NHLBI Stops Study Testing How Long Children with Sickle Cell Anemia Should Have Blood Transfusions to Prevent Stroke|
Clinical Alert Issued to U.S. Physicians
San Diego, California The National Heart, Lung, and Blood Institute
(NHLBI) of the National Institutes of Health (NIH) has stopped early
a clinical trial studying whether children with sickle cell anemia
at high risk for stroke could at some point after a minimum of 30
months (range 30-91 months) safely stop receiving the periodic blood
transfusions that prevent strokes. The study found a return to high
risk of stroke in children who stopped receiving the transfusions.
The NHLBI is issuing a clinical alert on the study's results to
inform physicians who treat children with sickle cell anemia.
The alert advises physicians that stopping transfusions cannot
be recommended. The document urges them to carefully discuss with
patients and their families the stroke prevention benefits of continuing
periodic transfusions as well as the risks of these transfusions,
which can include such long-term side effects as iron overload.
Management of these side effects should also be discussed, according
to the alert.
The results of the Stroke Prevention Trial II (STOP II) are being
presented in San Diego today as a special "late-breaking"
announcement at the annual meeting of the American Society of Hematology
(ASH). To further inform physicians, the NHLBI is posting the alert
on the National Library of Medicine's Clinical Alert and Advisories
Web page. STOP II investigators are notifying patients enrolled
in the study and their families.
STOP II, which began in 2000, expected to recruit 100 patients
age 2 to 18 over 6 years. When the study was stopped 2 years early
on November 10, 79 patients had been enrolled. At the time the study
was halted, 14 of the 41 patients who had been randomly assigned
to stop transfusions reverted to high risk of stroke as measured
by a special ultrasound technique and 2 patients had suffered a
stroke. There were no strokes or reversions to high stroke risk
in the group that continued with transfusions.
"This important study shows the value of continuing periodic
blood transfusions in preventing the serious and debilitating consequences
of stroke," said NHLBI Acting Director Barbara Alving, M.D.
"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," she added.
The risks of chronic blood transfusions include iron overload, which
can be harmful to several vital organs and must be treated with
chelation therapy. Other risks include alloimmunization, an immune
system reaction which can interfere with the benefits of subsequent
transfusions, and exposure to blood-borne infections.
The STOP II trial, conducted at 23 clinical centers in the U.S.
and 2 in Canada, enrolled patients at increased risk of stroke.
Stroke risk was determined with transcranial doppler (TCD) screening,
an ultrasound technique that measures the velocity of blood flow
in the brain. A high blood flow velocity in one or more major arteries
of the brain is linked with narrowing in key blood vessels supplying
the brain, which in turn increases the risk of a stroke.
STOP II participants had been transfused for at least 30 months
before entering the trial. Eligibility criteria for entry into STOP
II were a normal TCD velocity (indicating low risk of stroke) and
a magnetic resonance imaging study of the patients' brain arteries
showing no severe blockages. Upon entry, patients were randomly
assigned to receive either standard care with periodic blood transfusions
or to be taken off these transfusions.
Patients in the transfusion arm of the study received blood transfusions
every 3 to 4 weeks to keep the amount of abnormal, or sickle, hemoglobin
in their blood to no more than 30 percent of total hemoglobin. Transfused
patients who received a cumulative dose of 250 ml/kg of blood began
to develop iron overload and were given chelation therapy. Chelation
involves subcutaneous infusions of deferoxamine, a drug that removes
After 79 patients had been enrolled in the study, the STOP II Data
and Safety Monitoring Board (DSMB), an independent advisory committee
charged with reviewing results and ensuring participant safety,
conducted a regular review of the data. The analysis showed a highly
significant difference in stroke risk and actual stroke between
the transfusion and non-transfusion treatment arms. The DSMB recommended
early closure of the clinical trial.
About 10 percent of sickle cell patients are at risk for stroke.
Twenty percent of patients are at risk for "silent cerebral
infarcts," small strokes that can interfere with cognitive
functioning and school performance because brain tissue is damaged.
The importance of transfusion therapy in preventing strokes in
patients with sickle cell anemia was established in 1997 when the
results of the Stroke Prevention Trial in Sickle Cell Anemia (STOP
I) were released in a clinical alert. STOP I found that administering
blood transfusions every 3 to 4 weeks to children with sickle cell
anemia who are at high risk for stroke reduces their rate of first-time
stroke by 90 percent.
"STOP I showed that we could prevent stroke and its debilitating
consequences, including brain damage. What we didn't know was whether
the transfusions could be safely stopped at some point. This was
an important question because there are some problems with blood
transfusions, including increased risk of iron overload," said
Robert Adams, M.D. principal investigator of both STOP I and STOP
II and Regents Professor of Neurology and Professor of Pediatrics,
Medical College of Georgia. Adams presented the STOP II findings
at the ASH meeting.
"Now we know that for high-risk patients, it is not safe to
stop transfusions even if the TCD has returned to normal range.
We need to weigh carefully the risks of this preventive therapy
and make sure we monitor patients closely with TCD. We also need
to come up with a better way to maintain the stroke prevention benefit
while lowering the side effects of transfusion treatment,"
The clinical alert calls for further research to identify and test
therapies that will provide safe and effective protection from stroke
with fewer side effects than transfusion.
Sickle cell anemia, the most common genetic blood disorder in the
U.S., affects about 1 in 350 African-Americans and 1 in 1,000 Hispanic
newborns every year. Patients with this disease have abnormal hemoglobin
molecules in their red blood cells. The molecules damage the red
cells, causing them to stick to blood vessel walls. This can lead
to narrowed, or blocked, blood vessels in the brain, causing a stroke.
The participating centers in STOP II were:
Children's Hospital Medical Center; Cincinnati, OH;
Children's Hospital Oakland, Oakland, CA;
Children's Hospital of Los Angeles/UCLA; Los Angeles, CA;
Children's Hospital of New Orleans; Louisiana State University Medical
Center, New Orleans, LA
Children's Hospital of Philadelphia; Philadelphia, PA;
Children's Mercy Hospital, Kansas City, MO;
Children's National Medical Center, Washington, DC;
Columbia University; New York, NY;
Columbus Regional Hospital, Columbus, GA;
East Carolina University, Greenville, NC;
Emory University; Atlanta, GA;
Jackson Memorial Hospital, Miami, FL
Johns Hopkins University, Baltimore, MD;
Medical College of Georgia; Augusta, GA;
Medical University of South Carolina, Charleston, S.C.;
Morehouse School of Medicine, Atlanta, GA;
Rainbow Babies & Children's Hospital, Cleveland, OH;
Scottish Rite Children's Medical Center, Atlanta, GA;
Sinai Hospital of Baltimore; Baltimore, MD;
St. Jude Children's Research Hospital, Memphis, TN;
State University of New York-Brooklyn, Brooklyn, NY;
The Hospital for Sick Children; Toronto, Ontario;
University Health Network, Toronto General Hospital, Toronto, Ontario;
University of Alabama, Birmingham, AL;
University of Mississippi Medical Center Children's Hospital, Jackson,
Note: the New England Research Institute, Watertown, MA, was the
Data Coordinating Center
To interview an NHLBI spokesperson about the STOP II study, please
call the NHLBI Communications Office at 301-496-4236. To interview
Dr. Adams, call Toni Baker at the Medical College of Georgia at
706-721-4421. The clinical alert is online at www.nhlbi.nih.gov.
NHLBI is part of the National Institutes of Health (NIH), the
Federal Government's primary agency for biomedical and behavioral
research. NIH is a component of the U.S. Department of Health and
Human Services. NHLBI press releases and fact sheets, including
a fact sheet on sickle cell anemia, can be found online at www.nhlbi.nih.gov.