Using a California-wide hospital discharge database, epidemiologic investigators identified that hospital admission rates for first clinical stroke in children with sickle cell disease recently declined. Widespread publicity in 1998 highlighting the beneficial results of pre-emptive transfusion in high-risk children may have galvanized a modification of therapy.
Can the 10% per year incidence of clinical stroke in high-risk young children with sickle cell anemia be reduced? The Stroke Prevention Trial in Sickle Cell Anemia (STOP) was a resolute evidence-based, randomized, National Institutes of Health (NIH)-supported clinical trial comparing red cell transfusion therapy to routine care for the prevention of clinical stroke in high-risk children. High risk was identified using transcranial Doppler (TCD) demonstrating increased blood flow velocity of the internal carotid, middle cerebral, or anterior cerebral arteries. Within 2.5 years of entry into this 5-year trial, it was significantly shown (P = .001) that the children on routine standard care (control group) had a greater frequency of developing a clinical stroke than those on a uniform transfusion/chelation program. Of the 63 subjects who were regularly transfused, 1 developed a clinical cerebral infarction. This was compared with the control group of 67, with 10 subjects who had a clinical cerebral infarction and 1 who had an intracerebral hematoma. The study was terminated 2.5 years ahead of schedule in 1997 and published in 1998.
Fullerton and colleagues (page 336) embarked upon an arduous epidemiologic study to evaluate the influence on medical practice of the published results of the STOP trial. These investigators used the database of the Office of State Wide Health Planning and Development of California in order to identify childhood hospital admissions for sickle cell anemia from 1991 through 2000. They found that among 93 hospital admissions for first stroke, the frequency of first stroke from 1991 through 1998 was 0.88 per 100 person-years. Remarkably, the incidence declined to 0.50 in 1999 and 0.17 in 2000 (P = .0047 for trend). No information from that database is available regarding prior transfusion therapy or other treatment such as hydroxyurea. Information regarding the diagnostic criteria for stroke, neuroimaging, or Doppler studies was not available.
How can this be explained? It appears that the positive results of the STOP trial did translate into a generalized modification of clinical intervention to prevent stroke. The identification of narrowed or stenotic cerebral vessels can now be obtained using transcranial Doppler, duplex color Doppler, or magnetic resonance angiography (MRA) in most radiology departments or neurovascular departments. Newer magnetic resonance technology documents that ischemic brain injury is present in 44% to 52% of young children with sickle cell anemia.1-3 Thus, the identification of the at-risk child is readily available. The patient identified to have cerebral infarction, elevated cerebral vessel blood velocities, or cerebral artery narrowing could have been placed on a transfusion/chelation program, thereby decreasing the risk of admission for clinical stroke. This practice of pre-emptive treatment is particularly common in the large centers focused on childhood hemoglobinopathies. After widespread publicity regarding the results of the STOP trial, the California Children's Services (CCS) program made financial support more readily available for transfusion/chelation services and hydroxyurea. The large health maintenance organizations (HMOs; eg, Kaiser) became more responsive to the added financial burden of long-term transfusion/chelation programs. Importantly, this financial support includes risk evaluation studies such as TCD, magnetic resonance imaging (MRI), MRA, and positron emission tomography (PET). Contributing to the improvement was the increased utilization of hydroxyurea. Data are now accumulating that therapy of young children with hydroxyurea is associated with a decreased cerebral vessel blood flow velocity. These factors taken together apparently encouraged an expanded use of supportive transfusion/chelation therapy or chemotherapy.
A new STOP II trial has been initiated that will focus on unanswered questions raised by the premature discontinuance of funding for the STOP I study. The main question is: can transfusion/chelation therapy be safely halted after 30 or more months when coupled with a decrease of cerebral vessel blood velocity to normal and normal magnetic resonance angiography?4,5
