Prevention of a First Stroke by Transfusions in Children with Sickle Cell Anemia and Abnormal Results on Transcranial Doppler Ultrasonography

The New England Journal of Medicine -- July 2, 1998 -- Volume 339, Number 1

 
Robert J. Adams, Virgil C. McKie, Lewis Hsu, Beatrice Files, Elliott Vichinsky, Charles Pegelow,Miguel Abboud, Dianne Gallagher, Abdullah Kutlar, Fenwick T. Nichols, Duane R. Bonds,Donald Brambilla, Gerald Woods, Nancy Olivieri, Catherine Driscoll, Scott Miller, Winfred
Wang, Anne Hurlett, Charles Scher, Brian Berman, Elizabeth Carl, Anne M. Jones, E. Steve
Roach, Elizabeth Wright, Robert A. Zimmerman, Myron Waclawiw

Abstract

Background. Blood transfusions prevent recurrent stroke in children with sickle cell
anemia, but the value of transfusions in preventing a first stroke is unknown. We used
transcranial Doppler ultrasonography to identify children with sickle cell anemia who
were at high risk for stroke and then randomly assigned them to receive standard
care or transfusions to prevent a first stroke.

Methods. To enter the study, children with sickle cell anemia and no history of
stroke had to have undergone two transcranial Doppler studies that showed that the
time-averaged mean blood-flow velocity in the internal carotid or middle cerebral
artery was 200 cm per second or higher. The patients were randomly assigned to
receive standard care or transfusions to reduce the hemoglobin S concentration to
less than 30 percent of the total hemoglobin concentration. The incidence of stroke
(cerebral infarction or intracranial hemorrhage) was compared between the two
groups.

Results. A total of 130 children (mean [±SD] age, 8.3±3.3 years) were enrolled; 63
were randomly assigned to receive transfusions, and 67 to receive standard care. At
base line, the transfusion group had a slightly lower mean hemoglobin concentration
(7.2 vs. 7.6 g per deciliter, P=0.001) and hematocrit (20.4 vs. 21.7 percent,
P=0.002). Ten patients dropped out of the transfusion group, and two patients
crossed over from the standard-care group to the transfusion group. There were 10
cerebral infarctions and 1 intracerebral hematoma in the standard-care group, as
compared with 1 infarction in the transfusion group -- a 92 percent difference in the
risk of stroke (P<0.001). This result led to the early termination of the trial.

Conclusions. Transfusion greatly reduces the risk of a first stroke in children with
sickle cell anemia who have abnormal results on transcranial Doppler
ultrasonography. (N Engl J Med 1998;339:5-11.)

Source Information

From the Departments of Neurology (R.J.A., F.T.N.), Pediatric Hematology and
Oncology (V.C.M.), and Medicine (A.K.), Medical College of Georgia, Augusta;
the Sickle Cell Center, Emory University School of Medicine, Atlanta (L.H.); the
Department of Pediatric Hematology and Oncology, East Carolina University School
of Medicine, Greenville, N.C. (B.F.); the Department of Hematology and Oncology,
Children's Hospital Oakland, Oakland, Calif. (E.V.); the Sickle Cell Center,
University of Miami School of Medicine, Miami (C.P.); the Pediatric Sickle Cell
Program, Medical University of South Carolina, Charleston (M.A.); the New
England Research Institutes, Watertown, Mass. (D.G., D.B.); and the National
Heart, Lung, and Blood Institute, Bethesda, Md. (D.R.B.). Address reprint requests
to Dr. Adams at the Department of Neurology, Medical College of Georgia, 1467
Harper St., HB-2060, Augusta, GA 30912-3200. Stroke Prevention Study STOP Trial

Menu: Introduction, Why a trial? What is stroke? Why transfusions? What was the STOP trial design?What is Transcranial Doppler? Why did it close early? What are the results? What are highlights of the Clinical Alert? Go to The Clinical Alert itself (Hyperlink) Any cautions? What is transfusion? What are iron overload and chelation? Who are contacts at Emory-Grady?

Introduction

The Georgia Comprehensive Sickle Cell Center at Grady Memorial Hospital and Emory University is one of the fourteen centers in the Stroke Prevention Trial in Sickle Cell Anemia (STOP), led by Dr.Robert Adams of the Medical College of Georgia and supported by the National Heart Lung and Blood Institute . The STOP trial was a randomized clinical trial testing whether regular blood transfusions could prevent stroke in sickle cell disease (SCD).

The Georgia Comprehensive Sickle Cell Center had 16 patients of the 130 enrolled in the STOP trial, second only to the lead institution MCG in patient enrollment. A Clinical Alert was issued on September 18, 1997, with early closure of the STOP trial due to positive findings.

Why have a trial to prevent stroke in children with sickle cell disease?

Sickle cell disease is one of the few conditions associated with childhood stroke, and occurs in 8 - 12% of children with certain types of sickle cell disease (SCD -HbSS and SCD - HbS beta-zero).

Strokes

Stroke in these children usually results from a narrowing or closure of arteries supplying blood flow to the brain. When the blood flow is interrupted, a stroke can occur which causes permanent damage to the brain (cerebral infarction, CNS protocol). The child may have weakness of one arm or leg, speech or memory problems, or other losses of brain function. These lost functions may recover with rehabilitation therapy after the stroke, but may also be permanent.

Why test transfusions as treatment?

If one stroke has occurred in a child with sickle cell disease, it has been known that regular blood transfusions generally prevent second and third strokes. Until the STOP trial, however, there was no way to prevent the first stroke from occurring. No other treatments have been tested for stroke prevention.

What was the design of the STOP trial ?

The STOP trial began treating patients in February 1995 and was scheduled to continue through December 1998:

1) using the transcranial Doppler ultrasound (TCD) screening test to identify which children with sickle cell disease who are at higher risk for stroke.

2) determining whether treatment of a group of these children with blood transfusion every 3 or 4 weeks will decrease their risk of stroke. These children were compared with a standard care group that had close surveillance but no regular blood transfusions. Additional details on the design of the STOP trial will be published in the Journal of Clinical Trials (In Press).

What is Transcranial Doppler?

Transcranial doppler ultrasound (TCD) is a device that uses painless ultrasound to detect areas of increased blood flow in the blood vessels of the brain. When the blood vessels are narrowed due to sickle cell damage, the blood makes a louder noise as is travels faster through the narrow area. This is like the noise in a water hose when you make the hose bend. When this test is positive, there is a greater risk of having a stroke and further testing is necessary.

Click Here for a  printable TCD Patient education hand out by Lee Patcher

What made the STOP trial close early ? What were the results?

The Data & Safety Monitoring Board appointed by the NHLBI reviewed the interim data analyses and recommended to the NHLBI that the STOP Trial should be halted so that children in the standard care arm could be offered the benefits of first stroke prevention by receiving periodic blood transfusions."

Transfusion proved to be so effective that the STOP trial question was answered 16 months earlier than expected. Ten children had developed stroke in the 67 children of the standard care group, compared to only one in the group of 63 children receiving transfusions. The data was so compelling that the decision was made to close the STOP trial early, on September 2, 1997. The results were discussed with the patients in both treatment arms and with their families over the next 2 weeks.

What are highlights of the Clinical Alert say?

A Clinical Alert (HYPERLINK to NHLBI CLINICAL ALERT) was issued by the National Institutes of Health on September 18, 1997, alerting doctors in the USA that the approach used in the STOP trial for stroke prevention was effective- detecting high stroke risk with TCD and treating and reducing that risk with transfusion. TCD screening of comparable quality and information content to those used in the STOP trial was recommended for children ages 2-16 with SCD-HbSS, in order to apply the results of the STOP trial and assess each child's stroke risk.

The Clinical Alert recommends that centers that wish to start screening children with sickle cell disease for stroke risk do studies to compare their current equipment with the STOP trial TCD equipment and protocols, and that Dr. Robert Adams should be contacted for further information and training (HYPERLINK to MCG Dr. Adams) at 706-721-4670.

All STOP trial sites will also be available for patient referrals and for TCD screening children with SCD, to determine stroke risk and to counsel the patient and family about treatment options. (Hyperlink to STOP trial sites list).

Cautions

The Clinical Alert warns that 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 a child with sickle cell disease.

What are Transfusions?

Transfusions are the administration of normal donor blood cells to help and replace the sickle red blood cells in the body. You may learn more by reading the transfusion guidelines

What is iron overload and chelation therapy?

Iron is inside the red blood cells and helps to carry oxygen inside the chemical hemoglobin. Iron is reused by the body and can accumulate when blood transfusions are given. Usually after 1 to 3 years of chronic transfusions, the iron in the transfused blood is kept in the body and builds to levels that can be harmful. Chelation therapy is a procedure of giving medication that binds to the iron in the body and allows the body pass it out in the urine. This medicine, called Desferal, must be given slowly with a pump through a small needle under the skin or through a port.

Do the STOP trial results apply to my clinical practice or to my child?

Probably yes, but generalizing the STOP trial results to clinical practice appears to have 3 cautions 1) early closure of the STOP trial limits the data on long-term risks and benefits in the two groups

2) further TCD screening needs to be comparable to STOP trial TCD equipment and procedure

3) transfusion decision should be made in consultation with a physician experienced in transfusions in children with sickle cell disease and management of iron overload

Detailed results of the STOP trial are being submitted for publication in a peer-reviewed biomedical journal, so that the medical community and the public can fully evaluate the data soon.

Who are involved in the STOP trial at Emory Health Care- Grady -Georgia Comprehensive Sickle Cell Center?

The multidisciplinary team involved in the STOP study and related sickle cell stroke studies at Emory includes Eldrida Carter, study coordinator, Dr. Lewis Hsu and Dr. Thomas Adamkiewicz, of pediatric hematology-oncology-BMT (hyperlinks),  Dr. Patricia Davis and Dr. Jay Cinnamon of neuroradiology, and Dr. Michael Frankel of Neurology and the Stroke unit.

For questions about STOP study, contact Dr. Robert Adams at MCG . For other research studies in sickle cell disease care at Georgia Comprehensive Sickle Cell Center at Grady Memorial Hospital and Emory University (404-616-3572)

World Wide Web Sites for Further Information

Medical College of Georgia, Dept of Neurology, Cerebrovascular Section,

Dr. Robert Adams

http://www.neuro.mcg.edu/cvhp.htm

http://www.neuro.mcg.edu/cvhp/tcd.htm

http://www.neuro.mcg.edu/cvhp/stop.html

http://www.neuro.mcg.edu/cvhp/STOP/centers.html

Emory University, Georgia Sickle Cell Center, Pediatric Hematology, Dr.Lewis Hsu 

http://www.cc.emory.edu/PEDS/HEMONC/

http://www.emory.edu:80/PEDS/HEMONC/faculty.htm

REFERRALS

Dr. Lewis Hsu

e-mail to This e-mail address is being protected from spambots. You need JavaScript enabled to view it

http://www.emory.edu:80/PEDS/REFERRAL/sickle.htm