incurs in high costs in a tertiary hematology LMIC center, both during ED visits and inpatient stays, especially for the treatment of anemia and chronic end-organ damage. Drivers of cost included housing and personnel. Hospitalization costs were higher among children compared with adults. Hydroxyurea therapy appears to reduce costs, but only for ED visits among patients with HbSS/HbSβ0-thalassemia and anemia exacerbation, and was dependent on adherence level. Hydroxyurea use should be expanded to both improve patient outcomes and potentially produce future cost-saving to the health care system by reducing acute care utilization and ED costs. Our data provide benchmarks to be used in future cost-effectiveness analysis to plan new care guidelines and estimate cost benefits of current and future therapies for SCD.
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