The 10 percent of children with sickle cell disease who are at risk for a stroke need ongoing blood transfusions to reduce their risk, according to a study at 25 sites in North America.
The National Heart, Lung and Blood Institute of the National Institutes of Health, which funded the $11 million study headquartered at the Medical College of Georgia in Augusta, issued a clinical alert to coincide with the Dec. 5 announcement of study findings at the American Society of Hematology meeting in San Diego.
“Whatever process puts these children at risk is fairly durable,” says Dr. Robert J. Adams, neurologist and stroke specialist at MCG and principal investigator on the Optimizing Primary Stroke Prevention in Children with Sickle Cell Anemia, or STOP II, study. “We believed that we had identified a group that might tolerate coming off transfusion but the results did not confirm this. Too many of those taken off had return of abnormal transcranial Doppler, the best indicator we have of stroke risk, and there were two strokes in this group. We need more research to come up with a better way to limit the use of transfusion while still preventing strokes.”
“This important study shows the value of continuing periodic blood transfusions in preventing the serious and debilitating consequences of stroke,” says NHLBI Acting Director Barbara Alving. “At the same time, there are risks of chronic transfusions and the decision to continue with this treatment must be made on a case-by-case basis.”
The STOP II study tested whether regular transfusions could be safely stopped after at least 30 months in a group of children who reverted to low stroke risk based on normal transcranial Doppler and magnetic resonance angiography after treatment.
The study was to have enrolled 100 children. However, the NHLBI-appointed Data and Safety Monitoring Board recommended early closure of the study after 79 children were enrolled and randomized – half continued transfusion, half did not –because too many of the children who did not receive transfusions were reverting to high-risk status.
Of the 41 children who came off transfusions, 14 reverted to high-risk status within 10 months and two others had strokes shortly after their first abnormal study but before a confirmatory test could be performed and transfusions resumed. No reversions or strokes were seen in children who continued to receive transfusions. Thirteen of the 14 children who reverted to high-risk status resumed transfusions; one patient opted against resumption.
“Some reversion to high risk was expected with discontinuing transfusion, but the number was too high,” Dr. Adams says. “Even with the strict TCD monitoring required in the study protocol, which is probably more rigorous than you can expect in clinical practice, we still had two children experience strokes. Although TCD indicated that stroke risk had returned, there was not much time after the first abnormal TCD in these children to respond and restart treatment.”
Dr. Adams and Dr. Virgil C. McKie, the now-retired chief of pediatric hematology/oncology at MCG, published a paper in the New England Journal of Medicine in 1992 identifying the painless transcranial Doppler as the first non-invasive method for identifying these children before their first stroke.
The finding led to the original STOP study, which found that monthly blood transfusions that raise the amount of healthy, oxygen-carrying red blood cells in these at-risk children reduced stroke risk by 90 percent. That study, which began in early 1995 and followed 130 at-risk children with sickle cell disease age 2-16 at 14 sites in the United States and Canada, also was halted early in September 1997 by the NHLBI because of the obvious transfusion benefit. The institute issued a physician advisory recommending regular transcranial Doppler studies in children age 2-16 with sickle cell disease and consideration of transfusions in children at risk.
STOP II sought to determine whether the normalizing benefits of 30-plus months of transfusions would hold up if therapy stopped.