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Clinical
Alert from
the National Heart, Lung, and Blood Institute
(December 05, 2004)
The National Heart, Lung, and Blood Institute (NHLBI)
announced today an advisory recommending that blood transfusions should be
continued in order to reduce the rate of strokes (cerebral infarctions or
hemorrhages) in children with sickle cell anemia who are at risk of strokes.
Strokes occur in approximately 10% of children with sickle cell anemia.
These cerebral vascular events can be very debilitating, leading to physical
and neuro-psychological impairment which can affect motor skills, school
performance, and overall quality of life.
In 1997, a Clinical Alert was issued by NHLBI based on the
Stroke Prevention Trial in Sickle Cell Anemia (STOP
I) Trial. In that study, a 90% reduction in the rate of first-time
stroke was reported when chronic blood transfusions were offered to children
with sickle cell anemia who had been identified as being at high risk by
transcranial Doppler (TCD). Periodic red blood cell transfusions reduced the
rate of stroke by 90 % in STOP I. By lowering the level of hemoglobin S (Hb
S) below 30%, strokes were prevented in children found to be at increased
risk by virtue of having elevated transcranial doppler (TCD) velocities in
the internal carotid and middle cerebral arteries.
In 2000, a second randomized, controlled clinical trial, STOP II, funded by
NHLBI, was initiated to test whether chronic transfusions for primary stroke
prevention could be safely discontinued after at least 30 months (range 30 -
91 months) in children who had not had an overt stroke, and who had
reversion to low risk TCD velocity with 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 needed continued therapy to
prevent stroke. 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.
The STOP II Trial showed that when transfusions were discontinued after a
minimum of 30 months, a significant number of children reverted to high risk
range of TCD velocities or, in the case of two children, developed an overt
stroke after an elevated TCD velocity was observed.
The STOP II Trial, headquartered at the Medical College of Georgia
(Dr. Robert Adams) and the New
England Research Institutes (Dr. Donald Brambilla), enrolled 79 children who
ranged from 2 to 18 years of age. The patients were drawn from 23 clinical
centers in the United States and two in Canada (list attached). The patients
were randomized to receive either standard supportive care with periodic
blood transfusions or to be withdrawn from periodic blood transfusions if
their TCD velocity had returned to low-risk range. Children with severe
stenosis of the middle cerebral or internal carotid arteries viewed by
magnetic resonance angiography (MRA) were excluded from randomization. The
primary endpoint was the comparison of the rate of reversion to abnormal TCD
velocity and/or stroke in the treated and control groups.
In both treatment arms, children received close clinical and TCD
surveillance for the first occurrence of reversion of TCD to abnormal,
confirmed with two or more TCD=s of 200 cm/sec or higher. This TCD change
indicated a return of high risk for overt stroke. In addition, overt stroke
was included as part of the primary endpoint. The main hypothesis was that
over 3 years of observation fewer than 50% of children in the experimental
arm would revert to high stroke risk or have an overt stroke, and that
quarterly (at least every 8 to 12 weeks) surveillance with TCD would provide
acceptable safety monitoring with respect to stroke risk.
The patients in the transfusion arm received periodic simple or exchange
blood transfusions every 3 to 4 weeks in an effort to maintain the Hb S
level below 30%. The trial protocol required that red blood cell
transfusions were matched for ABO, C, D, E, and K antigens. The children in
both arms were followed for exposure to transfusion transmitted viral
diseases and iron overload. Patients who had been on the transfusion
protocol and received a cumulative dose of 250 ml/kg of blood began to
develop elevated serum ferritin levels greater than 2500 mg/L and were
started on chelation therapy.
After 79 of a planned sample size of 100 children were randomized, the Data
and Safety Monitoring Board, appointed by NHLBI, recommended closure of the
study for safety concerns when an interim analysis showed a highly
significant difference between the transfusion and non-transfusion treatment
arms with respect to the composite endpoint of TCD reversion to high risk
and overt stroke. At the time of closure of the trial, in 41 subjects
randomized to come off transfusion, there had been 16 endpoints. Of the 16
endpoints, 14 reversions to high risk TCD (without stroke) occurred, and two
ischemic strokes occurred shortly after the first TCD reverted to abnormal
but before a confirmatory TCD could be obtained and transfusion therapy
resumed. Six other subjects were returned to periodic transfusion therapy
for clinical reasons before endpoints occurred (crossovers), primarily due
to recurrent acute chest syndrome or sickle cell related painful episodes.
No neurologic events or reversions to high risk TCD were observed in those
subjects who were in the chronic transfusion treatment arm. The reversions
to abnormal TCD velocity were seen early after discontinuation of periodic
transfusions, between 4-9 months. The length of time on transfusion therapy
prior to randomization was the only potential indicator of TCD reversion to
abnormal that was identified by secondary analyses. There was a trend toward
lower risk of reversion to abnormal TCD in subjects who were transfused for
greater than 54 months prior to randomization. Age, gender, presence of
silent infarct lesions on magnetic resonance imaging, %Hb S on transfusion,
and number of transfusions prior to randomization did not predict increased
risk of reversion to abnormal TCD.
While some children tolerate removal from chronic transfusion therapy
without apparent problems, discontinuation of transfusion after 30 months
cannot be recommended based on STOP II due to the high TCD reversion rate,
and the small risk of overt stroke despite frequent TCD surveillance. In
addition, there is the likelihood that some children may need to return to
transfusions for other sickle cell related clinical reasons.
It should be emphasized that the patients studied in STOP II were those with
TCD velocities that reverted to low risk on periodic transfusions, and
without severe arterial lesions on MRA. This subset of children who
participated in STOP II are thought to be at lower risk for stroke than
those children who had been in STOP I but did not qualify for STOP II
because their TCD velocities did not revert to normal on transfusions or
because they had arterial lesions on MRA.
Further research will be needed to: (1) determine better ways to predict
those who can be removed safely from transfusion while still accomplishing
effective primary stroke prevention, or (2) identify and test alternative
therapies to transfusion that will provide safe and effective protection
from stroke with fewer side effects than transfusion. Physicians will have
to carefully discuss with patients and their families the risk-benefit ratio
of continuing periodic transfusions for stroke prevention when compared to
the long term side effects of iron overload. The choice of clinical
management, including whether to continue periodic transfusions or to stop
transfusions with TCD monitoring every 2-3 months, must be made on a
case-by-case basis. Children who continue on chronic transfusions should
also receive appropriate management of iron overload.
STOP II Principal
Investigators as of November 02, 2004
Robert J. Adams, MS, MD
(Principal Investigator Clinical Consortium)
Regents Professor of Neurology
Medical College of Georgia
1429 Harper Street, HF 1154
Augusta, GA 30912
phone: 706-721-4670
fax: 706-721-6950
email: rjadams@mcg.edu
Donald J. Brambilla, PhD (Principal
Investigator Data Coordinating Center)
New England Research Institutes
9 Galen Street
Watertown, MA 02172
phone: 617-923-7747 ext. 230
fax: 617-926-8246
email: donb@neri.org
STOP II Peripheral Site Investigators
Alvarez, Ofelia, MD
Jackson Memorial Hospital
1611 NW 12th Avenue
ACC West R-555
Miami, FL 33136
phone: 305-585-5635
fax: 305-545-8387
email: oalvarez2@med.miami.edu
Barredo, Julio MD
Medical University of South Carolina
135 Rutledge Avenue
Charleston, SC 29425
phone: 843-792-2957
fax: 843-792-8912
email: barredjc@musc.edu
Berman, Brian MD
Rainbow Babies & Children=s Hospital
Ped/Hem/Onc
11100 Euclid Avenue, Room 310
Cleveland, OH 44106
phone: 216-844-3345
fax: 216-844-5431
email: brian.berman@uhhs.com
Casella, James MD
Johns Hopkins University
School of Medicine
720 Rutland Avenue, Ross 1125
Baltimore, MD 21205
phone: 410-955-6132
fax: 410-955-8208
email: jcasella@jhmi.edu
Coates, Thomas MD
Children's Hospital of Los Angeles
University of Southern California
School of Medicine
4650 Sunset Blvd, MS 54
Los Angeles, CA 90027
phone: 323-669-2352
fax: 323-660-9321
email: tcoates@hsc.usc.edu
Daeschner, Charles MD
Director of Pediatric Hematology/Oncology
Associate Professor of Pediatrics
School of Medicine, Dept. of Pediatrics
East Carolina University
Brody Medical Sciences Building
600 Moye Boulevard
Greenville, NC 27858
phone: 252-816-4676 or 4151
fax: 252-816-8199
email: daeschnerc@mail.ecu.edu
Driscoll, Catherine MD
Children's National Medical Center
Dept. Hem/Onc
111 Michigan Avenue NW
Washington, DC 20010
phone: 202-884-2867
fax: 202-884-5685
email: cdriscol@cnmc.org
Files, Beatrice MD
Scottish Rite Children's Medical Center
5455 Meridian Mark Rd #400
Atlanta, GA 30342
phone: 404-785-3634
fax: 404-785-3520
email: beatrice.files@choa.org
Gee, Beatrice MD
Assistant Professor of Clinical Pediatrics
Morehouse School of Medicine
Dept. of Pediatrics
720 Westview Drive, SW
Atlanta, GA 30310
phone: 404-756-1335 (gen office: 756-1330)
fax: 404-756-1357
email: geeb@msm.edu
Hilliard, Lee MD
Assistant Professor of Pediatrics
University of Alabama at Birmingham
Pediatric Sickle Cell Center
1600 7th Avenue South CHT 651
Birmingham, AL 35233
phone: 205-939-9285
fax: 205-975-6377
email: lhilliard@peds.uab.edu
Iyer, Rathi MD
The University of Mississippi Medical Center Children's Hospital
Division of Pediatric Hematology/Oncology
2500 N State Street
Jackson, MS 39216
phone: 601-984-5220
fax: 601-984-5279
email: riyer@ped.umsmed.edu
Kalinyak, Karen MD
Children's Hospital Medical Center
Hematology/Oncology Division
3333 Burnet Avenue
Cincinnati, OH 45036
phone: 513-636-4379
fax: 513-636-5845
email: karen.kalinyak@chmcc.org
Kirby, Melanie MD
The Hospital for Sick Children
555 University Avenue
Hem/Onc
Toronto, Ontario
Canada M5G1X8
phone: 416-813-7606
fax: 416-813-5759
email: melanie.kirby@sickkids.on.ca
Kwiatkowski, Janet MD
Children's Hospital of Philadelphia
Division of Hematology
Wood Bldg 4th Floor
34th Street and Civic Center Boulevard
Philadelphia, PA 19104
phone: 215-590-3681
fax: 215-590-3992
email: kwiatkowski@email.chop.edu
Lane, Peter MD
Emory University
Dept. Hem/Onc
2040 Ridgewood Drive, NE
Suite 106
Atlanta, GA 30322
phone: 404-727-1288
fax: 404-727-4455
email: plane@emory.edu
McKie, Virgil MD
Medical College of Georgia
The Marks Building, HF 1107
1429 Harper Street
Augusta, GA 30912
phone: 706-721-3626
fax: 706-721-2643
email: vmckie@deptpeds.mcg.edu
Miller,Scott MD
SUNY-Brooklyn
Kings County Hospital
450 Clarkson Avenue, Box 49
Brooklyn, NY 11203
phone: 718-270-1692
fax: 718-270-1985
email: stmseelig@aol.com
Olivieri, Nancy MD
University Health Network
Toronto General Hospital
200 Elizabeth Street, CW-3-338
Toronto, Ontario
Canada M5G 2C4
phone: 416-340-4800 ext 6507
fax: 416-340-3348
email: noliv@attglobal.net
Piomelli, Sergio MD
Columbia University
3959 Broadway BHB Room 21
New York, NY 10032
phone: 212-305-6538
fax: 212-305-8408
email: sp23@columbia.edu
Provisor, Arthur MD
Columbus Regional Hospital
710 Center Street
Columbus, GA 31902
phone: 706-571-1221
fax: 706-571-1070
email: arthur.provisor@chrs.net
Vichinsky, Elliott MD
Children's Hospital Oakland
747 52nd Street, Dept. Hematology
Oakland, CA 94609
phone: 510-428-3651
fax: 510-450-5647
email: evichinsky@mail.cho.org
Wang, Winfred MD
St. Jude Children's Research Hospital
332 North Lauderdale St
Ped/Hem/Onc
Memphis, TN 38105
phone: 901-495-3497
fax: 901-521-9005
email: win.wang@stjude.org
Wiley, Joseph MD
Sinai Hospital of Baltimore
2401 W. Belvedere Avenue
Baltimore, MD 21215
phone: 410-601-5864
fax: 410-601-8390
email: jwiley@lifebridgehealth.org
Woods, Gerald MD
Children's Mercy Hospital
2401 Gilham Road
Hem/Onc
Kansas City, MO 64108
phone: 816-234-3265
fax: 816-471-5460
email: gwoods@cmh.edu
Warrier, Raj MD
Children's Hospital of New Orleans
Louisiana State University Medical Center
Dept. Ped/Hem/Onc
1542 Tulane Avenue
New Orleans, LA 70112
phone: 504-896-9740
fax: 504-896-9758
email: rwarri@lsuhsc.edu