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From the Journals

Sickle Cell Stroke Rates Rise Post-STOP

Despite STOP trial interventions, ischemic stroke rates for children in California with sickle cell disease increased by 42% from 1999-2009 to 2010-2019, a large population-based study reveals.

Conexiant

A large population-based study of patients in California with sickle cell disease found that rates of ischemic stroke increased in both children and adults since the publication of the Stroke Prevention Trial in Sickle Cell Anemia (STOP) in 1998. The study, published in Blood, analyzed data from 7,636 patients with sickle cell disease between 1991 and 2019.

Key Findings

  1. Ischemic stroke rates increased in children from 165.1 per 100,000 person-years in 1999-2009 to 234.9 per 100,000 person-years in 2010-2019 (P=0.012).
  2. Adult ischemic stroke rates also increased, with the highest rates in those aged 51 and older.
  3. Cumulative incidence of first ischemic stroke was 2.1% by age 20 and 13.5% by age 60.
  4. Risk factors for ischemic stroke included hypertension (HR 1.71; 95% CI, 1.31-2.22), hyperlipidemia (HR 1.45; 95% CI, 1.00-2.11), and prior cerebral/extracerebral vasculopathy (HR 4.38; 95% CI, 2.55-7.50).

Methods

Researchers utilized the Health Care Access and Innovation (HCAI) database, which included Emergency Department Utilization (EDU, 2005-2019) and Patient Discharge Data (PDD, 1991-2019) from California. The sickle cell disease (SCD) cohort was identified using ICD-9/ICD-10-CM codes, requiring either 2 admissions with SCD as the principal diagnosis or 1 admission with SCD as the principal diagnosis and two additional admissions with SCD as a secondary diagnosis.

Cerebrovascular events (CVEs) were identified using validated ICD-9/ICD-10-CM codes for ischemic stroke, hemorrhagic stroke, and transient ischemic attacks (TIAs). Cumulative incidence functions were calculated using Fine & Gray methodology, accounting for the competing risk of death. Predicted age-specific stroke incidence rates were calculated using Poisson regression for three time periods: 1991-1998 (pre-STOP), 1999-2009, and 2010-2019.

Results:

Of 7,636 patients with SCD (53.3% female, 88.9% non-Hispanic Black), 733 (9.6%) experienced at least one CVE during the study period. The breakdown of first CVEs was: 451 (5.9%) ischemic strokes, 227 (3%) intracranial hemorrhages (ICH), and 205 (2.7%) TIAs. Frequently hospitalized patients (≥3 hospitalizations/year) comprised 45.5% of the cohort.

The cumulative incidence of first ischemic stroke was 2.1% (95% CI, 1.8%-2.4%) by age 20 and 13.5% (95% CI, 12.3%-14.7%) by age 60. For ICH, cumulative incidence was 0.5% (95% CI, 0.4%-0.7%) by age 20 and 6.8% (95% CI, 5.9%-7.7%) by age 60.

Ischemic stroke rates increased across all age groups from 1999-2009 to 2010-2019:

  • Ages 0-17: 165.1 to 234.9 per 100,000 person-years (P=0.012)
  • Ages 18-30: 221.7 to 298.8 per 100,000 person-years (P=0.129)
  • Ages 31-50: 303.2 to 431.1 per 100,000 person-years (P=0.031)
  • Ages ≥51: 990.1 to 1285.9 per 100,000 person-years (P=0.221)

ICH rates also showed an increasing trend, particularly in the 18-30 age group (84.4 to 150.1 per 100,000 person-years, P=0.039).

Multivariable Cox proportional hazards regression models identified several risk factors for ischemic stroke:

  • Frequent hospitalization (HR 1.31; 95% CI, 1.07-1.60)
  • Hypertension (HR 1.71; 95% CI, 1.31-2.22)
  • Hyperlipidemia (HR 1.45; 95% CI, 1.00-2.11)
  • Prior cerebral/extracerebral vasculopathy (HR 4.38; 95% CI, 2.55-7.50)
  • Prior TIA (HR 2.87; 95% CI, 1.76-4.66)
  • Posterior reversible encephalopathy syndrome (HR 2.30; 95% CI, 1.10-4.79)

For ICH, significant risk factors included:

  • History of acute chest syndrome (HR 1.46; 95% CI, 1.06-2.02)
  • Renal failure (HR 2.11; 95% CI, 1.33-3.36)
  • Prior ischemic stroke (HR 1.91; 95% CI, 1.15-3.20)
  • Prior cerebral/extracerebral vasculopathy (HR 3.25; 95% CI, 1.63-6.47)
  • Thrombocytopenia (HR 2.02; 95% CI, 1.43-2.85)

Among patients who experienced a first CVE, 21% (158/733) had a subsequent event. The cumulative incidence of a subsequent CVE was 6.5% at 12 months, 10.5% at 24 months, and 17.8% at 48 months after the initial event. The distribution of subsequent events was 65% ischemic stroke, 19% ICH, and 16% TIA.

In pediatric patients, high-volume SCD facilities saw a decline in ischemic stroke rates from 1991-1998 (pre-STOP) to 1999-2009 (359.0 vs 202.6 per 100,000 person-years, P=0.01). However, there was a trend towards increasing rates in 2010-2019 compared to 1999-2009, regardless of hospital SCD volume.

Comorbidities prior to first events were common:

  • Acute chest syndrome: 58.7% of total cohort, 61.7% of ICH patients
  • Renal failure: 12.3% of total cohort, 22% of ICH patients
  • Liver disease: 12.5% of total cohort, 17.2% of ICH patients
  • Hypertension: 33.1% of total cohort, 38.8% of ischemic stroke patients, 42.7% of ICH patients
  • Hyperlipidemia: 9.7% of total cohort, 11.5% of ischemic stroke patients, 13.7% of TIA patients

The study had several limitations, including lack of data on silent cerebral infarction (SCI) due to absence of ICD-9/10 codes, potential underestimation of CVEs if patients had strokes outside California or died before hospital presentation, and evolving definitions of TIA versus ischemic stroke that may have contributed to observed increases in stroke rates.

The authors declared having no competing interests.