Impact of fatigue on health care resource utilization and costs in sickle cell disease in the United States Free

Introduction: Fatigue is a common symptom of sickle cell disease (SCD). However, the economic burden associated with fatigue among individuals with SCD remains largely unknown. The goal of this study was to evaluate the impact of fatigue on health care resource utilization (HCRU) and direct medical costs among patients with SCD.

Methods: A retrospective longitudinal cohort study was conducted using the TriNetX Linked Network claims database and TriNetX Dataworks-USA electronic health record data from individuals aged ≥12 years who were diagnosed with SCD between October 1, 2015, and June 21, 2024. Patients with a diagnosis of sickle cell trait at any point during the study period or who had evidence of gene therapy or stem cell transplantation prior to the index date were excluded. Fatigue was defined using the following criteria: (1) hemoglobin (Hb) levels ≤10.0 g/dL used as a proxy for fatigue, or (2) fatigue diagnosis using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM)codes R53.81, R53.82, and R53.83. For the former criterion, patients were required to have ≥2 recorded Hb measurements more than 30 days apart but within a 1-year period, with the second Hb measurement used for classification. The index date was defined as the first observed encounter with fatigue occurring after at least 12 months of continuous health insurance coverage. Controls were assigned random pseudo-index dates after at least 12 months of prior continuous health insurance coverage. ICD-10-CM codes are underutilized in patients with SCD, and there is currently no validated algorithm to identify fatigue in patients with SCD. Thus, sensitivity analyses were conducted using a subset of patients for whom fatigue was defined solely by ICD-10-CM codes. Patients were required to have at least 12 months of continuous enrollment following the index date. Annual all-cause HCRU and direct medical costs (2023 US dollars) during the first 12 months post index were compared between patients with SCD with fatigue and those with SCD without fatigue. Comparisons were adjusted for demographic characteristics (including age at index, sex, race, ethnicity, geographic region, and type of insurance coverage), baseline clinical characteristics, SCD-related comorbidities (including hypertension, chronic pulmonary disease, and anxiety), and SCD treatments using multivariable regression models.

Results: A total of 2,220 patients with SCD with (n=960) and without (n=1,260) fatigue were included in the study. Patients with fatigue were older (aged 35 vs 32 years, respectively; P<.001) and were more commonly insured through Medicaid (72% vs 69%, respectively; P<.001) than patients without fatigue. Compared with those without fatigue, patients with fatigue were more likely to receive hydroxyurea treatment (31% vs 20%; P<.001) and transfusions (37% vs 19%; P<.001) and have higher baseline rates of comorbidities, most notably hypertension (33% vs 22%; P<.001) and chronic pulmonary disease (31% vs 21%; P<.001). Patients with fatigue had a much greater probability of adjusted inpatient (odds ratio [OR], 2.17), outpatient (OR, 2.22), emergency department (OR, 2.11), and pharmacy (OR, 2.37) utilization compared with patients without fatigue (all P<.001), resulting in a statistically significant increase of $7,500 in adjusted average annual all-cause costs per patient and a 130% increase in unadjusted total medical costs ($27,734 vs $12,174, respectively). Results from the sensitivity analyses were consistent with those from the full sample: patients with fatigue had higher probability of adjusted HCRU and incurred an average of $8,166 more in annual costs than those without fatigue (all P<.001).

Conclusions: This study highlights the substantial and previously underrecognized economic burden of fatigue among patients with SCD. Presence of fatigue was associated with a significantly greater probability of annual HCRU and increased associated costs. These findings reinforce the need for effective and safe treatments for patients with SCD to address the unmet need of managing fatigue.