This clinical alert was reproduced from the US NHLBI site. For the original,
National Heart, Lung, and Blood Institute (NHLBI)
September 18, 1997
The National Heart, Lung, and Blood Institute today announced
that periodic red blood cell transfusions in children with sickle
cell anemia has been found to reduce the rate of stroke in those
patients. Findings from a clinical trial made up of 130 children,
who ranged in age from 2 to 16, showed that red blood cell
transfusions every three or four weeks significantly cut the rate
The study--the Stroke Prevention Trial in Sickle Cell Anemia
(STOP)--compared stroke rates in 63 children who received
periodic transfusions with 67 children who were getting standard
supportive care. The study was based on clinical observations
that showed a decreased risk of stroke in children who already
suffered one stroke if hemoglobin S levels were maintained at or
less than 30%.
The children used in the study were known to be at high risk
for stroke because of elevated cerebral blood flow, which was
measured by using transcranial doppler screening tests.
The STOP trial found that after one year, 10 children in the
standard care group had had a stroke, while only one child in the
transfusion group suffered a cerebral infarction. The results
represent a 90% relative decline in the stroke rate.
The study, which was supposed to continue through December
1998, has been halted so that the standard care group could begin
receiving the periodic transfusion treatment.
The STOP study also confirmed that transcranial doppler
screening can be used to identify children with sickle cell
anemia who are at high risk for a first-time stroke. As a result,
it is now recommended that sickle-cell patients between two and
16 receive transcranial doppler screening. Children with normal
screens should be re-screened about every six months. An abnormal
screen is a velocity of 200 cm/sec or greater, and should be
elevated on two separate readings.
Before screening children with sickle cell anemia for stroke
risk, it is recommended that screening centers evaluate their TCD
equipment and compare it with that used in the STOP trial. NHLBI
contact: Dr. Duane Bonds (301) 496-6931
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
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
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
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
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. NHLBI contact: Dr. Duane Bonds (301) 496-6931.