Stroke risk increases when children with sickle cell disease cease transfusions

Stopping regular blood transfusions in children with sickle cell disease who are at risk for a stroke means their stroke risk likely will return, researchers have found.

A study of children whose stroke risk was reduced by blood transfusions found that within a few months of halting transfusion, 14 of the 41 children resumed at-risk status and two children had strokes, says Dr. Robert J. Adams, neurologist and stroke specialist at the Medical College of Georgia who authored the article in the Dec. 29 New England Journal of Medicine.

None of the 38 children who continued transfusions resumed at-risk status or had a stroke.

"We hoped that maybe we were dealing with something that was relatively short-lived over a few years in a child's life," says Dr. Adams. "Most of the time, that doesn't seem to be the case. Although there were eight children in the halted-transfusion arm that were followed for more than 25 months without any apparent problem, they were the minority and we have no way to predict who they are."

The study, headquartered at MCG and involving 25 sites in North America, was to enroll 100 patients, but the Data and Safety Monitoring Board appointed by the National Heart, Lung and Blood Institute recommended early closure in late 2004 because so many children resumed their at-risk status. The NHLBI issued a clinical alert in December 2004 to coincide with the closure saying the 10 percent of children with sickle cell disease who have a high stroke risk need ongoing transfusions.

The NHLBI funded the $11 million STOP II study looking at whether children needed to continue transfusions after their stroke risk normalized. That followed another NHLBI-funded study, led by MCG, which showed monthly transfusions cut stroke risk by 90 percent.

STOP II participants included patients identified at risk by abnormal blood flow studies of their brain whose studies had normalized after at least 30 months of transfusion; participants were randomized to either continue or halt transfusion.

The two strokes occurred shortly after a single abnormal transcranial Doppler study, which uses ultrasound to measure blood flow through the brain, and before confirmatory tests could be performed.

Drs. Adams and Virgil C. McKie, Professor Emeritus of Pediatrics, identified the painless, relatively inexpensive transcranial Doppler as a way to identify children at risk in a New England Journal of Medicine article in 1992. Their work to identify and help at-risk children began after Dr. McKie came to Dr. Adams with concerns that some of his young patients with sickle cell disease were experiencing strokes.

End points for the STOP II study included a reversion to an abnormal transcranial Doppler or a stroke and almost half the children in the halted transfusion arm experienced an end point within 10 months, some in as few as two months, Dr. Adams says. He noted data on nine patients in the halted transfusion arm were censored because they either resumed transfusion or began taking Hydroxyurea, a drug to treat the pain crises that are a hallmark of sickle cell disease.

One child who had a stroke had his first abnormal Doppler about eight months after halting transfusions and a stroke 14 days later. The second stroke occurred in a child eight days after his first abnormal study.

"I think it's clear that some people are going to look at these findings and suggest if we do Doppler exams often enough, we can get children off transfusions," says Dr. Adams. "But children in STOP II had frequent Doppler exams, much more frequently than likely would be used in usual clinical practice, and there were still problems." Participants had Doppler exams at least every 12 weeks and more frequently when anything abnormal was found.

Of the 209 children enrolled in the two STOP studies, 20 had strokes and all those children had abnormalities on their most recent exam. This confirms the technique's efficacy as a stroke indicator before transfusions are started and after they are stopped, according to the study.

"These results suggest that if stroke is to be prevented after transfusion is stopped, transcranial Doppler examinations must be performed at frequent intervals and transfusions resumed expeditiously," Dr. Adams writes.

Two children in the original STOP had strokes despite being on transfusion, probably because their disease was so advanced when treatment began, Dr. Adams says. STOP, which followed 130 at-risk children, also was halted early because of the dramatic findings of a 90 percent reduction in stroke risk. A physician advisory issued by the NHLBI in September 1997 recommended regular transcranial Doppler studies in children age 2-16 with sickle cell disease and that transfusion be considered for those at risk.

That's what Dr. McKie, who now works part time in the MCG Pediatric Sickle Cell Clinic, recommends today.

"I'm not surprised at how effective transfusion is," Dr. Adams says, noting that most children tended to do well on transfusion, with higher hemoglobin levels, fewer pain crises and cases of acute chest syndrome, better liver function and just generally growing and feeling better.

However, transfusions are not without problems. No transfusion-related infections were reported but there were nine transfusion reactions reported in STOP II, including one that required hospitalization.

Also, iron overload, which damages vital organs, necessitated chelation therapy five nights a week for most transfusion recipients to remove excess iron. Patients and families don't like the time-consuming and expensive therapy, Dr. McKie says, noting an oral therapy approved this year by the Food and Drug Administration may make chelation more palatable.

Many fundamental questions remain, including why these 10 percent of children have problems with stroke and how transfusion works to stop them. Whether there are better options than transfusion is another.

Dr. Adams' research team is providing neurological and transcranial Doppler expertise for a study coordinated by St. Jude's Children's Research Hospital that should help determine whether Hydroxyurea is one option. The study is comparing the drug to transfusion as a way to prevent second strokes. Dr. Adams doubts Hydroxyurea will be as effective, especially in patients who already have severe abnormalities in their blood vessels. But, "If this were to work in secondary prevention, it would be obvious to study it in primary prevention as well. We'll be watching it," Dr. Adams says.