Acute Events Significantly Increase Risk for Long-Term End-Organ Sequelae in Sickle Cell Disease - a Retrospective Cohort Study Using Optum Electronic Health Records
Authors: Sun Xunming , Arkin Steven , Gu Yun , Schachterle Stephen E , Zhou Xiaofeng , Edwards Thomas , Xiao Sherry , Huang Kui A 
Published: December 2023

Introduction: Sickle cell disease (SCD) is a hereditary red blood cell disorder characterized by hemolytic anemia and vaso-occlusive crisis (VOC), which are associated with acute organ insults and cumulative end-organ damage. However, real-world data (RWD) are lacking for a host of acute events and rates of long-term organ damage in people with SCD, including priapism and leg ulcers. The objective of this study was to use RWD from US patients to comprehensively assess the rates of acute and long-term SCD events, and to explore the association between acute events and the potential implications for long-term organ damage.
Methods: This was a retrospective, non-interventional cohort study using Optum US-based Electronic Health Records data from January 1, 2007, to June 30, 2022. The index date followed a 183-day baseline period after initial diagnosis of SCD in the database. Patients with ≥1 inpatient or 2 outpatient SCD ICD-9-CM or ICD-10-CM codes ≥30 days apart were included. Follow-up for acute events and long-term organ damage started at the index date and continued until a patient was censored for lack of database activity, death, or the study period ended. The prevalences of acute events and long-term organ damage were estimated. Cox regression models were used to determine if acute events were associated with long-term organ damage. Acute events reported 1, 2, 3, and ≥4 times were captured and evaluated for their association with outcomes of long-term organ damage. Exposure was time-varying as patients contributed to the unexposed risk group prior to exposure (acute events) and then to subsequent risk groups after exposures accumulated. Hazard ratios (HR) for long-term organ damage between exposed acute event individuals and unexposed individuals with SCD were estimated.
Results: A total of 19,214 patients with SCD were included in this study; median (range) age was 29 (0-88) years, 59% were women, and 81% were African American. The most common acute events were VOC episodes assessed through medical utilization (MU) in 39% of patients, acute chest syndrome (ACS) in 15%, and ischemic stroke and seizures, each in 8% of patients. The most common long-term events of organ damage were heart failure (HF) in 7% of patients, neurocognitive deficit in 6%, and pulmonary hypertension (PH) and chronic kidney disease in 5% of patients each (Table 1).
After adjusting for age and sex, patients who at any time had an ischemic stroke had an increased risk of a recurrent event (HR=29.86, 95% CI 26.07-34.21), neurocognitive deficit (HR=8.67, 95% CI 7.22-10.40), and paralysis/hemiparesis (HR=21.19, 95% CI 17.25-26.04) compared with those with no pre-existing ischemic stroke event. Patients with ACS at any time had an increased risk of PH (HR=5.39, 95% CI 4.38-6.35), HF (HR=3.88, 95% CI 3.33-4.52), and oxygen dependency (HR=5.25, 95% CI 4.30-6.41) compared with those with no pre-existing ACS event. Patients who had leg ulcers at any time had an increased risk of amputation (HR=16.70, 95% CI 8.24-33.88) and osteomyelitis (HR=15.17, 95% CI 10.83-21.24) compared with those with no pre-existing leg ulcer event. In a similar manner, the risks were higher for long-term organ damage in corresponding organs among patients with an event of hemorrhagic stroke, avascular necrosis of the humerus or femur, gross hematuria, proteinuria, or priapism, than in patients with no pre-existing events. The risk of developing long-term organ damage following one or multiple acute events was assessed (Table 2). For all the HRs, both the upper and lower bounds of the 95% CI were greater than 1.
Conclusions: Acute events remain common among patients with SCD, particularly for VOC episodes assessed via MU, ACS, ischemic stroke, and seizure. Compared with patients who never had acute events, those who had any acute events were at higher risk of long-term organ damage in the same organ. Despite improvements in clinical care, RWD in this study suggest patients with SCD who continue to experience a high rate of acute insults are at higher risk of long-term complications that can lead to organ damage. A limitation of this study is the results have not been corrected for hemoglobin (Hb), despite the known correlation between lower Hb levels and higher rates for some types of organ damage. With the development of new therapeutic interventions, it is critical to understand the impact of these new therapies on acute events and rates of long-term organ damage in patients with SCD.