Correspondence

Correction

Prevention of Stroke by Transfusions in Children with Sickle Cell Anemia

N Engl J Med 1998; 339:1477-1478November 12, 1998

Article

To the Editor:

The results of the carefully conducted study by Adams et al. (July 2 issue)1 of the value of transfusion in preventing strokes in children with sickle cell anemia and abnormal results on transcranial Doppler studies were impressive and promise to change approaches to the management of strokes in this disease. Adams et al. do not address the timing of the first transcranial Doppler study or the interval between studies. These important issues need to be addressed before a protocol based on transcranial Doppler ultrasonography can be universally applied.

A point requiring clarification is the total number of transcranial Doppler studies that the subjects underwent to determine their eligibility for the study. Only 79 children who had normal results at the first screening subsequently had abnormal results and thus would have required a third imaging examination. From the total number of transcranial Doppler studies (3929) performed on the 1934 patients in the study, it appears that an inordinately large number of patients had a third study. The authors should describe their criteria for a third study, since there is a potential for bias in this regard.

It is hardly surprising that transfusions prevented a first episode of stroke in children with sickle cell anemia. Since the late 1970s several studies2,3 have shown that maintaining hemoglobin S levels below 30 percent by means of transfusion can prevent recurrent strokes and largely eliminate the symptoms of the disease. However, the risks and difficulties of multiple transfusions, particularly given the need for long-term iron-chelation therapy, are formidable, as clearly stated in the accompanying editorial.4 The value of screening with transcranial Doppler ultrasonography in predicting a stroke is suggested by the finding of Adams et al. of a stroke rate of 10 per 102 patient-years in the untransfused group of study patients with repeatedly positive transcranial Doppler studies. This represents an increase by a factor of 10 over the results of previous studies, which showed a rate of 1.02 per 100 patient-years in a similar age group of unscreened children.5 It is disappointing that the authors did not present any data regarding the clinical outcome of the roughly 1700 patients who were found to have normal results on transcranial Doppler ultrasonography on one or more occasions. Ascertaining the prevalence of stroke in this cohort would have added considerable credibility to their conclusions about the value of screening with transcranial Doppler ultrasonography as a predictor of stroke.

Sharada A. Sarnaik, M.D.
Children's Hospital of Michigan, Detroit, MI 48201

5 References

1. 1

   Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5-11
   Full Text | Web of Science | Medline

2. 2

   Pegelow CH, Adams RJ, McKie V, et al. Risk of recurrent stroke in patients with sickle cell disease treated with erythrocyte transfusions. J Pediatr 1995;126:896-899
   CrossRef | Web of Science | Medline

3. 3

   Sarnaik S, Soorya D, Kim J, Ravindranath Y, Lusher J. Periodic transfusions for sickle cell anemia and CNS infarction. Am J Dis Child 1979;133:1254-1257
   Web of Science | Medline

4. 4

   Cohen AR. Sickle cell disease -- new treatments, new questions. N Engl J Med 1998;339:42-44
   Full Text | Web of Science | Medline

5. 5

   Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998;91:288-294
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Dr. Sarnaik points out several important aspects of our study, which confirmed the ability of transcranial Doppler ultrasonography to identify a subgroup of children with a high risk of stroke and demonstrated that transfusion therapy significantly reduced the risk of stroke. The study was designed to investigate the efficacy of such treatment, but further research is needed to develop an optimal screening program.

The age at which the first screening study was performed in our study was two years, because stroke is not common in children younger than two years and younger patients often cannot lie quietly for the 30 to 40 minutes needed for the examination. The interval between studies and the total number of studies were determined by the screening algorithm, which based the interval between tests on the results of the first screening. It could be as short as a few weeks if the results of the first study were abnormal or as long as six to nine months if the initial results were normal, assuming the patient's compliance with the date arranged for the next test. Finally, children who were first screened late in the trial may not have had subsequent studies.

With such a design, described in detail elsewhere,1 rescreening is biased toward patients who comply with the protocol of the study and who have more abnormal results. However, the rate of stroke in the standard-care group was sufficient to test the study question, and any screening bias was not detrimental to the trial.

We agree that the current state of knowledge of sickle cell disease is not optimal2 and that better treatment for complications of the disease are being sought. However, our study provides solid information on the risks and benefits of a treatment that can be used today.

When Dr. Adams reviewed the galley proofs of the article, he made changes in the order of authorship without the permission of the four authors involved and added a further author to the list. The correct list of authors and other authors is as follows:

Robert J. Adams, M.D., Virgil C. McKie, M.D., Lewis Hsu, M.D., Ph.D., Beatrice Files, M.D., Elliott Vichinsky, M.D., Charles Pegelow, M.D., Miguel Abboud, M.D., Gerald Woods, M.D., Nancy Olivieri, M.D., Catherine Driscoll, M.D., Scott Miller, M.D., and Donald Brambilla, Ph.D.

Other authors were Winfred Wang, M.D., Anne Hurlet, M.D., Charles Scher, M.D., Brian Berman, M.D., Elizabeth Carl, B.A., Fenwick T. Nichols, M.D., E. Steve Roach, M.D., Abdullah Kutlar, M.D., Elizabeth Wright, Ph.D., Robert A. Zimmerman, M.D., Dianne Gallagher, M.S., Myron A. Waclawiw, Ph.D., and Duane R. Bonds, M.D.

Lewis Hsu, M.D.
Emory University School of Medicine, Atlanta, GA 30303

Beatrice Files, M.D.
East Carolina University School of Medicine, Greenville, NC 27858

Robert J. Adams, M.D.
Medical College of Georgia, Augusta, GA 30912-3200

2 References

1. 1

   Adams RJ, McKie VC, Brambilla D. et al. Stroke Prevention Trial in Sickle Cell Anemia. Control Clin Trials 1997;19:110-129
   CrossRef

2. 2

   Cohen AR. Sickle cell disease -- new treatments, new questions. N Engl J Med 1998;339:42-44
   Full Text | Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Gavin Cho, Ian R Hambleton, Gavin Cho. 2011. Regular long-term red blood cell transfusions for managing chronic chest complications in sickle cell disease. .
   CrossRef

2. 2

   Gavin Cho, Ian R Hambleton, Gavin Cho. 2010. Regular long-term red blood cell transfusions for managing chronic chest complications in sickle cell disease. .
   CrossRef

3. 3

   Ceri Hirst, Winfred C Wang, Ceri Hirst. 2002. Blood transfusion for preventing stroke in people with sickle cell disease. .
   CrossRef

4. 4

   Ceri Hirst, Shirley Owusu-Ofori, Ceri Hirst. 2002. .
   CrossRef

5. 5

   Allison Ashley-Koch, Catherine C. Murphy, Muin J. Khoury, Coleen A. Boyle. (2001) Contribution of sickle cell disease to the occurrence of developmental disabilities: A population-based study. Genetics in Medicine 3:3, 181-186
   CrossRef

6. 6

   Darleen R. Powars. (2000) Management Of Cerebral Vasculopathy In Children With Sickle Cell Anaemia. British Journal of Haematology 108:4, 666-678
   CrossRef