Stroke Prevention in Sickle Cell Anemia (STOP 1)


Phase 3 Results

Trial Description

To reduce episodes of first time stroke by 75 percent in children with sickle cell anemia by the administration of prophylactic transfusion therapy.

Detailed Description

Stroke, occurring in about 10 percent of pediatric patients with sickle cell disease, is one of the most devastating complications, with a high recurrence rate after the first episode. Several non-randomized studies have shown reduction in stroke recurrence when periodic blood transfusions are administered to maintain hemoglobin S under 30 percent. Periodic blood transfusions are associated with significant risks of iron overload and other complications and must be accompanied by parenteral iron chelation therapy. However, this has become a standard of care for prevention of recurrent stroke in SS children. Thus, a randomized trial of blood transfusion for secondary prevention would not be feasible because it would be considered unethical. Based on various studies, the recurrence rate is reduced from 46 to 67 percent to approximately 7 percent on transfusion therapy. Because most stroke patients are left with some neurological deficit, and face a lifetime of disability, primary prevention would have a significant impact on the management of patients. However, because of complications of blood transfusions, the hypothesis should be proven by a randomized clinical trial.
A primary prevention trial had not been possible because an acceptable means of detecting those children at risk of stroke was not available. The advent of TCD to identify arterial abnormalities for the prediction of stroke has provided a means of detection. TCD abnormalities have a high specificity (100 percent) and high sensitivity (90 percent) for detecting angiographically proven narrowing of arterial diameter. Thus, TCD examination of the basal cerebral arteries is predictive of who will develop a stroke.
Randomized, Phase III, multicenter. Approximately 3,000 children from 12 clinics were screened with transcranial Doppler (TCD). A total of 130 were randomized to receive either standard supportive care or periodic blood transfusions if they were found to be at high risk of stroke on the basis of elevated cerebral blood flow as measured by TCD screening tests. Primary endpoints included clinically evident symptoms of cerebral infarction with consistent findings on magnetic resonance imaging (MRI), and/or symptomatic intracranial hemorrhage. Secondary endpoints included asymptomatic brain lesions detected by MRI in brain areas not involved in primary endpoints. Hematologic characteristics of the high risk group were analyzed and serum and DNA samples frozen for future analysis. Recruitment ended in October 1997 with the accrual of 130 subjects. The clinical phase ended in 1999.



Trial Design

  • Allocation: Randomized
  • Purpose: Prevention

Patient Involvement

Interested patients were enrolled in a screening process, during which they underwent a minimum of 2 TCDs, pregnancy, HIV, and HTLV testing, red-blood-cell phenotyping, ferritin quantification, as well as various other hematological tests. Eligible patients underwent a baseline MRI/MRA, a full neurological examination, several hematological, genetic, and blood-chemistry tests, and were evaluated for hepatitis B and C. Patients were randomized to receive either standard supportive care or regular transfusions. In the transfusion group, the target hemoglobin S (HbS) level of =< 30% total Hb was to be reached within the first 21 days of enrollment, without allowing the total hemoglobin to exceed 12 g/dL, or the total hematocrit to exceed 36%. Subsequent transfusions occurred every 3-4 weeks, and were calculated to maintain HbS at the target level. All patients were to be evaluated quarterly for a period of at least 2 years.


Type Measure Time Frame Safety Issue
Primary Magnetic Resonance Imaging and Angiography (MRI/MRA) confirmed symptomatic cerebral infaction, symptomatic intracranial hemorrhage
Secondary MRI-detected asymptomatic brain lesions