The National Heart, Lung, and Blood Institute (NHLBI) announced today a treatment that reduces the rate of stroke (cerebral infarction) in children with sickle cell anemia. Strokes occur in approximately 10% of children with sickle cell anemia. These events can be very debilitating, leading to physical and neuro-psychological impairment which can affect motor skills, school performance, and overall quality of life. The treatment, periodic red blood cell transfusions to maintain the level of hemoglobin S (HbS) below 30%, reduced the rate of cerebral infarction by 90% in children found to be at increased risk by virtue of having elevated transcranial doppler velocities.
The Stroke Prevention Trial in Sickle Cell Anemia (STOP) proposed to reduce first-time stroke in children with sickle cell anemia by 70% by the administration of prophylactic transfusion therapy. The study design was based on the clinical observation that if hemoglobin S (HbS) levels are maintained at or below 30% in children who have had a stroke, the incidence of recurrence can be reduced from 80% to approximately 10% with periodic exchange or simple transfusions.
Between February, 1995 and October, 1996, the NHLBI-sponsored trial, headquartered at the Medical College of Georgia (Dr. Robert Adams) and the New England Research Institutes (Dr. Donald Brambilla), enrolled 130 subjects, ages 2 to 16, who had been found to be at high risk for stroke on the basis of elevated cerebral blood flow measured by transcranial doppler screening tests (greater than or equal to 200 cm/sec time averaged mean velocities). The patients, drawn from 13 U.S. clinical centers and one in Canada (list attached), were randomized to receive either standard supportive care or periodic blood transfusions. The primary endpoint was the comparison of stroke rates in the treated and control groups.
The primary analysis of data from the STOP Trial compared stroke rates in 63 children randomized to receive repeated exchange or simple transfusions and 67 children who received standard supportive care. A stroke was defined as clinically significant neurologic impairment and physical findings, supported by an abnormal magnetic resonance imaging (MRI) study. The clinical records and MRI's were analyzed by a panel that was blinded to the treatment assignment of the study subjects.
The patients in the transfusion arm received simple or exchange transfusions every 3-to- 4 weeks in an effort to maintain the Hb S level below 30%. After one year, 10 of the children in the standard care group had had a cerebral infarction, compared with one child in the transfusion group, This difference represents a 90% relative decrease in the stroke rate.
The protocol required that red blood cell transfusions be matched for ABO, C, D, E, and K antigens, and the children in both study arms were followed for signs of alloimmunization, exposure to transfusion-transmitted viral diseases, and iron overload. Although none of the children in the transfusion arm of the study contracted a transfusion-transmitted virus, 9 developed alloimmunization. Patients in the transfusion group who had received 250 ml/kg of blood began to develop elevated serum ferritin levels greater than 2500 mg/L and were started on chelation therapy.
The STOP Trial was scheduled to continue until December, 1998. The results found during interim analyses were so compelling that the study's Data and Safety Monitoring Board, composed of independent, outside experts in the fields of pediatric hematology, neurology, radiology, statistics, and ethics, recommended that the study be terminated early so that the children who had been receiving standard supportive care could be offered an effective treatment to prevent first-time stroke. On September 2, 1997, the study was halted, and the investigators in the 14 participating centers were notified of the results and the efficacy of transfusion therapy. During the past 2 weeks, the results were discussed with the patients in both treatment arms and their parents.
The STOP Trial confirmed that TCD can identify children with sickle cell anemia at high risk for first-time stroke. Since the greatest risk of stroke occurs in early childhood, it is recommended that children ages 2-16 receive TCD screening. Screening should be conducted at a site where clinicians have been trained to provide TCDs of comparable quality and information content to those used in the STOP Trial and to read them in a manner consistent with what was done in STOP. To apply the predictive and therapeutic information developed in the STOP Trial, two abnormal STOP-comparable TCDs are needed to identify patients at high risk of stroke (velocity greater than 200 cm/sec on two separate occasions). During follow-up, some children in the large screening population, who had had normal or conditional TCD readings originally, were found to have abnormal TCD readings, indicating that children with normal TCDs should be re-screened at an interval which depends on their age and the prior result of TCD. Although the optimal timing is not known, re-screening should occur approximately every 6 months.
The TCD equipment used in the STOP Trial was adapted by Dr. Robert Adams for use in children with sickle cell disease. It is smaller and less expensive than the TCD currently used in most radiology departments. It is also portable. In addition, it will not overestimate velocity, and its use will ensure that children will not be misclassified as abnormal and unnecessarily transfused. It is recommended that centers that wish to start screening children with sickle cell anemia for stroke risk do studies to compare their current equipment with STOP Trial TCD equipment. Dr. Adams should be contacted for further information and to arrange training.
The decision to start a child on chronic blood transfusion therapy is a clinical decision that should be made only after careful consideration of the risks and benefits. This decision should be made in consultation with a physician who has knowledge of the STOP Trial protocol and results and who is experienced in the safe delivery of blood products, the management of transfusion complications, and the care of the child with sickle cell anemia.
For more information on the STOP Trial, contact Dr. Robert Adams at 706-721-4670 or the Sickle Cell Disease Scientific Research Group Office, NHLBI at 301-435-0055. All STOP Trial performance sites will be available for patient referrals and for screening children with sickle cell anemia to ascertain stroke risk and to counsel the patient and parents about treatment options.