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

Lise J Estcourt; Patricia M Fortin; Sally Hopewell; Marialena Trivella; Winfred C Wang

doi:10.1002/14651858.CD003146.pub3

Cochrane Database of Systematic Reviews

Transfusión de sangre para la prevención del accidente cerebrovascular primario y secundario en pacientes con anemia de células falciformes

Información

DOI:

https://doi.org/10.1002/14651858.CD003146.pub3 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

17 enero 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Fibrosis quística y enfermedades genéticas

Copyright:

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Lise J Estcourt

Correspondencia a: Haematology/Transfusion Medicine, NHS Blood and Transplant, Oxford, UK

[email protected]

[email protected]
Patricia M Fortin

Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK
Sally Hopewell

Oxford Clinical Trials Research Unit, University of Oxford, Oxford, UK
Marialena Trivella

Centre for Statistics in Medicine, University of Oxford, Oxford, UK
Winfred C Wang

Department of Hematology, St Jude Children's Research Hospital, Memphis, USA

Contributions of authors

The original review was conceived by the Cochrane Cystic Fibrosis and Genetic Disorders Group and designed by Dr Hirst (née Riddington).

In this most recent update all listed authors contributed to the review.

Lise Estcourt: searching; selection of trials; eligibility assessment; content expert, and review content update and development.
Patricia Fortin: searching; selection of trials; eligibility assessment; and review content update and development.
Sally Hopewell: methodological expert and review development.
Marialena Trivella: statistical and methodological expert and review development
Winfred Wang: protocol development, review development and content expert.

Sources of support

Internal sources

No sources of support supplied

External sources

National Institute for Health Research, UK.

This systematic review was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group.

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.

Acknowledgements

We acknowledge the substantial contribution by Dr Ceri Hirst in undertaking the original version of this review (Hirst 2002), and Dr Kerry Kirkham (née Dwan) in the update of the review (Wang 2013).

We thank the editorial base of the Cochrane Cystic Fibrosis and Genetic Disorders Group for their help and support during the course of this review.

We thank NHS Blood and Transplant (NHSBT).

We thank the National Institute for Health Research (NIHR). This review is part of a series of reviews that have been partly funded by the NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components. This research was also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme.The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Version history

Published

Title

Stage

Authors

Version

2020 Jul 27

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

Review

Lise J Estcourt, Ruchika Kohli, Sally Hopewell, Marialena Trivella, Winfred C Wang

https://doi.org/10.1002/14651858.CD003146.pub4

2017 Jan 17

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

Review

Lise J Estcourt, Patricia M Fortin, Sally Hopewell, Marialena Trivella, Winfred C Wang

https://doi.org/10.1002/14651858.CD003146.pub3

2013 Nov 14

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

Review

Winfred C Wang, Kerry Dwan

https://doi.org/10.1002/14651858.CD003146.pub2

2002 Jan 21

Blood transfusion for preventing stroke in people with sickle cell disease

Review

Ceri Hirst, Winfred C Wang

https://doi.org/10.1002/14651858.CD003146

Revision date This is the date when the review was published	Event	Description
2009 May 22	New search has been performed	A search of the Group's Trials Register did not identify any new references which may have been eligible for inclusion in this review.
2008 Jul 31	New search has been performed	A search of the Group's Haemoglobinopathies Trials Register identified no new trials potentially eligible for inclusion in the review.
2008 Jul 31	Amended	Converted to new review format.
2007 Aug 01	New search has been performed	A search of the Trials Register identified a total of 10 new references. Eight were of the STOP trials (two of which refer to both the STOP and STOP 2 trials and so appear in both lists (Adamkiewicz 2006; Kwiatkowski 2002)): six new references to the STOP trial (STOP 1998) as follows (Adamkiewicz 2006; Kwiatkowski 2002; Kwiatkowski 2006; Lee 2006; Lezcano 2006; Wang 2005). The search also identified a further two abstracts (DeBaun 2005; Ware 2006) which have been listed in the 'Ongoing studies' section of the review.
2006 Feb 01	New search has been performed	A search of the Trials Register identified seven new references to the included trial (STOP 1998) as follows: Abboud 2004; Adams 2004; Bulas 2000; Gates 2002; Hsu 2003; Kwiatkowski 2002; Kwiatkowski 2003. It has also been reported that the STOP II trial has been terminated early, although published findings are not yet available.
2004 Aug 31	New search has been performed	A search of the trials register identified no new trials eligible for inclusion in the review.
2003 Aug 31	New search has been performed	Additional references to the already included STOP 1998 study have been added. However, no new data have been found. The references added to the STOP 1998 study ID were: Adams 1998 Wang 1998 Adams 2002 Files 2002
2002 Sep 30	New search has been performed	Additional references to the already included STOP 1998 study have been added. Therefore, further results are presented on the following outcomes ‐ 1. Transfusion related complications 2. Incidence of transient ischaemic attack or silent infarction 3. Incidence of other sickle cell complications The references added to the STOP 1998 study ID were: Abbound 1999 Adams 1996 Adams 1997 Adams 1999 ‐ two references Adams 2001 Duncan 1997 Kutlar 2000 Lee 2002 Nichols 2001 Miller 2000 ‐ two references Miller 2001 Pegelow 1999 Pegelow 2001 Vichinsky 1999 Vichinsky 2001

Differences between protocol and review

The title has been amended to include the terms 'primary and secondary'.

Excluded quasi‐randomised trials.

New subgroups TCD and silent cerebral infarcts.

Excluded outcome of SCI as it is being addressed within another review (Estcourt 2016).

Includes cluster‐randomised trials.

Included Summary of Findings tables.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Adolescent; Child; Child, Preschool; Humans; Young Adult;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Blood transfusion versus standard care, Outcome 1 Clinical stroke.

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Analysis 1.2

Comparison 1 Blood transfusion versus standard care, Outcome 2 Clinical stroke ‐ velocity.

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Analysis 1.3

Comparison 1 Blood transfusion versus standard care, Outcome 3 Clinical stroke ‐ SCI.

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Analysis 1.4

Comparison 1 Blood transfusion versus standard care, Outcome 4 Mortality.

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Analysis 1.5

Comparison 1 Blood transfusion versus standard care, Outcome 5 Transfusion‐related adverse events.

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Analysis 1.6

Comparison 1 Blood transfusion versus standard care, Outcome 6 TIA.

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Analysis 1.7

Comparison 1 Blood transfusion versus standard care, Outcome 7 Other sickle cell related complications.

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Analysis 2.1

Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 1 Clinical stroke ‐ Secondary prevention.

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Analysis 2.2

Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 2 Mortality.

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Analysis 2.3

Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 3 Transfusion‐related complications ‐ Serum ferritin; Primary prevention.

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Analysis 2.4

Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 4 Transfusion related complications ‐ Liver iron concentration ‐ Primary prevention.

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Analysis 2.5

Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 5 Other neurological event.

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Analysis 2.6

Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 6 Other sickle cell related complications.

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Analysis 2.7

Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 7 Haemoglobin levels.

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Analysis 2.8

Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 8 Haemoglobin S levels.

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Summary of findings for the main comparison. Long‐term red cell transfusion versus no transfusion in people who are at risk of a primary stroke who have not had previous long‐term red cell transfusions

Primary prevention
Patient or population: individuals with sickle cell disease who are at risk of a primary stroke who have not had previous long‐term red cell transfusions Setting: outpatients Intervention: long‐term red cell transfusion Comparison: standard care
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (trials)	Quality of the evidence (GRADE)	Comments
	Risk with standard care	Risk with Blood transfusion
Clinical stroke follow‐up: mean 24 months	Trial population		RR 0.12 (0.03 to 0.49)	326 (2 RCTs)	⊕⊕⊕⊝ Moderate ³
	110 per 1000	13 per 1000 (3 to 54)
All‐cause mortality	No deaths occurred in either trial arm		‐	326 (2 RCTs)	⊕⊝⊝⊝ Very low ^{1 2 3}
Adverse events associated with transfusion assessed with: alloimmunisation	Moderate^a		RR 3.16 (0.18 to 57.17)	121 (1 RCT)	⊕⊝⊝⊝ Very low ^{2 3 4}
	10 per 1000	32 per 1000 (2 to 572)
TIA	Trial population		Peto OR 0.13 (0.01 to 2.11)	323 (2 RCTs)	⊕⊝⊝⊝ Very low ^{3 4}
	21 per 1000	5 per 1000 (0 to 43)
Serious adverse events as a result of sickle cell‐related complications assessed with: ACS	Trial population		RR 0.24 (0.12 to 0.48)	326 (2 RCTs)	⊕⊕⊝⊝ Low ^{2 3}
	232 per 1,000	56 per 1000 (28 to 111)
	Moderate
	230 per 1000	55 per 1000 (28 to 110)
Measures of neurological impairment assessed with: WASI IQ score	Least square mean 1.7 (SE 95% CI ‐1.1 to 4.4)		‐	166 (1 RCT)	⊕⊕⊝⊝ Low ^{2 3}	Author reported data from SIT 2014
Quality of life assessed with: Child Health Questionnaire Parent Form 50	Difference estimate ‐0.54 (‐0.92 to ‐0.17)		‐	196 (1 RCT)	⊕⊕⊝⊝ Low ^{2 3}	Author reported data from SIT 2014
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: ACS: acute chest syndrome; CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio; TIA: transient ischaemic attack.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ We downgraded the quality of evidence by 1 due to imprecision. Rare event. No deaths occurred. ² We downgraded the quality of the evidence by 1 due to risk of bias. Unblinded trial and cross‐overs, and imbalance between loss to follow‐up between trial arms ³ We downgraded the quality of the evidence by 1 due to indirectness. Only children with HbSS or HbSβº thalassaemia included in trials ⁴ We downgraded the quality of evidence by 2 due to imprecision. The estimate has very wide CIs ^a Based on Chou 2013

Summary of findings for the main comparison. Long‐term red cell transfusion versus no transfusion in people who are at risk of a primary stroke who have not had previous long‐term red cell transfusions

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Summary of findings 2. Long‐term red cell transfusion versus no transfusion in people who are at risk of a primary stroke who have had previous long‐term red cell transfusions

Primary prevention
Patient or population: individuals with sickle cell disease who are at risk of a primary stroke who have had long‐term red cell transfusions to prevent a stroke Setting: outpatients Intervention: long‐term red cell transfusion Comparison: halted transfusion
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (trials)	Quality of the evidence (GRADE)	Comments
	Risk with standard care	Risk with blood transfusion
Clinical stroke follow‐up: mean 24 months	Trial population		RR 0.22 (0.01 to 4.35)	79 (1 RCT)	⊕⊝⊝⊝ Very low ^{1 2 3}
	49 per 1000	11 per 1000 (0 to 212)
All‐cause mortality	Moderate^a		Peto OR 8.00 (0.16 to 404.12)	79 (1 RCT)	⊕⊝⊝⊝ Very low ^{1 2 3}
	10 per 1000	75 per 1000 (2 to 803)
Adverse events associated with transfusion assessed with: alloimmunisation	See comment			79 (1 RCT)	‐	No comparative numbers reported
TIA	See comment			79 (1 RCT)	‐	No comparative numbers reported
Serious adverse events as a result of sickle cell‐related complications assessed with: ACS	See comment			79 (1 RCT)	‐	No comparative numbers reported
Measures of neurological impairment ‐ not reported	Outcome not reported		‐	‐	‐
Quality of life ‐ not reported	Outcome not reported		‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: ACS: acute chest syndrome; CI: confidence interval; RR: risk ratio; OR: odds ratio; TIA: transient ischaemic attack
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ We did not downgrade the evidence due to risk of bias because the evidence was already very low grade evidence. There was attrition bias. Imbalance between loss to follow‐up between trial arms ² We downgraded the quality of the evidence by 1 due to indirectness. Only children with HbSS or HbSβº thalassaemia included in trials ³ We downgraded the quality of evidence by 2 due to imprecision. The estimate has very wide CIs ^a Assuming a mortality rate of 1%

Summary of findings 2. Long‐term red cell transfusion versus no transfusion in people who are at risk of a primary stroke who have had previous long‐term red cell transfusions

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Summary of findings 3. Long‐term red cell transfusion versus hydroxyurea and phlebotomy in people who are at risk of a primary stroke who have had previous long‐term red cell transfusions

Primary prevention
Patient or population: individuals with sickle cell disease who are at risk of a primary stroke who have had long‐term red cell transfusions to prevent a stroke Setting: outpatient Intervention: blood transfusion with iron chelation Comparison: hydroxyurea with phlebotomy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (trials)	Quality of the evidence (GRADE)	Comments
	Risk with hydroxyurea and phlebotomy	Risk with Blood transfusion
Clinical stroke	No strokes occurred in either trial arm		‐	121 (1 RCT)	⊕⊝⊝⊝ Very low ^{1 2}
All‐cause mortality	No deaths occurred in either trial arm		‐	121 (1 RCT)	⊕⊝⊝⊝ Very low ^{1 2}
Adverse events associated with transfusion assessed with: Liver iron concentration mg Fe/g dry weight liver	The mean liver iron concentration was 9.5 mg Fe/g dry weight	MD 1.8 mg Fe/g dry weight lower (5.16 lower to 1.56 higher)	‐	121 (1 RCT)	⊕⊕⊝⊝ Low^{2 3}	Switching to hydroxyurea and phlebotomy may reduce serum ferritin levels compared to continuing to receive red cell transfusions and chelation (MD) ‐1398 μg/L, 95% CI ‐1929 to ‐867; one trial, 121 participants)
Incidence of TIA	49 per 1000	50 per 1,000 (10 to 238)	RR 1.02 (0.21 to 4.84)	121 (1 RCT)	⊕⊝⊝⊝ Very low ^{2 3 4}
Serious adverse events as a result of sickle cell‐related complications assessed with: ACS	Trial population		RR 2.03 (0.39 to 10.69)	121 (1 RCT)	⊕⊝⊝⊝ Very low ^{2 3 4}
	33 per 1000	67 per 1,000 (13 to 350)
Measures of neurological impairment ‐ not reported	Outcome not reported		‐	‐	‐	‐
Quality of life ‐ not reported	Outcome not reported		‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: ACS: acute chest syndrome; CI: confidence interval; RR: risk ratio; OR: odds ratio; TIA: transient ischaemic attack.
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ We downgraded the quality of the evidence by 2 due to imprecision. Rare event. No deaths or stroke occurred. ² We downgraded the quality of the evidence by 1 due to indirectness. Only children with HbSS or HbSβº thalassaemia included in trials ³ We downgraded the quality of the evidence by 1 due to risk of bias.Trial was not blinded and stopped early ⁴ We downgraded the quality of the evidence by 1 due to imprecision. The estimate has very wide CIs

Summary of findings 3. Long‐term red cell transfusion versus hydroxyurea and phlebotomy in people who are at risk of a primary stroke who have had previous long‐term red cell transfusions

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Summary of findings 4. Long‐term red cell transfusion versus hydroxyurea and phlebotomy in people who are at risk of a secondary stroke who have had previous long‐term red cell transfusions

Secondary prevention
Patient or population: individuals with sickle cell disease who have had a stroke who have had long‐term red cell transfusions to prevent another stroke Setting: outpatients Intervention: blood transfusion with iron chelation Comparison: hydroxyurea with phlebotomy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (trials)	Quality of the evidence (GRADE)	Comments
	Risk with hydroxyurea and phlebotomy	Risk with Blood transfusion
Clinical stroke assessed with: no previous red cell transfusion follow‐up: mean 24 months	Trial population		RR 14.78 (0.86 to 253.66)	133 (1 RCT)	⊕⊝⊝⊝ Very low ^{1 2 3}
	0 per 1000	0 per 1000 (0 to 0)
All‐cause mortality	15 per 1000	15 per 1000 (1 to 198)	Peto OR 0.98 (0.06 to 15.92)	133 (1 RCT)	⊕⊝⊝⊝ Very low ^{1 2 3}
Transfusion‐related adverse events ‐ assessed with liver iron concentration mg Fe/g dry weight liver	Hydroxyurea arm: median 17.2 mg IQR 10.0 to 30.6 Transfusion arm: median 17.3 mg IQR 8.8 to 30.7			56 (1 RCT)	⊕⊕⊝⊝ Low ^{1 2}	P = 0.7920^a Switching to hydroxyurea and phlebotomy may reduce serum ferritin levels compared to continuing to receive red cell transfusions and chelation 1994 μg/L, interquartile range (IQR) 998 to 3475, in the hydroxyurea arm and 4064 μg/L, IQR 2330 to 7126, in the transfusion arm; one trial, 133 participants; P < 0.001 ^a
Incidence of TIA	Trial population		RR 0.66 (0.25 to 1.74)	133 (1 RCT)	⊕⊝⊝⊝ Very low ^{1 2 3}
	136 per 1000	90 per 1000 (34 to 237)
Serious adverse events as a result of sickle cell‐related complications assessed with: ACS	Trial population		RR 0.33 (0.04 to 3.08)	133 (1 RCT)	⊕⊝⊝⊝ Very low^{1 2 3}
	45 per 1000	15 per 1000 (2 to 140)
Measures of neurological impairment ‐ not reported	Outcome not reported		‐	‐	^‐
Quality of life ‐ not reported	Outcome not reported		‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: ACS: acute chest syndrome; CI: confidence interval; RR: risk ratio; OR: odds ratio; TIA: transient ischaemic attack
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ We downgraded the quality of the evidence by 1 due to risk of bias. Trial was not blinded and stopped early ² We downgraded the quality of the evidence by 1 due to indirectness. Only children with HbSS or HbSβº thalassaemia included in trials ³ We downgraded the quality of the evidence by 1 due to imprecision. The estimate has very wide CIs ^a Analysis performed by the trial authors

Summary of findings 4. Long‐term red cell transfusion versus hydroxyurea and phlebotomy in people who are at risk of a secondary stroke who have had previous long‐term red cell transfusions

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Table 1. Adverse events per 100 person‐years and incidence rate ratios for transfusion‐related complications

Outcomes	Trials	Number of participants with at least one event		Adverse events/100 person‐years		Incidence rate ratio^c (95% CI)
Outcomes	Trials	Transfusion	Standard	Transfusion	Standard	Incidence rate ratio^c (95% CI)
Transfusion reactions	SIT 2014	15 out of 90^a	1 out of 31^b	8.85	1.66	5.33 (1.67 to 23.52)
Ferritin > 1500 μg/L	SIT 2014	76 out of 90^a	3 out of 31^b	534.70	37.07	14.42 (5.41 to 85.17)
^aNine participants who declined transfusion were excluded from the analysis. ^b31 participants assigned to observation received one or more transfusions. ^cThe incidence ratio was calculated as the rate of adverse events per 100 person‐years in the transfusion group divided by the rate of adverse events per 100 person‐years in the observation group. The 95% confidence intervals were calculated with the use of the bootstrap method with 10,000 replications. Abbreviations: CI: confidence interval

Table 1. Adverse events per 100 person‐years and incidence rate ratios for transfusion‐related complications

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Table 2. Adverse events per 100 person years and incidence rate ratios for SCD complications

Outcomes	Trials	Number of participants with at least one event		Adverse events/100 person‐years		Incidence rate ratio^a (95% CI)
Outcomes	Trials	Transfusion	Standard	Transfusion	Standard	Incidence rate ratio^a (95% CI)
Acute chest syndrome	STOP 1998	4 out of 63	14 out of 67	4.8^b	15.3^b	‐
Acute chest syndrome	SIT 2014	5 out of 99	24 out of 97	1.81^b	14.35^b	0.41 (0.20 to 0.75)
Painful crisis	STOP 1998	11 out of 63	13 out of 67	16.2	27.6	‐
Painful crisis	SIT 2014	32 out of 99	56 out of 97	41.58	102.21	0.13 (0.04 to 0.28)
Priapism	SIT 2014	1 out of 59	7 out of 52	0.84	6.65	0.13 (0.03 to 0.55)
Symptomatic avascular necrosis of the hip	SIT 2014	1 out of 99	6 out of 97	0.4	2.25	0.22 (0.05 to 0.85)
^a The incidence ratio was calculated as the rate of adverse events per 100 person‐years in the transfusion group divided by the rate of adverse events per 100 person‐years in the observation group. The 95% confidence intervals were calculated with the use of the bootstrap method with 10,000 replications. ^b One child from the standard care group was excluded from these analyses due to a stroke on day 16 of the trial. Abbreviation: CI: confidence interval

Table 2. Adverse events per 100 person years and incidence rate ratios for SCD complications

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Table 3. Mean or median haemoglobin (Hb) levels and HbS percentage

Trial	Intervention	Baseline		6 to 12 months		12 to 18 months		18 to 24 months
Trial	Intervention	Hb (g/L)	Hb S (%)	Hb (g/L)	Hb S (%)	Hb (g/L)	Hb S (%)	Hb (g/L)	Hb S (%)
No previous long‐term transfusions
SIT 2014	Transfusion	Median 77 IQR (72 to 84)	Median 85 90% CI (51 to 95)	‐	Median 30 90% CI (17 to 43)	‐	Median 29 90% CI (16 to 43)	‐	Median 30 90% CI (16 to 43)
SIT 2014	Standard	Median 79 IQR (74 to 89)	‐	‐	‐	‐	‐	‐	‐
STOP 1998	Transfusion	Mean (SD) 72 (8)	Mean (SD) 87 (10)	‐	‐	‐	‐	‐	‐
STOP 1998	Standard	Mean (SD) 76 (7)	Mean (SD) 87 (7)	‐	‐	‐	‐	‐	‐
Previous long‐term transfusions
STOP 2 2005	Transfusion	Mean (SD) 93 (9)	Mean (SD) 21 (8.6)	Mean (SD) 94 (9)	Mean (SD) 25.4 (10.9)	‐	‐	‐	‐
STOP 2 2005	Standard	Mean (SD) 98 (12)	Mean (SD) 19 (11)	Mean (SD) 77 (8)	Mean (SD) 81.0 (8.6)	‐	‐	‐	‐
Abbreviations: CI: confidence interval; IQR: interquartile range; SD: standard deviation

Table 3. Mean or median haemoglobin (Hb) levels and HbS percentage

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Table 4. Pre‐transfusion Haemoglobin S levels

Trial	Number of transfusions	Number of HbS levels measured	HbS less than 30%	HbS 30 to 40%	HbS greater than 40%
No previous long‐term transfusions
STOP 1998	1521	‐	‐	101	42
Previous long‐term transfusions
STOP 2 2005	1070	988	748 (76%)	192 (19%)	48 (5%)

Table 4. Pre‐transfusion Haemoglobin S levels

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Comparison 1. Blood transfusion versus standard care

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical stroke Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 No previous long‐term red cell transfusions	2	326	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.03, 0.49]
1.2 Previous long‐term red cell transfusions	1	79	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.01, 4.35]
2 Clinical stroke ‐ velocity Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 Normal TCD velocities and no previous long‐term red cell transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Normalised TCD velocities and previous long‐term red cell transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Abnormal TCD velocities	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Clinical stroke ‐ SCI Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Presence of previous SCI on MRI	2	243	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.02, 0.59]
3.2 Absence of previous SCI on MRI	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.03, 2.31]
4 Mortality Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

5 Transfusion‐related adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.1 Alloimmunisation ‐ No previous long‐term red cell transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Transfusion reactions ‐ No previous long‐term red cell transfusion	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 TIA Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

6.1 No previous long‐term red cell transfusions	2	323	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.13 [0.01, 2.11]
7 Other sickle cell related complications Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 Acute chest syndrome	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.12, 0.48]
7.2 Painful crises	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.46, 0.84]
7.3 Priapism	1	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.13 [0.02, 0.99]
7.4 Avascular necrosis of the hip	1	196	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.02, 1.33]

Comparison 1. Blood transfusion versus standard care

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Comparison 2. Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical stroke ‐ Secondary prevention Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Mortality Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

2.1 Mortality ‐ Primary prevention	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Mortality ‐ Secondary prevention	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Transfusion‐related complications ‐ Serum ferritin; Primary prevention Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4 Transfusion related complications ‐ Liver iron concentration ‐ Primary prevention Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5 Other neurological event Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.1 TIA ‐ Primary prevention	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 TIA ‐ Secondary prevention	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Other sickle cell related complications Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

6.1 Total SCD‐related SAEs ‐ Secondary prevention	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.2 Acute chest syndrome ‐ Primary prevention	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.3 Acute chest syndrome ‐ Secondary prevention	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.4 Painful crisis ‐ Primary prevention	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.5 Painful crisis ‐ Secondary prevention	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.6 Infections and infestations SAEs ‐ Primary prevention	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.7 Infections and infestations SAEs ‐ Secondary prevention	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Haemoglobin levels Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

8 Haemoglobin S levels Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 2. Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation)

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Transfusión de sangre para la prevención del accidente cerebrovascular primario y secundario en pacientes con anemia de células falciformes

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