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STOP II
Questions and Answers
Questions about the study
Questions about stroke risk in children with sickle cell anemia
Questions
about blood transfusions to prevent strokes
Questions about using TCD to identify children at risk for stroke
Questions
about other preventive treatments for stroke
Questions about the study
What is the STOP II Trial?
STOP II, funded by the National Heart, Lung, and Blood Institute (NHLBI),
tested whether chronic blood transfusions for primary stroke prevention
could be safely discontinued after 30 or more months by children who had not
had an overt stroke and who had a reversion to low-risk transcranial Doppler
(TCD) ultrasound velocity while on chronic transfusion therapy. Low-risk TCD
velocity is defined as < 170 cm/sec time-averaged mean of the maximum. The
purpose of the STOP II trial was to optimize transfusion for stroke
prevention by determining which children need to continue chronic blood
transfusion therapy to prevent strokes. Chronic blood transfusion therapy is
costly, and can be associated with significant morbidities including risk of
iron overload, alloimmunization, and exposure to infectious blood-borne
agents.
What were the most important findings in STOP II?
Blood transfusions should be continued to reduce the rate of strokes
(cerebral infarctions or hemorrhages) in children with sickle cell anemia (SCA)
who are at risk of strokes. The STOP II Trial showed that when transfusions
were discontinued after at least 30 months (range, 30-91 months), a
significant number of children either reverted to the high-risk range of TCD
velocities or, in the case of two children, developed an overt stroke after
an elevated TCD velocity was observed.
Why did the STOP II Trial end early?
On Nov. 10, 2004, after 79 of a planned sample size of 100 children were
randomized, the Data and Safety Monitoring Board, appointed by NHLBI,
recommended that the study be closed for safety concerns. An interim
analysis showed a highly significant difference between the two treatment
arms (transfusion and non-transfusion) with respect to reversion to
high-risk (or abnormal) TCD and stroke.
When the trial was closed, 16 of the 41 research subjects randomized to come
off transfusion experienced an endpoint. Fourteen of the endpoints were
reversions to high-risk TCD (without stroke) and two were ischemic strokes.
The strokes occurred shortly after the first abnormal TCD but before another
TCD could be obtained and transfusion therapy resumed.
Where can my doctor get more information?
For more information, contact the Medical College of Georgia STOP II Trial
Central Administrative Office at 706-721-4670 or the Hemoglobinopathies and
Genetics Scientific Research Group, NHLBI, at 301-435-0055.
More can be found on stroke and stroke research in SCA at the Medical
College of Georgia website (http://www.mcg.edu/neurology/research.htm).
Questions can also be directed to the centers participating in STOP
II.
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Questions about stroke risk in children with sickle cell anemia
What is sickle cell anemia?
Sickle cell anemia (SCA) is the most common genetic blood disorder in the
U.S., affecting approximately 1 in 350 African American and 1 in 1,000
Hispanic newborns each year, based on the 2000 U.S. National Newborn
Screening HRSA database. It occurs when an infant inherits the gene for the
sickle hemoglobin (HbS) from both parents (sickle cell anemia) or the gene
for HbS from one parent and the gene for another abnormal hemoglobin from
the other parent (sickle cell disease types such as HbSC and HbS-beta
thalassemia).
How many children with sickle cell anemia are there in this country
today?
There is no national registry of SCA, so we can only estimate the number of
affected individuals in the U.S. Current estimates based on the gene
frequency of HbS and the national birth rate of African American and
Hispanic children put the number of affected individuals at approximately
72,000.
Are there different kinds of strokes in children with sickle cell anemia?
A stroke occurs when the blood supply to the brain is interrupted, either by
the blockage of a major brain blood vessel (infarction) or a rupture of a
brain blood vessel (hemorrhage). A stroke results in brain damage. A stroke
can cause weakness and loss of sensation, difficulty with vision and speech,
and trouble with learning and memory, and even death. Multiple strokes have
a cumulative effect on overall behavior and function particularly in
learning and cognitive development.
While all children with SCA are at some increased risk, the highest risk is
found among children with prior stroke, symptoms of transient ischemic
attack (TIA), those who have abnormal TCD velocities, those who already have
areas of brain that are abnormal even though no motor or sensory symptoms
were reported (silent cerebral infarcts), and those with recent acute chest
syndrome.
Most children (about 80%) with SCA have cerebral infarctions. About 20% of
strokes in children are hemorrhagic strokes, which occur more frequently in
adults with SCA. Blood transfusions can prevent cerebral infarctions. It is
not clear if hemorrhagic strokes can be prevented by transfusions,
particularly in adults with SCA.
How many children with sickle cell anemia are at risk of stroke?
From the Cooperative Study of Sickle Cell Disease (CSSCD), we estimate that
approximately 10% of SCA children will be at risk for stroke. In STOP I,
14.9% of children in the standard care arm suffered a stroke. The STOP I and
II Trials enrolled subjects who were at higher risk than the average patient
with SCA in the CSSCD study. This means that about 3,000-7,200 children with
SCA in the U.S. will need to be screened for stroke risk.
Once a child with sickle cell anemia has one stroke, is he or she more
likely to have another one?
Yes, 90% of children who have a stroke and are not placed on chronic
transfusion therapy may have another stroke.
What is the mortality rate for children with sickle cell
anemia who have a stroke?
The CSSCD followed 2,824 patients under the age of 20 between 1979 and 1987.
The mortality rate from stroke in this cohort was 12.3%. Stroke was second
only to bacterial infections (mortality rate of 38.4%) as the leading cause
of death.
What are the anticipated cost savings from preventing
strokes in children with sickle cell anemia?
It is anticipated that the cost savings by preventing strokes will include
decreased intensive care costs associated with severe cerebrovascular
accidents, decreased rehabilitation costs, and improved ability to function
in school and work. Current cost estimates per patient for acute stroke care
are from $5,400 to $15,900 during the first 30 days. The cost estimate per
patient over a lifetime after cerebral infarction is $500,000.
In the case of children, family members and caregivers who already have a
greater-than-normal burden in handling the medical and psycho-social needs
created by SCA, have an even greater task caring for a child who has had a
stroke.
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Questions
about blood transfusions to prevent strokes
How do blood transfusions prevent strokes in these children?
We believe that blood transfusions may prevent strokes by decreasing the
amount of sickle hemoglobin (HbS) circulating in the brain’s blood vessels,
which would prevent further damage to the cerebral blood vessels.
Although transfusions lower blood flow velocities as shown by transcranial
Doppler (TCD) ultrasound, not all children on transfusion revert to a normal
TCD. Even in those children with persistently high TCD, the risk of stroke
is reduced.
What led to this discovery?
Dr. Robert Adams published a Medical College of Georgia study which showed
that TCD could identify sickle cell anemia (SCA) children at risk for
stroke. The use of blood transfusions to prevent further strokes after a
child had a stroke has been accepted medical practice for over 15 years.
STOP I tested the hypothesis that transfusions may prevent strokes from
occurring in the first place. The ability to use TCD to identify children
with a high stroke risk justified the use of blood transfusions for this
purpose.
What is needed now is a new approach for long-term stroke prevention
treatment. This may be either better ways to predict which children can come
off blood transfusions after some years of therapy, or other treatments that
prevent stroke without the problems of iron overload, alloimmunization, and
blood-borne infections.
Will blood transfusions prevent all strokes in children with sickle cell
anemia?
No, probably not all strokes can be prevented by blood transfusions. In STOP
I, there were 10 strokes in the standard care arm and 1 stroke in the
transfusion arm. The rate of stroke recurrence in patients on chronic
transfusions is approximately 10%. If not transfused, 90% of children who
have had an overt stroke go on to have another one. In STOP II, there were
no strokes and no returns to abnormal TCD velocity in the group receiving
transfusions. In addition, there were two strokes in the non-transfusion arm
in two children whose TCDs were abnormal. They were to come in for a
confirmatory TCD when the neurological events occurred.
How often can children with sickle cell anemia receive blood transfusions
now?
Children with SCA are usually transfused when they develop a clinical
problem that can be treated successfully with blood replacement, such as
acute chest syndrome, aplastic crisis, or severe sickle cell crisis. In
addition, chronic blood transfusion therapy is the standard of care in the
U.S. for children who have had a stroke to prevent recurrence. After the end
of STOP I, periodic blood transfusions (every 3-4 weeks to lower the HbS
level below 30%) was recommended for children found to be at high risk for
stroke if they had an elevated TCD velocity (> 200 cm/sec).
How often should they receive them now that we have the STOP II study
results?
Children in the transfusion arm of the study were transfused to keep their
HbS below 30%. No reversions to high stroke risk occurred in this treatment
arm. So, it is recommended that patients continue to receive a blood
transfusion approximately every 3- weeks.
What are the risks of frequent blood transfusions for these children?
One risk is iron overload. The ferritin level increases with the amount
of blood transfused. Subjects in the transfusion arm of the STOP I Trial
needed chelation to remove excess iron from their bodies after about a year
of chronic transfusions. Similarly, subjects in STOP II had evidence of iron
overload, and chelation therapy was recommended to treat this problem.
The blood supply in the U.S. is safe. However, there may be risks of viral
transmission of diseases in chronic blood transfusions. The risk of
post-transfusion hepatitis caused by hepatitis B virus has been estimated to
be 1 in 200,000. The risk from hepatitis C virus is estimated to be 1 in
1,800,000 units. The risk of contracting HTLV from a blood transfusion is
estimated to be 1 in 641,000, and for HIV, is estimated to be 1 in
2,000,000. The donated blood is screened for these viruses to reduce the
risk of transmission to the recipient.
The third risk for children with SCA is alloimmunization (developing
antibodies to red blood cell antigens). In STOP II, no children developed
new alloantibodies. The investigators succeeded in minimizing this problem
by carefully cross-matching blood for minor and major blood group antigens.
These risks are related to individual issues which will have to be handled
on a case-by-case basis with every child who is found to be at risk for
first time stroke.
Are there special centers for transfusion therapy for people with sickle
cell anemia?
It is important that transfusions be supervised by experienced
physicians with appropriate resources for delivering and monitoring the
therapy safely. Proper cross-matching of the blood product for major and
minor subgroup antigens is also needed. Since transfusion is commonly
employed in SCA for several reasons, sickle cell specialized treatment
centers are the best place to go for advice on where, when, and how to get
safe and effective blood transfusion therapy.
How much do blood transfusions cost for children with sickle cell anemia?
The costs of blood transfusions depend on the size and age of the child. A
larger child will require more blood at one sitting than a smaller child to
maintain the level of HbS at less than 30%. Children in the group receiving
transfusions in the STOP II Trial received blood every 3-4 weeks. On the
average, this would cost about $15,000 to $25,000 per year.
How much does chelation cost?
Chelation costs about $1500 per month, or $18,000 per year.
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Questions about using TCD ultrasound to identify children at risk for stroke
What is a transcranial Doppler ultrasound test?
Transcranial Doppler (TCD) ultrasound is the only widely tested and
validated method for stroke prevention in SCA. It is an approved medical
diagnostic ultrasound device that measures blood flow velocity in large
arteries of the brain. A high flow velocity suggests that arteries that
supply the brain may have narrowed. TCD is a non-invasive method to estimate
the velocities in the large intracranial vessels of the circle of Willis.
Using established TCD techniques, sections of the distal internal carotid
artery (dICA), middle cerebral artery (MCA), anterior carotid artery (ACA),
posterior cerebellar artery (PCA) and the basilar and periorbital arteries
can be examined. TCD typically uses a 2 MHz pulse ultrasound.
How is TCD administered?
TCD is performed by having the patient lie still on a table or bed, and a
small cylinder-shaped transducer about the size of a tube of lipstick is
placed against the temple area of the head. The ultrasound signals are sent
toward the blood vessels and bounce back to the transducer which transmits a
recording of the information to a microcomputer. Specially trained
technicians performed these studies in the STOP I and STOP II Trials. TCD
was used to evaluate patients with other forms of cerebrovascular disease in
the mid-1980s and was adapted to sickle cell anemia (SCA), primarily by
Medical College of Georgia researchers. This method is painless, relatively
inexpensive, and can usually be completed in 30-45 minutes.
What does TCD show in a child with sickle cell anemia who is at risk of a
stroke?
The blood flow profile is measured by TCD cycles with each heart beat, which
is fastest right after the heart contracts (systole) and slowest just before
the next heart beat (diastole). Both the STOP I and STOP II Trials used the
average velocity throughout the heart cycle (time-averaged mean) which is
normally 130 cm/sec or less. If a subject had a blood flow velocity of 200
cm/sec or more on two separate occasions, the subject was considered to be
at risk for stroke. Approximately 10% of 2,020 children screened with TCD
were found to have elevated brain blood flow velocities.
Adults without SCA typically have time-averaged maximum mean (TAMM)
velocities in the MCA of 60 + 12 cm/sec, while children have MCA velocities
closer to 90 cm/sec. SCA, with its significant anemia, causes an increase in
cerebral blood flow velocity in the major arteries and is associated with
velocities of 130 cm/sec to 140 cm/sec, even without vessel narrowing.
The STOP I Trial used a dedicated Doppler which produced the velocity
spectrum without any visual reference. The MCA is located, then, moving in 2
mm increments, the vessel is insonated and the most representative velocity
spectrum is found by adjusting the probe's depth and angle. Depth and flow
direction assist the technician in identifying the vessels. The same
technique is used for transcranial Doppler imaging (TCDI), which uses
imaging of the vessels and may take less time for technicians to master.
Three correlation studies show that TCDI provides similar although slightly
lower velocities and can readily be used for screening children with SCA.
TCDI is widely available around the U.S., especially at non-STOP II Trial
sites.
How often are children with sickle cell anemia screened with TCD now?
Children with SCA should be screened at least once a year with TCD for
stroke risk. TCD screening is recommended for children with SCA who are 2-16
years old and have not had a stroke. TCD identifies children at elevated
risk for stroke so that transfusion therapy can be considered. Two separate
TCD exams with velocities over 200 cm/sec in the MCA or dICA are related to
a significant risk of stroke unless transfusion is begun. At present there
is no role for TCD after a child has had a stroke because chronic
transfusion would already be recommended to prevent subsequent strokes.
How often should they be screened by TCD according to the STOP II study?
Based on the results of the study, it is recommended that children with SCA
be screened with TCD every 6-12 months during early childhood, and less
often afterward if the previous tests were normal.
Are there special centers for TCD ultrasound for people with sickle cell
anemia?
TCD can be performed in many larger medical centers and some of these
centers have special training in use of TCD in SCA. Large-scale screening
and management of children with increased stroke risk is possible by using
the network of NHLBI-funded Comprehensive Sickle Cell Disease Centers and
the STOP II Trial centers. All 25 STOP II sites will be able to immediately
handle referrals for stroke risk screening.
Most experienced ultrasound labs using Doppler sonography are accredited by
the Intersociety Commission for the Accreditation of Vascular Laboratories (ICAVL)
(http://www.intersocietal.org/icavl/laboratories/labs.htm). The ICAVL
website lists accredited labs by state, and many of these provide TCD
services. The Medical College of Georgia website also has information on
where TCD can be obtained.
In addition, local hospitals can be asked if they offer TCD screening for
children with SCA or references to such a site.
How much does a TCD cost?
In the U.S., the average cost of TCD is between $150 and $300 per
examination.
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Questions
about other preventive treatments for stroke
Why is there still no cure for sickle cell anemia?
Sickle cell anemia (SCA) can be completely cured by bone marrow
transplantation. However, it is currently not being recommended for all
children with SCA because of the risks of significant morbidity including
permanent sterility, infection, chronic graft-versus-host disease and the
5%-10% risk of dying from this procedure. Only children with significant
complications and an HLA-matched donor are being considered for the current
study of bone marrow transplantation in hemoglobinopathies. The NHLBI
supports basic science research which hopefully will lead to a more widely
applicable cure for SCA.
What new developments are on the horizon for people with sickle cell
anemia?
Investigators have proposed a comparison of hydroxyurea to blood
transfusions for stroke prevention as the next major multicenter clinical
trial. In addition, hydroxyurea is being studied in infants to determine if
it can prevent the onset of chronic end organ damage.
Are any gene therapy trials going on or planned for the near future?
Gene therapy has been curative in transgenic mouse models of sickle cell
disease and thalassemia. Scientists are exploring the possibility of
adapting this experimental animal model approach to human studies.
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