Changes in Stroke Incidence in Californians with Sickle Cell Disease: A Population-Based Study in the Context of the STOP Trial

Background and Objective

Sickle Cell Disease (SCD) is a hereditary blood disorder characterized by abnormal hemoglobin, causing red blood cells to deform into a sickle shape under low-oxygen conditions. This deformation increases the likelihood of vascular blockage and inflammatory responses. Cerebrovascular complications, particularly ischemic strokes and intracranial hemorrhages, are among the most common and severe comorbidities of SCD patients. Early data indicated that in patients without preventive measures, the cumulative incidence of strokes reached 11% by age 20 and about 24% by age 45.

To address this high-risk population, the 1998 publication of the STOP (Stroke Prevention Trial in Sickle Cell Anemia) trial established transcranial doppler ultrasound (TCD) screening and chronic blood transfusion therapy as standard preventive measures. These interventions significantly reduced stroke incidence in high-risk children. However, with time, data suggested that while pediatric stroke rates declined after STOP, adult stroke data remain limited, and stroke incidence has shown a resurgence in recent years. This study aims to leverage real-world California healthcare data to analyze trends in stroke and transient ischemic attack (TIA) incidence across three time periods (1991–1998, 1999–2009, and 2010–2019). It also aims to explore the impact of age, sex, and modifiable risk factors (e.g., hypertension and hyperlipidemia) on stroke risk.

Source and Authors

This study was published in the December 12, 2024 issue of Blood (Volume 144, Issue 24) and was conducted by researchers from several institutions, including the University of Pittsburgh, the University of Washington, and the University of California, Davis Comprehensive Cancer Center. Key authors include Olubusola Oluwole, Ann M. Brunson, Oyebimpe O. Adesina, Shaina M. Willen, Theresa H. M. Keegan, Kleber Yotsumoto Fertrin, and Ted Wun.

Methods

The study used the California Healthcare Access and Innovation (HCAI) database, which includes hospitalization and emergency department (ED) data from 1991 to 2019. A total of 7,636 individuals with SCD were followed longitudinally to calculate stroke and TIA incidence rates and assess associated risk factors.

Data Source and Patient Characteristics

Patients were identified using International Classification of Disease (ICD-9 and ICD-10-CM) codes, capturing medical history, socioeconomic information, and hospitalization frequencies. The median follow-up period was 15.9 years. Among the cohort, 5.9% (451 individuals) experienced ischemic strokes, 3% (227) had intracranial hemorrhages, and 2.7% (205) experienced TIAs.

Analytical Procedures and Statistical Methods

To compare changes in stroke incidence across time, data were divided into three periods, and rates were calculated per 100,000 person-years. Fine and Gray methods were used to calculate cumulative incidence while accounting for competing risks of death. Multivariable Cox proportional hazards models were utilized to evaluate risk factors for ischemic strokes and intracranial hemorrhages.

Specific Analyses

• Stroke Categories and Risk Factors: The study explored clinical characteristics and risk factors for ischemic strokes and intracranial hemorrhages, such as frequent hospitalizations, hypertension, renal failure, and cerebrovascular disease history.
• Impact of Hospital Resource Utilization: For pediatric patients, the study analyzed whether receiving care predominantly at high-volume SCD facilities influenced outcomes.

Results

Cumulative Incidence of Cerebrovascular Events (CVEs)

• First Events: By age 20, the cumulative incidence of ischemic stroke was 2.1%, rising to 13.5% by age 60. For intracranial hemorrhages and TIAs, the cumulative incidence by age 60 reached 6.8% and 5.9%, respectively.
• Stroke Trends: Between 2010 and 2019, ischemic stroke rates significantly increased in children and adults (ages 18–50), with rates of 234.9 and 431.1 per 100,000 person-years, respectively.

Risk Factor Analysis

• Ischemic Stroke: Frequent hospitalizations (HR 1.31), hypertension (HR 1.71), and hyperlipidemia (HR 1.45) were independently associated with ischemic stroke risk. Previous cerebrovascular disease and TIA history posed the greatest risks, with hazard ratios of 4.38 and 2.87, respectively.
• Intracranial Hemorrhage: Acute chest syndrome (HR 1.46), renal failure (HR 2.11), and thrombocytopenia (HR 2.02) were significant risk factors.

Recurrent Events

Of the 733 patients who experienced an initial stroke, 21% (158 individuals) had a subsequent stroke or TIA during the study period. The cumulative risk of a second event reached 17.8% by four years post-initial stroke.

Significance

This study provides an updated, real-world analysis of cerebrovascular events among a large SCD cohort, revealing an alarming resurgence in stroke incidence across pediatric and adult populations. Key findings include: 1. Reemergence of Stroke Risk: Despite the initial success of the STOP trial in reducing stroke rates, failures in consistent adherence to TCD guidelines and other preventive measures may be driving the observed increase in stroke prevalence. 2. Unmet Needs in Adults: There remains a critical lack of screening and prevention guidelines for adults with SCD, whose stroke risks differ significantly from children. 3. Role of Modifiable Risk Factors: Traditional risk factors such as hypertension and hyperlipidemia have emerged as important contributors to stroke risk in SCD populations, underscoring the need for targeted interventions.

Study Highlights and Limitations

While the study was strengthened by its large-scale, multi-decade dataset, limitations included the absence of genotypic information, missing individual treatment records, and an inability to capture silent cerebral infarctions. Despite this, the study paves the way for future research on precision interventions and screening strategies for SCD patients.

Conclusion

The bimodal distribution of strokes observed in SCD populations appears to be evolving with the increasing prevalence of strokes across all age groups despite the introduction of STOP trial guidelines. This study highlights the critical need for renewed public health efforts to enhance adherence to existing guidelines and develop tailored stroke prevention strategies for adults. The results emphasize the importance of targeting both SCD-specific and traditional cerebrovascular risk factors to extend the life expectancy and quality of life for this vulnerable population.