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Meta-Analysis
. 2017 Jan 17;1(1):CD003146.
doi: 10.1002/14651858.CD003146.pub3.

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

Lise J Estcourt  1 , Patricia M Fortin  2 , Sally Hopewell  3 , Marialena Trivella  4 , Winfred C Wang  5
Affiliations
Meta-Analysis

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

Lise J Estcourt et al. Cochrane Database Syst Rev. .

Update in

Abstract

Backround: Sickle cell disease is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. Sickle cell disease can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Stroke affects around 10% of children with sickle cell anaemia (HbSS). Chronic blood transfusions may reduce the risk of vaso-occlusion and stroke by diluting the proportion of sickled cells in the circulation.This is an update of a Cochrane Review first published in 2002, and last updated in 2013.

Objectives: To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease for primary and secondary stroke prevention (excluding silent cerebral infarcts).

Search methods: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 04 April 2016.We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 25 April 2016.

Selection criteria: Randomised controlled trials comparing red blood cell transfusions as prophylaxis for stroke in people with sickle cell disease to alternative or standard treatment. There were no restrictions by outcomes examined, language or publication status.

Data collection and analysis: Two authors independently assessed trial eligibility and the risk of bias and extracted data.

Main results: We included five trials (660 participants) published between 1998 and 2016. Four of these trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of sickle cell disease.Three trials compared regular red cell transfusions to standard care in primary prevention of stroke: two in children with no previous long-term transfusions; and one in children and adolescents on long-term transfusion.Two trials compared the drug hydroxyurea (hydroxycarbamide) and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children); and one in secondary prevention (children and adolescents).The quality of the evidence was very low to moderate across different outcomes according to GRADE methodology. This was due to the trials being at a high risk of bias due to lack of blinding, indirectness and imprecise outcome estimates. Red cell transfusions versus standard care Children with no previous long-term transfusionsLong-term transfusions probably reduce the incidence of clinical stroke in children with a higher risk of stroke (abnormal transcranial doppler velocities or previous history of silent cerebral infarct), risk ratio 0.12 (95% confidence interval 0.03 to 0.49) (two trials, 326 participants), moderate quality evidence.Long-term transfusions may: reduce the incidence of other sickle cell disease-related complications (acute chest syndrome, risk ratio 0.24 (95% confidence interval 0.12 to 0.48)) (two trials, 326 participants); increase quality of life (difference estimate -0.54, 95% confidence interval -0.92 to -0.17) (one trial, 166 participants); but make little or no difference to IQ scores (least square mean: 1.7, standard error 95% confidence interval -1.1 to 4.4) (one trial, 166 participants), low quality evidence.We are very uncertain whether long-term transfusions: reduce the risk of transient ischaemic attacks, Peto odds ratio 0.13 (95% confidence interval 0.01 to 2.11) (two trials, 323 participants); have any effect on all-cause mortality, no deaths reported (two trials, 326 participants); or increase the risk of alloimmunisation, risk ratio 3.16 (95% confidence interval 0.18 to 57.17) (one trial, 121 participants), very low quality evidence. Children and adolescents with previous long-term transfusions (one trial, 79 participants)We are very uncertain whether continuing long-term transfusions reduces the incidence of: stroke, risk ratio 0.22 (95% confidence interval 0.01 to 4.35); or all-cause mortality, Peto odds ratio 8.00 (95% confidence interval 0.16 to 404.12), very low quality evidence.Several review outcomes were only reported in one trial arm (sickle cell disease-related complications, alloimmunisation, transient ischaemic attacks).The trial did not report neurological impairment, or quality of life. Hydroxyurea and phlebotomy versus red cell transfusions and chelationNeither trial reported on neurological impairment, alloimmunisation, or quality of life. Primary prevention, children (one trial, 121 participants)Switching to hydroxyurea and phlebotomy may have little or no effect on liver iron concentrations, mean difference -1.80 mg Fe/g dry-weight liver (95% confidence interval -5.16 to 1.56), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: risk of stroke (no strokes); all-cause mortality (no deaths); transient ischaemic attacks, risk ratio 1.02 (95% confidence interval 0.21 to 4.84); or other sickle cell disease-related complications (acute chest syndrome, risk ratio 2.03 (95% confidence interval 0.39 to 10.69)), very low quality evidence. Secondary prevention, children and adolescents (one trial, 133 participants)Switching to hydroxyurea and phlebotomy may: increase the risk of sickle cell disease-related serious adverse events, risk ratio 3.10 (95% confidence interval 1.42 to 6.75); but have little or no effect on median liver iron concentrations (hydroxyurea, 17.3 mg Fe/g dry-weight liver (interquartile range 10.0 to 30.6)); transfusion 17.3 mg Fe/g dry-weight liver (interquartile range 8.8 to 30.7), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy: increases the risk of stroke, risk ratio 14.78 (95% confidence interval 0.86 to 253.66); or has any effect on all-cause mortality, Peto odds ratio 0.98 (95% confidence interval 0.06 to 15.92); or transient ischaemic attacks, risk ratio 0.66 (95% confidence interval 0.25 to 1.74), very low quality evidence.

Authors' conclusions: There is no evidence for managing adults, or children who do not have HbSS sickle cell disease.In children who are at higher risk of stroke and have not had previous long-term transfusions, there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke, and low quality evidence they also reduce the risk of other sickle cell disease-related complications.In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration.In secondary prevention of stroke there is low-quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events.All other evidence in this review is of very low quality.

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Conflict of interest statement

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

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Blood transfusion versus standard care, Outcome 1 Clinical stroke.
1.2
1.2. Analysis
Comparison 1 Blood transfusion versus standard care, Outcome 2 Clinical stroke ‐ velocity.
1.3
1.3. Analysis
Comparison 1 Blood transfusion versus standard care, Outcome 3 Clinical stroke ‐ SCI.
1.4
1.4. Analysis
Comparison 1 Blood transfusion versus standard care, Outcome 4 Mortality.
1.5
1.5. Analysis
Comparison 1 Blood transfusion versus standard care, Outcome 5 Transfusion‐related adverse events.
1.6
1.6. Analysis
Comparison 1 Blood transfusion versus standard care, Outcome 6 TIA.
1.7
1.7. Analysis
Comparison 1 Blood transfusion versus standard care, Outcome 7 Other sickle cell related complications.
2.1
2.1. Analysis
Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 1 Clinical stroke ‐ Secondary prevention.
2.2
2.2. Analysis
Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 2 Mortality.
2.3
2.3. Analysis
Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 3 Transfusion‐related complications ‐ Serum ferritin; Primary prevention.
2.4
2.4. Analysis
Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 4 Transfusion related complications ‐ Liver iron concentration ‐ Primary prevention.
2.5
2.5. Analysis
Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 5 Other neurological event.
2.6
2.6. Analysis
Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 6 Other sickle cell related complications.
2.7
2.7. Analysis
Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 7 Haemoglobin levels.
2.8
2.8. Analysis
Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 8 Haemoglobin S levels.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

SIT 2014 {published data only}
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SWiTCH 2012 {published data only}
    1. Alvarez O, Yovetich NA, Scott JP, Owen W, Miller ST, Schultz W, et al. Pain and other non‐neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: results from the SWiTCH clinical trial. American Journal of Hematology 2013;88(11):932‐8. [CENTRAL: 963136; CRS: 5500125000000520; PUBMED: 23861242] - PMC - PubMed
    1. Aygun B, Mortier NA, Kesler K, Schultz WH, Alvarez OA, Rogers ZR, et al. Therapeutice phlebotomy in children with sickle cell anemia, stroke, and iron overload: the SWiTCH experience. 53rd ASH Annual Meeting and Exposition; 2011 Dec 10‐13; San Diego, California. 2011. [Abstract no: 1044]
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    1. Kwiatkowski JL, Cohen AR, Garro J, Alvarez O, Nagasubramanian R, Sarnaik S, et al. Transfusional iron overload in children with sickle cell anemia on chronic transfusion therapy for secondary stroke prevention. American Journal of Hematology 2012;87(2):221‐3. [CENTRAL: 864015; CRS: 5500100000011226; PUBMED: 22120913] - PubMed
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TWiTCH 2016 {published data only}
    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; PUBMED: 22231377] - PubMed
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    1. NCT01425307. Transcranial doppler (TCD) with transfusions changing to hydroxyurea (TWiTCH). clinicaltrials.gov/ct2/show/NCT01425307 accessed 29 May 2016).
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References to studies excluded from this review

Bernaudin 2015 {published data only}
    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.
SCATE 2015 {published data only}
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