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. 2013 Nov 14:(11):CD003146.
doi: 10.1002/14651858.CD003146.pub2.

Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease

Winfred C Wang  1 , Kerry Dwan
Affiliations

Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease

Winfred C Wang et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: In sickle cell disease, a common inherited haemoglobin disorder, abnormal haemoglobin distorts red blood cells, causing anaemia, vaso-occlusion and dysfunction in most body organs. Without intervention, stroke affects around 10% of children with sickle cell anaemia (HbSS) and recurrence is likely. Chronic blood transfusion dilutes the sickled red blood cells, reducing the risk of vaso-occlusion and stroke. However, side effects can be severe.

Objectives: To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease to prevent first stroke or recurrences.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings.Date of the latest search of the Group's Haemoglobinopathies Trials Register: 28 January 2013.

Selection criteria: Randomised and quasi-randomised controlled trials comparing blood transfusion as prophylaxis for stroke in people with sickle cell disease to alternative or no treatment.

Data collection and analysis: Both authors independently assessed the risk of bias of the included trials and extracted data.

Main results: Searches identified three eligible randomised trials (n = 342). The first two trials addressed the use of chronic transfusion to prevent primary stroke; the third utilized the drug hydroxycarbamide (hydroxyurea) and phlebotomy to prevent both recurrent (secondary) stroke and iron overload in patients who had already experienced an initial stroke. In the first trial (STOP) a chronic transfusion regimen for maintaining sickle haemoglobin lower than 30% was compared with standard care in 130 children with sickle cell disease judged (through transcranial Doppler ultrasonography) as high-risk for first stroke. During the trial, 11 children in the standard care group suffered a stroke compared to one in the transfusion group, odds ratio 0.08 (95% confidence interval 0.01 to 0.66). This meant the trial was terminated early. The transfusion group had a high complications rate, including iron overload, alloimmunisation, and transfusion reactions. The second trial (STOP II) investigated risk of stroke when transfusion was stopped after at least 30 months in this population. The trial closed early due to a significant difference in risk of stroke between participants who stopped transfusion and those who continued as measured by reoccurrence of abnormal velocities on Doppler examination or the occurrence of overt stroke in the group that stopped transfusion. The third trial (SWiTCH) was a non-inferiority trial comparing transfusion and iron chelation (standard management) with hydroxyurea and phlebotomy (alternative treatment) with the combination endpoint of prevention of stroke recurrence and reduction of iron overload. This trial was stopped early after enrolment and follow up of 133 children because of analysis showing futility in reaching the composite primary endpoint. The stroke rate (seven strokes on hydroxyurea and phlebotomy, none on transfusion and chelation, odds ratio 16.49 (95% confidence interval 0.92 to 294.84)) was within the non-inferiority margin, but the liver iron content was not better in the alternative arm.

Authors' conclusions: The STOP trial demonstrated a significantly reduced risk of stroke in participants with abnormal transcranial Doppler ultrasonography velocities receiving regular blood transfusions. The follow-up trial (STOP 2) indicated that individuals may revert to former risk status if transfusion is discontinued. The degree of risk must be balanced against the burden of chronic transfusions. The combination of hydroxyurea and phlebotomy is not as effective as "standard" transfusion and chelation in preventing secondary stroke and iron overload. Ongoing multicentre trials are investigating the use of chronic transfusion to prevent silent infarcts, the use of hydroxyurea as an alternative to transfusion in children with abnormal transcranial Doppler ultrasonography velocities, and the use of hydroxyurea to prevent conversion of transcranial Doppler ultrasonography velocities from conditional (borderline) to abnormal values.

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Conflict of interest statement

Declarations of Interest Lise Estcourt: partly funded by the NIHR Cochrane Programme Grant - Safe and Appropriate Use of Blood Components. Patricia Fortin: funded by the NIHR Cochrane Programme Grant - Safe and Appropriate Use of Blood Components. Sally Hopewell: partly funded by the NIHR Cochrane Programme Grant - Safe and Appropriate Use of Blood Components. Marialena Trivella: partly funded by the NIHR Cochrane Programme Grant - Safe and Appropriate Use of Blood Components. Winfred Wang: was a PI on several of the included trials (STOP 1998; STOP 2 2005; SWiTCH 2012). He has been a consultant for: Celgene (at a one-day meeting involving an anti-sickling drug); and Baxter (at a one-day meeting involving gene therapy for haemoglobinopathies). These consultancies did not involve treatment that would be used in the management of stroke in people with SCD.

Figures

Figure 1
Figure 1. Study flow diagram.
Figure 2
Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.
Figure 3
Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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    5. NCT00122980. Stroke with transfusions changing to hydroxyurea (SWiTCH) [accessed 16th August 2011]; www.clinicaltrials.gov/show/NCT00122980 [2987125]
    6. Sheehan VA, Howard TA, Sabo A, Nagasaswamy U, Crosby JR, Davis B, et al. Genetic predictors of hemoglobin F response to hydroxyurea in sickle cell anemia. Blood. 2012;120(21) [Abstract no 241; CENTRAL: 977454; CRS: 5500125000000531; 2987126]
    7. Ware RE, Helms RW. Stroke with transfusions changing to hydroxyurea (SWiTCH): a phase 3 randomised clinical trial for treatment of children with sickle cell anemia; 52nd ASH Meeting and Exposition; 2010 Dec 4-7; Orlando, Florida: 2010. [Abstract no 844; 2987128]
    8. Ware RE, Helms RW, SWiTCH Investigators Stroke with transfusions changing to hydroxyurea (SWiTCH) Blood. 2012;119(17):3925–32. [2987127] - PMC - PubMed
    9. Ware RE, McMurray MA, Schultz WH, Alvarez OA, Aygun B, Cavalier ME, et al. Academic community standards for chronic transfusion therapy in children with sickle cell anemia and stroke. Blood. 2006;108(11) [Abstract no: 1213; 2987129]
    10. Ware RE, Schultz WH, Yovetich N, Mortier NA, Alvarez O, Hilliard L, et al. Stroke with transfusions changing to hydroxyurea (SWiTCH): A phase III randomized clinical trial for treatment of children with sickle cell anemia, stroke, and iron overload. Pediatric Blood & Cancer. 2011;57(6):1011–7. [2987130] - PMC - PubMed
    1. Aygun B, Wruck LM, Schultz WH, Mueller BU, Brown C, Luchtman-Jones L, et al. Chronic transfusion practices for prevention of primary stroke in children with sickle cell anemia and abnormal TCD velocities. American Journal of Hematology. 2012;87(4):428–30. [CENTRAL: 1139772; CRS: 5500135000001510; 4681003] - PubMed
    2. Helton KJ, Roberts D, Schultz WH, Davis BR, Kalfa TA, Pressel SL, et al. Effects of chronic transfusion therapy on MRI and MRA in children with sickle cell anemia at risk for primary stroke: baseline imaging from the Twitch Trial. Blood. 2014;124(21):4052. [4681004]
    3. Imran H, Aygun B, Davis BR, Pressel SL, Schultz WH, Jackson S, et al. Effects of chronic transfusion therapy on transcranial doppler ultrasonography velocities in children with sickle cell anemia at risk for primary stroke: Baseline findings from the twitch trial. Blood. 2014;124(21):87. [4681005]
    4. NCT01425307. Transcranial doppler (TCD) with transfusions changing to hydroxyurea (TWiTCH) [accessed 29 May 2016]; [4681006] clinicaltrials.gov/ct2/show/NCT01425307.
    5. Ware RE, Davis BR, Schultz WH, Brown C, Aygun B, Sarnaik SA, et al. TCD with transfusions changing to hydroxyurea (TWITCH): Hydroxyurea therapy as an alternative to transfusions for primary stroke prevention in children with sickle cell anemia. Blood. 2015;126(23):3. [4681007]
    6. Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia - TCD with Transfusions Changing to Hydroxyurea (TWiTCH): A multicentre, open-label, phase 3, non-inferiority trial. Lancet. 2016;387(10019):661–70. [CENTRAL: 1138971; CRS: 5500050000000362; 4681008; EMBASE: 20160126001; NCT01425307: TCD With Transfusions Changing to Hydroxyurea (TWiTCH): A Phase III Randomized Trial to Compare Standard Therapy (Erythrocyte Transfusions) With Alternative Therapy (Hydroxyurea) for the Maintenance of Lowered TCD Velocities in Pediatric Subjects With Sickle Cell Anemia and Abnormal Pre–treatment TCD Velocities] - PMC - PubMed
    7. Wood JC, Cohen A, Aygun B, Imran H, Luchtman-Jones L, Thompson AA, et al. Extrahepatic iron deposition in chronically transfused children with sickle cell anemia - Baseline findings from the twitch trial. Blood. 2013;122(21):2238. [4681009]
    8. Wood JC, Cohen AR, Pressel SL, Aygun B, Imran H, Luchtman-Jones L, et al. Organ iron accumulation in chronically transfused children with sickle cell anaemia: Baseline results from the TWiTCH trial. British Journal of Haematology. 2016;172(1):122–30. [CENTRAL: 1133502; CRS: 5500050000000361; 4681010; EMBASE: 20151011308] - PMC - PubMed
    9. Wood JC, Pressel S, Rogers ZR, Odame I, Kwiatkowski JL, Lee MT, et al. Liver iron concentration measurements by MRI in chronically transfused children with sickle cell anemia: Baseline results from the TWiTCH trial. American Journal of Hematology. 2015;90(9):806–10. [CENTRAL: 1090263; CRS: 5500050000000271; 4681011; EMBASE: 2015311270] - PMC - PubMed

References to studies excluded from this review

    1. Bernaudin FV, Ducros-Miralles S, Ducros-Miralles E, Delatour RP, Dalle J-H, Petras E, et al. French national drepagreffe trial: Cognitive performances and neuroimaging at enrollment and after 12 months on transfusion program or transplantation (AP-HP: NCT 01340404) Blood. 2015;126(23):544. [4681013]
    1. Hankins JS, McCarville MB, Rankine-Mullings A, Reid ME, Lobo CL, Moura PG, et al. Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial. American Journal of Hematology. 2015;90(12):1099–105. [2987134] - PMC - PubMed
    1. NCT01531387. Sparing conversion to abnormal TCD (transcranial doppler) elevation (SCATE) [accessed 06 November 2013]; [2987135] clinicaltrials.gov/show/NCT01531387.

Additional references

    1. Adams RJ, Nichols FT, Figueroa R, McKie V, Lott T. Transcranial Doppler correlation with cerebral angiography in sickle cell disease. Stroke. 1992;23(8):1073–7. - PubMed
    1. Adams RJ, McKie VC, Brambilla D, Carl E, Gallagher D, Nichols FT, et al. Stroke prevention trial in sickle cell anemia. Controlled Clinical Trials. 1998;19(1):110–29. - PubMed
    1. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial doppler ultrasonography. New England Journal of Medicine. 1998;339(1):5–11. - PubMed
    1. Ansong D, Osei Akoto A, Ocloo D, Ohene-Frempong K. Sickle cell disease: management options and challenges in developing countries. Mediterranean Journal of Hematology and Infectious Diseases. 2013;5(1):e2013062. - PMC - PubMed
    1. Aygun B, McMurray MA, Schultz WH, Kwiatkowski JL, Hilliard L, Alvarez O, et al. Chronic transfusion practice for children with sickle cell anaemia and stroke. British Journal of Haematology. 2009;145(4):524–8. - PubMed

References to other published versions of this review

    1. Hirst C, Wang WC. Blood transfusion for preventing stroke in people with sickle cell disease. Cochrane Database of Systematic Reviews. 2002;(1) doi: 10.1002/14651858.CD003146. - DOI - PubMed
    1. Wang WC, Dwan K. Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease. Cochrane Database of Systematic Reviews. 2013;(11) doi: 10.1002/14651858.CD003146.pub2. - DOI - PMC - PubMed

    2. Indicates the major publication for the study

Publication types