Stroke rates among individuals with sickle cell disease have increased steadily over the last 25 years despite guidelines aimed at prevention, according to results of a retrospective study.
Incidence of cerebrovascular events rose significantly with age, with an approximate 13-fold increase of intracranial hemorrhage among people aged 20 to 60 years.
"It is concerning," study author Olubusola Oluwole, MD, assistant professor at University of Pittsburgh, told Healio. "Strokes can be life threatening or cause long-term impacts for patients. It is discouraging to see these trends in children despite established guidelines for stroke prevention. In the adult population, we need more data on stroke prevention -- and [we need to] figure out how we can tackle these emerging trends."
Background and methods
The Cooperative Study of Sickle Cell Disease, conducted from 1978 to 1988, showed 11% of individuals with sickle cell anemia had a stroke by age 20 years. About one-quarter (24%) had one by age 45, according to study background.
Children and adults aged 30 years or older exhibited a higher likelihood of ischemic stroke, whereas young adults -- those aged 20 to 29 years -- exhibited greater odds for hemorrhagic stroke.
These findings led to the Stroke Prevention Trial in Sickle Cell Anemia (STOP), which showed chronic transfusion therapy could decrease risk for stroke by 90% among children with abnormal transcranial Doppler velocities.
"That led to our current guidelines for chronic transfusion therapy for primary prevention of stroke for patients who are deemed high risk," Oluwole said. "That also led to the National Heart, Lung, and Blood Institute recommendation that children who are between the ages of 2 and 16 should undergo transcranial Doppler [ultrasound] to help identify those who are high risk. Hydroxyurea is another alternative [for] preventing stroke [among] children."
A 2004 study showed stroke incidence for children with sickle cell disease declined 80.6% in the 2 years following the STOP trial.
"We wanted to see if we could replicate those findings and explore what's happened since then," Oluwole said.
The analysis included 7,636 individuals (53.3% women; 88.9% non-Hispanic Black) with sickle cell disease from the California Department of Health Care Access and Innovation database, which includes data from 1991 to 2019.
Incidence of first cerebrovascular events -- including ischemic stroke, intracranial hemorrhage and transient ischemic attack -- before and after STOP served as the primary endpoint.
Key findings
Overall, 9.6% of people in the cohort had a cerebrovascular event (ischemic stroke, 5.9%; intracranial hemorrhage, 3%; transient ischemic attack, 2.7%).
Results showed a 66% reduction in ischemic strokes in the first 2 years following STOP. However, rates of all cerebrovascular events increased across all age groups from 1999 to 2009, and again from 2010 to 2019.
Researchers observed statistically significant increases in ischemic stroke incidence among children (234.9 vs. 165.1 per 100,000 person-years; P = .012) and adults aged 31 to 50 years (431.1 vs. 303.2; P = 0.031). They also observed statistically significant increases in intracranial hemorrhage among adults aged 18 to 30 years (P = 0.017), and transient ischemic attack among children (P = 0.027).
Oluwole described the trends as "discouraging."
Rates of first cerebrovascular events are increasing with age, with this pattern observed for first ischemic stroke (2.1% by age 20 to 13.5% by age 60), intracranial hemorrhage (0.5% by age 20 vs. 6.8% by age 60) and transient ischemic attack (0.7% by age 20 vs. 5.9% by age 60).
Risk factors for ischemic stroke included frequent hospitalization (HR = 1.31; 95% CI; 1.07-1.6), hypertension (HR = 1.71; 95% CI, 1.31-2.22), hyperlipidemia (HR = 1.45; 95% CI, 1-2.11), previous cerebral or extracerebral vasculopathy (HR = 4.38; 95% CI, 2.55-7.5), prior transient ischemic attack (HR = 2.87; 95% CI, 1.76-4.66) and posterior reversible encephalopathy syndrome (HR = 2.3; 95% CI, 1.1-4.79).
Risk factors for intracranial hemorrhage 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), previous ischemic stroke (HR = 1.91; 95% CI, 1.15-3.2), prior cerebral or extracerebral vasculopathy (HR = 3.25; 95% CI, 1.63-6.47) and thrombocytopenia (HR = 2.02; 95% CI, 1.43-2.85).
Rationale for trends
Several factors could contribute to rising stroke rates, Oluwole said.
One example is the transition from pediatric to adult care.
"In sickle cell disease, there is a noticeable difference inpatient adherence to treatment regimen" she said. "In childhood, parents are more involved and actively engaged with the healthcare system, however, the transition to adult care can lead to less adherence to treatment"
Additionally, adherence to transfusion therapy can wane due to time constraints.
"Transfusion therapy is every 3 to 6 weeks of someone's life," Oluwole said. "It really impacts quality of life and maintaining it long-term is challenging."
Access to transcranial Doppler ultrasound may be a barrier, too.
"For patients who are not seen at a comprehensive sickle cell center, it might be a bit more challenging implement STOP protocol," Oluwole said.
Oluwole and colleagues evaluated stroke rate by hospital volume. They found ischemic strokes among patients followed at high-volume facilities declined from 1991 to 1998, and from 1999 to 2009, but they increased from 2010 to 2019.
Address the issue 'right now'
In a follow-up to the STOP trial, other researchers found individuals who stopped transfusion therapy after 2 years reverted to having abnormal transcranial Doppler scans, Oluwole said.
Continued transfusion therapy could cause alloimmunization or iron overload, though.
Hydroxyurea could be a consideration instead of transfusion therapy. As Healio previously reported, hydroxyurea reduced vaso-occlusive crises -- which can lead to stroke -- by 44%
Hydroxyurea is one of three disease-modifying therapies approved for sickle cell disease, with the others being L-glutamine and crizanlizumab (Adakveo, Novartis). Voxelotor (Oxbryta, Pfizer) had been approved, but Pfizer pulled the drug from the market this fall due to safety concerns.
Only about three-quarters of patients with sickle cell disease use disease-modifying therapies.
Oluwole emphasized the need for more treatment options.
"In addition to that, we need include stroke risk assessment whenever we do these research studies," she added.
Further studies also are needed to investigate appropriate screening methods for adults with sickle cell disease as most current treatment strategies rely on data collected from children.
"We currently lack an effective screening method for adults," Oluwole said. "We need have a better understanding of how to manage adults -- how different is it from pediatrics? [We need] more longitudinal, prospective studies in our adult population"
In the meantime, it is important for providers to follow established guidelines and implement STOP protocol, Oluwole said.
"We also need more attentive to traditional stroke risk factors, Oluwole said. "Patients are living a lot longer now," she added. "We need to address these trends right now. We can't afford to wait another decade to realize that we aren't doing as well as we thought."
References: