Hydroxyurea (hydroxycarbamide) for sickle cell disease

Angela E Rankine-Mullings; Sarah J Nevitt

doi:10.1002/14651858.CD002202.pub3

Cochrane Database of Systematic Reviews

Hidroxiurea (hidroxicarbamida) para la drepanocitosis

Información

DOI:

https://doi.org/10.1002/14651858.CD002202.pub3 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

01 septiembre 2022see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Fibrosis quística y enfermedades genéticas

Copyright:

Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Cifras del artículo

Altmetric:

Citado por:

Citado 0 veces por enlace Crossref Cited-by

Contraer

Autores

Angela E Rankine-Mullings

Correspondencia a: Sickle Cell Unit, Caribbean Institute for Health Research, University of the West Indies, Kingston, Jamaica

[email protected]
Sarah J Nevitt

Department of Health Data Science, University of Liverpool, Liverpool, UK

Contributions of authors

Original review (2001)

Sally Davies (SD) and Ade Olujohungbe (AO) conceived review and evaluated studies. SD drafted the review.

2005 (minor) update

SD drafted the review (with input from AO), but stepped down as lead author in September 2005 (remained as co‐author). Ashley Jones (AJ) became lead author in September 2005 and assisted in drafting the update and now acted as guarantor of the review.

2010 (minor) update

AJ drafted the update with input from SCD and AO. AJ acted as guarantor of the review.

2017 (major) update

SJN became lead author in 2016 and led the current update on screening, data extraction, risk of bias assessment, analysis, summary of findings table and drafting results and discussion.
JH provided clinical interpretation of the review, drafted the text of the discussion and commented on all sections of the review.
AJ extracted and data and drafted the text as well as commenting on later draft versions.
SD stepped down as co‐author.

2022 (minor) update

ARM became lead author and led the current update on screening, data extraction, risk of bias assessment, analysis, summary of findings table and drafting results and discussion.
SJN extracted data and drafted the text as well as commenting on later draft versions.
JH stepped down as co‐author.

Sources of support

Internal sources

No sources of support provided

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 Cochrane Cystic Fibrosis and Genetic Disorders.

Declarations of interest

Sarah Nevitt: none known.

Angela E Rankine‐Mullings: none known.

Acknowledgements

We note the previous contribution of Adebayo Olujohungbe (AO) to previous versions of the review.

This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Cystic Fibrosis and Genetic Disorders. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Version history

Published

Title

Stage

Authors

Version

2022 Sep 01

Hydroxyurea (hydroxycarbamide) for sickle cell disease

Review

Angela E Rankine-Mullings, Sarah J Nevitt

https://doi.org/10.1002/14651858.CD002202.pub3

2017 Apr 20

Hydroxyurea (hydroxycarbamide) for sickle cell disease

Review

Sarah J Nevitt, Ashley P Jones, Jo Howard

https://doi.org/10.1002/14651858.CD002202.pub2

2001 Apr 23

Hydroxyurea for sickle cell disease

Review

Ashley P Jones, Sally C Davies, Adebayo Olujohungbe

https://doi.org/10.1002/14651858.CD002202

Revision date This is the date when the review was published	Event	Description
2010 Nov 10	New search has been performed	A search of the Group's Haemoglobinopathies Trials Register identified 25 new references potentially eligible for inclusion in this review. Fifteen of these were additional references to the BABY HUG study which is listed as ongoing (Baby Hug 2007). Eight references were to the already included MSH trial and provide no further data or information not already included within the review (MSH 1995). The remaining two references (each published in abstract form) have been added to 'Studies awaiting classification', and we await publication of the full papers in order to accurately assess eligibility (Jain 2010; Wang 2009).
2008 Nov 05	New search has been performed	No new trials were identified by the search of the Group's Haemoglobinopathies trials Register.
2008 Jul 01	Amended	Converted to new review format.
2008 Feb 01	New search has been performed	The search identified four new references. One was an additional reference to the already included MSH 1995 study (Ballas 2006), however, this did not include any new data that can be aded to the review. A further reference was to the already excluded De Montalembert 2006 study (De Montalembert 2006). The third reference was an additional reference to the Baby Hug 2007 study now listed in Ongoing studies (Wynn 2007); and the final reference has been added to Excluded studies (Silva‐Pinto 2007). In addition, the Plain Language Summary has been updated in line with latest guidance from The Cochrane Collaboration.
2007 Feb 01	New search has been performed	The search identified 12 new references to four studies. Two of the new references were additional references to the already included MSH 1995 study; however, no further data have been included in the review. Seven of the references were to one study, which is listed in 'Studies awaiting assessment' (Baby Hug 2005). The remaining three new references have been excluded (De Montalembert 2005; Voskaridou 2005; Ware 2006).
2006 Feb 01	New search has been performed	The search identified one new reference (Charache 1993) which is an additional reference to the already included MSH 1995 trial. This reference provided no additional data. Ashley Jones became lead author in September 2005 and acts as guarantor of the review.
2004 Nov 01	New search has been performed	The search identified one new reference to the already included MSH 1995 trial: Orringer EP, Jones S, Strayhorn D, Hoffman E, Parker J, Greenberg CS. The effect of hydroxyurea (HU) administration on circulating d‐dimer levels in patients with sickle cell anemia [abstract]. Blood 1996;88(10 Suppl 1):496a. Following on from the inclusion of this reference, a further outcome has been added to the review: cost effectiveness of hydroxyurea.
2003 Nov 01	New search has been performed	Two additional references to the already included MSH 1995 study have been incorporated into the review.
2002 Feb 01	New search has been performed	Quality of life data, presented in an abstract by Terrin (Terrin 1999), which reports on the MSH study (MSH 1995), has now been incorporated into the review.

Differences between protocol and review

2017 update

The final secondary outcome (cost‐effectiveness of hydroxyurea) was added at the 2005 update of this review but removed in the 2017 update of the review as economic methods that are outside the scope of Cochrane Reviews are required to truly reflect cost‐effectiveness of an intervention.

The protocol stated that odds ratios would be used as the measure of treatment effect for dichotomous data, however, on reflection, we felt it more appropriate to present risk ratios in preference to odds ratios (OR), as odds ratios give an inflated impression of the size of effect where event rates are high, as is the case in these studies.

The definition of the primary outcome 'Pain alteration' has been updated to better reflect the measures that are suitable for inclusion under this outcome.

We changed the definition of the outcome: "Any reported adverse effects or toxicity of hydroxyurea recorded" to "Reported adverse effects or toxicity" as it is difficult to distinguish between adverse reactions (i.e. adverse events that are definitely drug‐related) and other adverse events that may be sickle‐ or transfusion‐related. Where reported in study reports, we have separated reported adverse effects into drug‐related, sickle‐related, transfusion‐related etc.

Serious adverse events reported in included studies (whether treatment‐related or not) were included under the definition of the primary outcome 'Life‐threatening illness.'

Notes

Information on the search results of previous versions of this review

The first versions of the review (Jones 2001, latest search conducted May 2010) included two studies reported in 44 references (Belgian Study 1996; MSH 1995); additionally, one ongoing study (23 references) was identified (now completed) (BABY HUG 2011). Furthermore, two studies (two references) were listed as awaiting classification (now included) (CHAMPS 2011; Jain 2012).

The 2017 update of the review (Nevitt 2017, latest search conducted January 2017) included eight studies reported in 118 references (BABY HUG 2011; Belgian Study 1996; CHAMPS 2011; Jain 2012; MSH 1995; SCATE 2015; SWiTCH 2012; TWiTCH 2016), 12 studies (reported in 14 references) were excluded (Al‐Nood 2011; De Montalembert 2006; NDEPTH 2013; NCT00004492; Misra 2017; NCT01960413*; NCT02149537; Pushi 2000; Silva‐Pinto 2007; Silva‐Pinto 2014; Vichinsky 2013; Voskaridou 2005), three studies (reported in three references) were listed as 'awaiting classification' due to uncertainties around the study design and population (Abdullahi 2020a; Anyanwu 2016; Field 2020), and one study (reported in one reference) was listed as 'ongoing' (NCT01389024).

* Now listed as Field 2020.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Adult; Child; Humans;

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 for this review (2022)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 2

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.1

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 1: Pain crises

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.2

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 2: Proportion experiencing pain

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.3

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 3: Proportion experiencing life‐threatening events during study

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.4

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 4: Number of life‐threatening events during study

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.5

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 5: Deaths during the study

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.6

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 6: Change from baseline in foetal haemoglobin (HbF%)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.7

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 7: Change from baseline in absolute neutrophil count (ANC, x10⁹/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.8

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 8: Foetal haemoglobin (HbF%) after treatment

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.9

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 9: Neutrophil response (x10⁹/L) after treatment

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.10

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 10: Change from baseline in haemoglobin (g/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.11

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 11: Change from baseline in mean corpuscular volume (fL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.12

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 12: Change from baseline in white blood cell (WBC) count (x10⁹/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.13

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 13: Change from baseline in absolute reticulocyte count (x10⁹/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.14

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 14: Change from baseline in reticulocytes (%)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.15

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 15: Change from baseline in platelet count (10⁹/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.16

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 16: Change from baseline in creatinine (mg/dL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.17

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 17: Change from baseline in total bilirubin (mg/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.18

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 18: Change from baseline in alanine transferase (ALT) (U/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.19

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 19: Haemoglobin (g/dL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.20

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 20: Mean corpuscular volume (fL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.21

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 21: White blood cells (WBC) count at the end of the study

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.22

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 22: Reticulocytes (10⁹/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.23

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 23: Reticulocytes (10⁵/mm³) at 18 months

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.24

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 24: Total bilirubin (mg/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.25

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 25: Platelet count (10⁹/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.26

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 26: Platelet count (10³/mm³) at 18 months

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.27

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 27: Packed cell volume

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.28

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 28: F reticulocytes

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.29

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 29: F cells

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.30

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 30: Red blood count

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.31

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 31: Dense cells

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.32

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 32: Leucocytes

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.33

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 33: Alanine transferase (ALT) (U/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.34

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 34: Creatinine (mg/dL) at the end of the study

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.35

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 35: Aspartate aminotransferase

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.36

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 36: Alkaline phosphatase

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.37

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 37: Change from baseline in growth

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.38

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 38: Quality of life: general health perception

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.39

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 39: Quality of life: pain recall

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.40

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 40: Quality of life: social function

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.41

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 41: Changes in 'Ladder of Life'

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.42

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 42: Proportion of participants with signs of organ damage

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.43

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 43: Signs of organ damage ‐ change from baseline in DTPA GFR

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.44

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 44: Signs of organ damage ‐ change from baseline in Howell‐Jolley body (per 10⁶ red blood cells)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.45

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 45: Signs of organ damage ‐ change from baseline in pitted cells (%)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.46

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 46: Signs of organ damage ‐ change from baseline in spleen: liver ratio of counts

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.47

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 47: Signs of organ damage ‐ change from baseline in spleen volume (cm³)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.48

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 48: Signs of organ damage ‐ change from baseline in creatinine (mg/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.49

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 49: Signs of organ damage ‐ change from baseline in Schwartz GFR

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.50

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 50: Signs of organ damage ‐ change from baseline in cystatin C

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.51

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 51: Signs of organ damage ‐ change from baseline in urine osmolality

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.52

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 52: Signs of organ damage ‐ change from baseline in urine pH

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.53

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 53: Signs of organ damage ‐ change from baseline in urine‐specific gravity

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.54

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 54: Signs of organ damage ‐ change from baseline in total kidney volume

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.55

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 55: Signs of organ damage ‐ change from baseline in TCD ultrasound velocity (time‐averaged mean maximum velocity)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.56

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 56: Signs of organ damage ‐ change from baseline in CNS measures

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.57

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 57: Proportion of participants experiencing adverse events and toxicity

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.58

Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 58: Proportion with SCA‐related events (composite outcome)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.1

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 1: Proportion experiencing pain

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.2

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 2: Proportion experiencing life‐threatening events during study

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.3

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 3: Deaths during the study

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.4

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 4: Change from baseline in foetal haemoglobin (HbF %)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.5

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 5: Change from baseline in absolute neutrophil count (x10⁹/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.6

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 6: Change from baseline in mean corpuscular volume (fL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.7

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 7: Change from baseline in sickle haemoglobin (%)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.8

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 8: Change from baseline in haemoglobin (g/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.9

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 9: Change from baseline in absolute reticulocyte count (10⁹ / L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.10

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 10: Change from baseline in white blood count (10⁹ / L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.11

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 11: Change from baseline in platelets (10⁹/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.12

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 12: Change from baseline in total bilirubin (mg/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.13

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 13: Change from baseline in liver iron concentration

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.14

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 14: Change from baseline in serum ferritin (ng/mL)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.15

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 15: Change from baseline in lactate dehydrogenase (U/L)

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.16

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 16: Signs of organ damage ‐ CNS measures at the end of the study

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.17

Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 17: Proportion of participants experiencing non‐neurological adverse events and toxicity

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.1

Comparison 3: Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 1: Proportion experiencing life‐threatening events during the study

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.2

Comparison 3: Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 2: Signs of organ damage ‐ proportion of participants with a change in CNS measures

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.3

Comparison 3: Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 3: Signs of organ damage ‐ change from baseline in CNS measures

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.4

Comparison 3: Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 4: Adverse events and toxicity

Ir a la figura de la revisiónAbrir en una pestaña nueva

Summary of findings 1. Summary of findings ‐ Hydroxyurea compared with placebo for sickle cell disease

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Hydroxyurea compared with placebo for sickle cell disease
Patient or population: adults and children with sickle cell disease Settings: outpatients Intervention: hydroxyurea Comparison: placebo
	Assumed risk	Corresponding risk
	Placebo	Hydroxyurea
Pain alteration^a Follow‐up: 6 to 24 months	All studies showed a significant advantage to hydroxyurea compared to placebo (different measures of pain alteration presented)^a		NA	784 (5 studies)^b	⊕⊕⊕⊝ moderate^e
Life‐threatening illness Follow‐up: 6 to 24 months	Significantly fewer occurrences of ACS (3 studies) and transfusions (4 studies) on hydroxyurea compared to placebo. No significant differences in terms of stroke, hepatic or splenic sequestration (2 studies). In 1 study, 6 serious adverse events of bacteraemia/sepsis were reported in each of the hydroxyurea and placebo groups and 1 serious adverse event of anaemia was reported in the placebo group.		NA	759 (4 studies)	⊕⊕⊕⊝ moderate^e
Death during the study (all deaths) Follow‐up: 6 to 24 months	16 per 1000	10 per 1000 (3 to 36 per 1000)	RR 0.65 (0.19 to 2.27)	784 (5 studies)^b	⊕⊕⊕⊝ moderate^e	There was also no significant difference between groups in terms of deaths related to SCD.
Measures of HbF (%) Follow‐up: 6 to 24 months	There was a significant increase in HbF(%) in the hydroxyurea group compared to the placebo group in all studies (different measures presented).³		NA	784 (5 studies)^b	⊕⊕⊝⊝ low^e,f
Measures of ANC Follow‐up: 6 to 24 months	There was a significant decrease in ANC in the hydroxyurea group compared to the placebo group in all studies (different measures presented).^c		NA	724 (4 studies)^b	⊕⊕⊕⊝ moderate^e
Quality of life: 'Health Status Survey', the 'Profile of Mood States' and the 'Ladder of Life' Follow‐up: 24 months	No significant difference in terms of any domain of any scale except for pain recall at 18 months (MD 0.70, 95% CI 0.11 to 1.29, P = 0.02).^d		NA	Up to 277 (1 study)	⊕⊕⊝⊝ low^e,g
Adverse events or toxicity: differences in rates of specific adverse events Follow‐up: 6 to 24 months	Significantly fewer events of hospitalisation, dactylitis, sepsis or bacteraemia, anaemia and gastroenteritis, and significantly more events of thrombocytopenia and ANC raised to between 500 to 1250 in the hydroxyurea compared to the placebo group. No significant differences between groups in terms of all other events.		NA	784 (5 studies)^b	⊕⊕⊝⊝ low^e,h	One study also reported statistically significantly fewer composite SCA‐related events (vaso‐occlusive pain crisis, dactylitis, acute chest syndrome, splenic sequestration or blood transfusion) in the hydroxyurea group compared to the placebo group: RR 0.66 (95% CI 0.51 to 0.84).
The basis for the assumed risk is the event rate in the control group unless otherwise stated in the comments and footnotes. The corresponding risk (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). ACS: acute chest syndrome; ANC: absolute neutrophil counts; CI: confidence interval; HbF: foetal haemoglobin; MD: mean difference;NA: not applicable; RR: risk ratio; SCA: sickle cell anaemia; SCD: sickle cell disease.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^a Pain alteration measured by mean annual pain crisis rate, time from initiation of treatment to first, second or third crisis, number of vaso‐occlusive crises, proportion of participants experiencing pain, proportion of hospitalisations for painful episodes. ^b One study of 25 participants is of a cross‐over design and participants are counted only once in this total (Belgian Study 1996). These results are not included in the meta‐analysis, but they provide relevant information and so contribute to the outcome. ^c Different measures presented ‐ change from baseline or post intervention measures ‐ therefore, data from all studies could not be pooled. ^d Within the study (MSH 1995, reported in Ballas 2006), to allow for multiple statistical testing of the quality of life domains, a P value < 0.01 was considered significant. Therefore this result is not interpreted as significant in the study publication. ^e Downgraded once due to applicability: only individuals with HbSS or HbSβº‐thalassaemia genotypes were included therefore the results are not applicable to individuals with the HbSC genotype. ^f Downgraded once due to inconsistency: substantial heterogeneity present in the analyses of HbF (%) (I² > 90%), indicating uncertainty in the pooled result due to the difference in the results of the individual studies. ^g Downgraded once due to imprecision/uncertainty: caution is encouraged regarding the interpretation of these results as not all participants contributed data to all quality of life domains and the study publication defines statistical significance differently to this review. ^h Downgraded once due to imprecision/uncertainty: caution is encouraged regarding the interpretation of these results due to the number of separate outcomes considered in analysis and the increased probability of a statistical type I error. Also, where data were pooled, the individual study proportions of some adverse events were very different.

Summary of findings 1. Summary of findings ‐ Hydroxyurea compared with placebo for sickle cell disease

Ir a la tabla de la revisión

Summary of findings 2. Summary of findings ‐ Hydroxyurea and phlebotomy compared to transfusion and chelation for people with sickle cell disease and an increased risk of stroke

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Hydroxyurea and phlebotomy compared to transfusion and chelation for people with sickle cell disease and an increased risk of stroke
Patient or population: adults and children with sickle cell disease and an increased risk of stroke Settings: outpatients Intervention: hydroxyurea and phlebotomy Comparison: transfusion and chelation
	Assumed risk	Corresponding risk
	Transfusion and chelation	Hydroxyurea and phlebotomy
Pain alteration: proportion experiencing serious VOC or sickle‐related pain events Follow‐up: 24 to 30 months	213 per 1000	718 per 1000 (339 to 1000 per 1000)	RR 3.37 (95% CI 1.59 to 7.11)	254 (2 studies)	⊕⊕⊝⊝ low^d,e	No significant difference between treatment groups in terms of all pain events (serious and non‐serious) in 1 study (RR 1.03, 95% CI 0.81 to 1.30).
Life‐threatening illness Follow‐up: 24 to 30 months	No significant difference between groups in life‐threatening neurological events, hepatobiliary disease and splenic sequestration; significantly more ACS and infections and infestations in the hydroxyurea and phlebotomy compared to the transfusion and chelation group.		NA	254 (2 studies)	⊕⊕⊕⊝ moderate^d
Death during the study (all deaths) Follow‐up: 24 to 30 months	1 death occurred in the transfusion and chelation group of 1 study^a .	1 death occurred in the hydroxyurea and phlebotomy group of 1 study^a .	RR 0.99 (95% CI 0.06 to 15.42)	254 (2 studies)	⊕⊕⊝⊝ low^d,e
Measures of HbF (%) Follow‐up: 24 to 30 months	There was a significant increase in HbF(%) in the hydroxyurea and phlebotomy group compared to the transfusion and chelation group for both studies (different measures presented)^b .		NA	254 (2 studies)	⊕⊕⊕⊝ moderate^d
Measures of ANC Follow‐up: 24 to 30 months	There was a significant decrease in ANC in the hydroxyurea and phlebotomy group compared to the transfusion and chelation group for both studies (different measures presented)^b .		NA	254 (2 studies)	⊕⊕⊕⊝ moderate^d
Quality of life	Outcome not reported^c .				NA
Adverse events or toxicity: differences in rates of specific adverse events	There was a statistically significant difference in terms of immune disorders (more in transfusion and chelation group), reticulocytopenia, neutropenia and anaemia (more in hydroxyurea and phlebotomy group) in 1 study and the rate of adverse events was balanced across groups in the other study.		NA	254 (2 studies)	⊕⊕⊝⊝ low^d,f
The basis for the assumed risk is the event rate in the control group unless otherwise stated in the comments and footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ACS: acute chest syndrome; ANC: absolute neutrophil counts; CI: confidence interval; HbF: foetal haemoglobin; NA: not applicable; RR: risk ratio; VOC: vaso‐occlusive crisis.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^a Absolute data presented for number of deaths as the confidence interval of the relative effect is very large due to the small number of events. ^b Different measures presented ‐ mean or median change from baseline ‐ therefore data from all studies could not be pooled. ^c Quality of life data were collected in TWiTCH 2016; to date, the primary results of this study have been published but not the quality of life data. When available, quality of life data will be included in an update of this review. ^d Downgraded once due to applicability: only children with HbSS or HbSβº‐thalassaemia were included therefore the results are not applicable to adults or individuals with the HbSC genotype. ^e Downgraded once due to imprecision: small number of events and large CI around the relative effect. ^f Downgraded once due to imprecision/uncertainty: caution is encouraged regarding the interpretation of these results due to the number of separate outcomes considered in analysis and the increased probability of a statistical type I error.

Summary of findings 2. Summary of findings ‐ Hydroxyurea and phlebotomy compared to transfusion and chelation for people with sickle cell disease and an increased risk of stroke

Ir a la tabla de la revisión

Summary of findings 3. Summary of findings ‐ Hydroxyurea compared with observation for people with sickle cell disease and an increased risk of stroke

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
Hydroxyurea compared with observation for people with sickle cell disease and an increased risk of stroke
Patient or population: adults and children with sickle cell disease and an increased risk of stroke Settings: outpatients Intervention: hydroxyurea Comparison: observation
	Assumed risk	Corresponding risk
	Observation	Hydroxyurea
Pain alteration Follow‐up: NA	Outcome not reported.				NA
Life‐threatening illness Follow‐up: 15 months	No significant differences between groups in terms of ACS, blood transfusions required or acute splenic sequestration.		NA	22 (1 study)	⊕⊝⊝⊝ verylow^c,d
Death during the study Follow‐up: 15 months	No deaths occurred.	No deaths occurred.	NA	22 (1 study)	⊕⊝⊝⊝ verylow^c,d
Measures of HbF Follow‐up: 15 months	There was a significant increase in HbF in the hydroxyurea group compared to the observation group^a .		NA	22 (1 study)	⊕⊝⊝⊝ verylow^c,d
Measures of ANC Follow‐up: 15 months	There was a significant decrease in ANC in the hydroxyurea group compared to the observation group^a .		NA	22 (1 study)	⊕⊝⊝⊝ verylow^c,d
Quality of life Follow‐up: NA	Outcome not reported^b .				NA
Adverse events or toxicity: differences in rates of specific adverse events Follow‐up: 15 months	No significant differences between groups in terms of transient neutropenia, reticulocytopenia, parasite infestation, headache and dizziness.		NA	22 (1 study)	⊕⊝⊝⊝ verylow^c,d
The basis for the assumed risk is the event rate in the control group unless otherwise stated in the comments and footnotes. The corresponding risk (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). ACS: acute chest syndrome; ANC: absolute neutrophil counts; CI: confidence interval; HbF: foetal haemoglobin; NA: not applicable; RR: risk ratio.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aMedian values reported so data cannot be entered into analysis. ^bOutcome was not collected or presented due to early termination of study. ^cDowngraded twice due to serious imprecision: study terminated early with only 22 of target 100 participants recruited. Small number of participants included in final analyses, which are likely to be underpowered. ^dDowngraded once due to applicability: only children with HbSS or HbSβº‐thalassaemia were included therefore the results are not applicable to adults or individuals with HbSC genotype.

Summary of findings 3. Summary of findings ‐ Hydroxyurea compared with observation for people with sickle cell disease and an increased risk of stroke

Ir a la tabla de la revisión

Summary of findings 4. Summary of findings ‐ Hydroxyurea compared with no hydroxyurea for people with sickle cell disease

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
Hydroxyurea compared with no hydroxyurea for sickle cell disease
Patient or population: adults and children with sickle cell disease Settings: outpatients Intervention: hydroxyurea Comparison: no hydroxyurea
	Assumed risk	Corresponding risk
	No hydroxyurea	Hydroxyurea
Pain alteration Follow‐up: NA	Outcome not reported.				NA
Life‐threatening illness Follow‐up: NA	Outcome not reported.				NA
Death during the study Follow‐up: 11 months	No deaths occurred.	No deaths occurred.	NA	Up to 44 (1 study)¹	⊕⊝⊝⊝ verylow^b,c,d
Measures of HbF Follow‐up: 24 weeks	There was a significant increase in HbF in the hydroxyurea group compared to the no hydroxyurea group¹.		NA	Up to 44 (1 study)¹	⊕⊝⊝⊝ verylow^b,c,d
Measures of ANC Follow‐up: 24 weeks	There was no significant difference in ANC between treatment groups^a .		NA	Up to 44 (1 study)¹	⊕⊝⊝⊝ verylow^b,c,d
Quality of life Follow‐up: NA	Outcome not reported.				NA
Adverse events or toxicity Follow‐up: 11 months	Vaso‐occlusive pain crises, headache/migraine, upper respiratory infection, skin rash diarrhoea and abdominal pain were the most common adverse events during the trial and these events were evenly distributed across treatment groups (not separated by group).		NA	Up to 44 (1 study)¹	⊕⊝⊝⊝ verylow^b,c,d
The basis for the assumed risk is the event rate in the control group unless otherwise stated in the comments and footnotes. The corresponding risk (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). ANC: absolute neutrophil counts; CI: confidence interval; HbF: foetal haemoglobin; NA: not applicable; RR: risk ratio.
GRADE Working Group grades of evidence. High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^a Due to the factorial design of the study (22 participants randomised to a treatment arm including hydroxyurea and 22 randomised to a treatment arm without hydroxyurea), the results are not entered into analysis. All results of this trial are considered exploratory (CHAMPS 2011). ^b Downgraded once due to indirectness: the factorial design of the study makes comparison of hydroxyurea to no hydroxyurea indirect. ^c Downgraded once due to imprecision and risk of bias: the study was terminated early with only 44 out of 188 participants recruited and outcome data are presented for only those who completed each follow‐up time. ^d Downgraded once due to applicability: participants with HbSC were included therefore the results are not applicable to individuals with HbSS or HbSβº‐thalassaemia genotypes.

Summary of findings 4. Summary of findings ‐ Hydroxyurea compared with no hydroxyurea for people with sickle cell disease

Ir a la tabla de la revisión

Table 1. Clinical events and markers of response in Jain 2012

	Baseline	18 months	Baseline	18 months	P value
	Hydroxyurea		Placebo		P value
Clinical events (number of events per participant per year)
VOC	12.13 (8.56)	0.60 (1.37)	11.46 (3.01)	10.2 (3.24)	< 0.001
Blood transfusions	2.43 (0.69)	0.13 (0.43)	2.13 (0.98)	1.98 (0.82)	< 0.001
Hospitalisations	10.13 (6.56)	0.70 (1.28)	9.56 (2.91)	9.59 (2.94)	< 0.001
Haematological parameters
Hb (g/dL)	8.1 (0.68)	9.29 (0.55)	8.21 (0.68)	7.90 (0.58)	< 0.001
HbF(%)	19.8 (0.9)	24 (5.9)	19.21 (6.37)	18.92 (5.77)	< 0.001
Reticulocytes (x10⁵/mm³)	1.83 (0.96)	1.15 (0.1)	1.73 (0.49)	1.81 (0.67)	< 0.001
Leucocytes (x10³/mm³)	7.36 (6.03)	6.54 (5.54)	7.26 (4.91)	7.38 (2.85)	< 0.001
Platelets (x10³/mm³)	1.78 (0.26)	2.01 (0.18)	1.91 (0.21)	2.06 (0.26)	0.28
RBC (x10⁶/mm³)	2.89 (0.57)	1.98 (0.22)	1.84 (0.47)	3.11 (0.20)	0.05
Total bilirubin (mg/dL)	2.32 (1.42)	1.10 (0.42)	2.27 (1.28)	2.71 (0.93)	< 0.001
Values are mean (standard deviation); P values are calculated using independent t‐test. Hb: haemoglobin HbF: foetal haemoglobin RBC: red blood count VOC: vaso‐occlusive crises WBC: white blood count

Table 1. Clinical events and markers of response in Jain 2012

Ir a la tabla de la revisión

Table 2. Laboratory measurements from MSH 1995

Baseline	Hydroxyurea		Placebo		P value
Baseline	Baseline	2 years	Baseline	2 years	P value
WBC (10⁹/L)	12.6 (3.4)	9.9 (3.1)	12.3 (3.2)	12.2 (2.8)	0.0001
Neutrophils (10⁹/L)	6.9 (2.4)	4.9 (2.0)	6.7 (2.3)	6.4 (2.0)	0.0001
Platelets (10⁹/L)	468 (147)	399 (124)	457 (130)	423 (122)	0.12
Hb (g/dL)	8.5 (1.4)	9.1 (1.5)	8.5 (1.2)	8.5 (1.3)	0.0009
PCV (%)	24.9 (4.4)	27 (5)	25.2 (4.0)	25.1 (4.2)	0.0007
MCV (fl)	94 (9)	103 (14)	93 (9)	93 (9)	0.0001
Reticulocytes (10⁹/L)	327 (98)	231 (100)	325 (94)	300 (99)	0.0001
HbF (%)	5 (3.5)	8.6 (6.8)	5.2 (3.4)	4.7 (3.3)	0.0001
F cells (%)	33 (17)	48 (23)	33 (17)	35 (18)	0.0001
F reticulocytes	15 (8)	17 (9)	15 (8)	15 (7)	0.0036
Dense cells (%)	14 (6)	11 (6)	14 (7)	13 (7)	0.004
Creatinine (mg/dL)	0.9 (0.3)	1.0 (0.5)	0.9 (0.2)	1.0 (0.5)	0.64
Total bilirubin (mg/dL)	3.7 (2.4)	2.9 (2.5)	3.7 (2.5)	4.2 (4.6)	0.004
Direct bilirubin (mg/dL)	0.5 (0.3)	0.4 (0.3)	0.5 (0.4)	0.7 (2.2)	0.08
Aspartate aminotransferase	44 (23)	39 (20)	41 (21)	43 (27)	0.16
Alkaline phosphatase	120 (59)	117 (48)	119 (67)	119 (71)	0.71
Values are mean (standard deviation); P values are calculated using independent t‐test. Hb: haemoglobin HbF: foetal haemoglobin MCV: mean corpuscular volume PCV: packed cell volume WBC: white blood count

Table 2. Laboratory measurements from MSH 1995

Ir a la tabla de la revisión

Table 3. Laboratory evaluations from the SWiTCH trial

Outcome	Hydroxyurea and phlebotomy group (n = 67)	Transfusions and chelation group (n = 66)	P value
HbF (%)	17.9 (92 to 22.9)	‐0.2 (‐0.8 to 0.4)	< 0.001
ANC (x10⁹/L)	‐3.3 (‐5.1 to ‐1.4)	0.8 (‐1.3 to 2.4)	< 0.001
Hb (g/dL)	0.0 (‐0.7 to 0.7)	0.0 (‐0.5 to 0.6)	0.898
HbA (%)	‐50.9 (‐66.8 to ‐33.7)	0.0 (‐12.7 to 6.7)	< 0.001
HbS (%)	35.0 (21.7 to 46.2)	0.3 (‐7.5 to 12.3)	< 0.001
MCV (fL)	19.5 (7.5 to 28.5)	0.1 (‐2.0 to 2.5)	< 0.001
WBC (x10⁹/L)	‐5.4 (‐8.1 to ‐2.2)	0.2 (‐2.0 to 2.3)	< 0.001
ARC (x10⁹/L)	‐149.1 (‐231.0 to ‐19.0)	‐11.8 (‐88.2 to 93.2)	< 0.001
Platelets (x10⁹/L)	‐83.0 (‐171.0 to ‐8.0)	‐28.0 (‐70.0 to 18.0)	0.0022
Total bilirubin (mg/dL)	‐1.1 (‐1.9 to ‐0.6)	0.4 (‐0.3 to 1.2)	< 0.001
LIC (mg Fe/g)	‐1.2 (‐2.8 to 7.2)	‐2.2 (‐5.5 to 4.9)	0.48888
Serum ferritin (ng/mL)	‐966.0 (‐1629.0 to 49.0)	1159.5 (‐662.0 to 2724.0)	< 0.001
LDH (U/L)	‐67.0 (‐143.0 to 7.0)	‐8.5 (‐74.0 to 74.0)	0.0015
ANC: absolute neutrophil count ARC: absolute reticulocyte count Hb: haemoglobin HbA: adult haemoglobin HbF: foetal haemoglobin HbS: sickle haemoglobin LDH: lactate dehydrogenase LIC: liver iron concentration MCV: mean corpuscular volume WBC: white blood count Values are median change from baseline and interquartile range. P values are calculated using Wilcoxon rank sum test.

Table 3. Laboratory evaluations from the SWiTCH trial

Ir a la tabla de la revisión

Table 4. Laboratory evaluations from the SCATE trial

Outcome	Hydroxyurea (n = 11)	Observation (n = 11)	P value
Hb (g/dL)	1.6	‐0.5	< 0.0001
MCV (fL)	8.7	1	0.0001
ARC (x10⁹/L)	22.7	‐33.2	0.76
WBC (x10⁹/L)	‐4.6	1.3	0.07
ANC (x10⁹/L)	‐2.2	1.4	0.05
Platelets (x10⁹/L)	‐76	‐35	0.56
HbF (%)	8.9	0.3	0.002
Weight (kg)	2.5	1.8	0.51
Height (cm)	6.8	3.8	0.22
ANC: absolute neutrophil count ARC: absolute reticulocyte count Hb: haemoglobin HbF: foetal haemoglobin MCV: mean corpuscular volume WBC: white blood count Values are median change from baseline and P values are calculated using Wilcoxon rank sum test.

Table 4. Laboratory evaluations from the SCATE trial

Ir a la tabla de la revisión

Table 5. Pregnancies in the MSH Study

Pregnancy		Hydroxyurea	Placebo
Patients	Normal full‐term delivery	1	2
Patients	Elective termination	2	1
Partners of patients	Normal full‐term delivery	2	0
	Spontaneous abortion	1	0
	Still pregnant	0	1
TOTAL		6	4

Table 5. Pregnancies in the MSH Study

Ir a la tabla de la revisión

Comparison 1. Hydroxyurea versus placebo for participants with sickle cell disease

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Pain crises Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.1.1 Mean annual crisis rate at 2 years (all crises)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.1.2 Mean annual crisis rate at 2 years (all crises requiring hospitalisation)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.1.3 Number of vaso‐occlusive crises after 18 months of treatment	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.2 Proportion experiencing pain Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.2.1 Proportion experiencing pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2.2 Proportion with serious vaso‐occlusive crisis (SAE)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.3 Proportion experiencing life‐threatening events during study Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.3.1 Acute chest syndrome	3	699	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.29, 0.63]
1.3.2 Hepatic sequestration	1	299	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.03, 3.06]
1.3.3 Stroke	2	492	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.12, 2.53]
1.3.4 Patients transfused	3	699	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.53, 0.82]
1.3.5 Splenic sequestration	2	400	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.48, 2.59]
1.3.6 Bacteremia or sepsis (SAE)	1	207	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.33, 2.97]
1.3.7 Anaemia (SAE)	1	207	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.01]
1.4 Number of life‐threatening events during study Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.4.1 Blood transfusions	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.4.2 Hospitalisations	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.4.3 Duration of hospitalisation (days)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.5 Deaths during the study Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.5.1 All deaths	4	759	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.19, 2.27]
1.5.2 Deaths related to SCD	3	552	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.09, 2.60]
1.6 Change from baseline in foetal haemoglobin (HbF%) Show forest plot	2	365	Mean Difference (IV, Fixed, 95% CI)	9.88 [8.72, 11.03]

1.7 Change from baseline in absolute neutrophil count (ANC, x10⁹/L) Show forest plot	2	348	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐2.38, ‐1.02]

1.8 Foetal haemoglobin (HbF%) after treatment Show forest plot	3	566	Mean Difference (IV, Fixed, 95% CI)	6.24 [5.28, 7.20]

1.9 Neutrophil response (x10⁹/L) after treatment Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.9.1 Neutrophils (x10⁹/L) at 10 weeks	1	299	Mean Difference (IV, Fixed, 95% CI)	‐1.90 [‐2.51, ‐1.29]
1.9.2 Neutrophils (x10⁹/L) at the end of the study	2	446	Mean Difference (IV, Fixed, 95% CI)	‐1.47 [‐1.87, ‐1.06]
1.10 Change from baseline in haemoglobin (g/L) Show forest plot	2	365	Mean Difference (IV, Fixed, 95% CI)	0.12 [0.09, 0.14]

1.11 Change from baseline in mean corpuscular volume (fL) Show forest plot	2	365	Mean Difference (IV, Fixed, 95% CI)	6.91 [5.71, 8.12]

1.12 Change from baseline in white blood cell (WBC) count (x10⁹/L) Show forest plot	2	365	Mean Difference (IV, Fixed, 95% CI)	‐4.37 [‐5.65, ‐3.09]

1.13 Change from baseline in absolute reticulocyte count (x10⁹/L) Show forest plot	2	348	Mean Difference (IV, Fixed, 95% CI)	‐117.38 [‐141.47, ‐93.29]

1.14 Change from baseline in reticulocytes (%) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.15 Change from baseline in platelet count (10⁹/L) Show forest plot	2	364	Mean Difference (IV, Fixed, 95% CI)	‐23.14 [‐58.14, 11.86]

1.16 Change from baseline in creatinine (mg/dL) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.17 Change from baseline in total bilirubin (mg/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.18 Change from baseline in alanine transferase (ALT) (U/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.19 Haemoglobin (g/dL) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.19.1 At 10 weeks	1	299	Mean Difference (IV, Fixed, 95% CI)	0.50 [0.19, 0.81]
1.19.2 At the end of the study	3	566	Mean Difference (IV, Fixed, 95% CI)	1.12 [0.94, 1.30]
1.20 Mean corpuscular volume (fL) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.20.1 At 10 weeks	1	299	Mean Difference (IV, Fixed, 95% CI)	12.30 [9.69, 14.91]
1.20.2 At the end of the study	2	506	Mean Difference (IV, Fixed, 95% CI)	8.30 [6.55, 10.04]
1.21 White blood cells (WBC) count at the end of the study Show forest plot	2	506	Mean Difference (IV, Fixed, 95% CI)	‐2.68 [‐3.28, ‐2.07]

1.22 Reticulocytes (10⁹/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.22.1 Reticulocytes (10⁹/L) at 10 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.22.2 Reticulocytes (10⁹/L) at the end of the study	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.23 Reticulocytes (10⁵/mm³) at 18 months Show forest plot	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.66 [‐0.90, ‐0.42]

1.24 Total bilirubin (mg/L) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.24.1 At the end of the study	2	359	Mean Difference (IV, Fixed, 95% CI)	‐1.56 [‐1.90, ‐1.23]
1.25 Platelet count (10⁹/L) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.25.1 Platelet count (x10⁹/L) at 10 weeks	1	299	Mean Difference (IV, Fixed, 95% CI)	‐35.00 [‐75.19, 5.19]
1.25.2 Platelet count (x10⁹/L) at the end of the study	2	506	Mean Difference (IV, Fixed, 95% CI)	‐39.50 [‐62.77, ‐16.24]
1.26 Platelet count (10³/mm³) at 18 months Show forest plot	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.16, 0.06]

1.27 Packed cell volume Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.27.1 Packed cell volume (%) at 2 years	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.28 F reticulocytes Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.28.1 F reticulocytes at 2 years	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.29 F cells Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.29.1 F cells (%) at 2 years	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.30 Red blood count Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.30.1 Red blood count (10⁶/mm³) at 18 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.31 Dense cells Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.31.1 Dense cells (%) at 2 years	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.32 Leucocytes Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.32.1 Leucocytes (10³/mm³) at 18 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.33 Alanine transferase (ALT) (U/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.34 Creatinine (mg/dL) at the end of the study Show forest plot	2	506	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.02, 0.04]

1.35 Aspartate aminotransferase Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.35.1 Aspartate aminotransferase at 2 years	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.36 Alkaline phosphatase Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.36.1 Alkaline phosphatase at 2 years	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.37 Change from baseline in growth Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.37.1 Height (cm)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.37.2 Weight (kg)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.37.3 Head circumference (cm)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.38 Quality of life: general health perception Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.38.1 General health perception at 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.38.2 General health perception at 1 year	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.38.3 General health perception at 18 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.38.4 General health perception at 2 years	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.39 Quality of life: pain recall Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.39.1 Pain recall at 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.39.2 Pain recall at 1 year	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.39.3 Pain recall at 18 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.39.4 Pain recall at 2 years	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.40 Quality of life: social function Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.40.1 Social function at 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.40.2 Social function at 1 year	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.40.3 Social function at 18 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.40.4 Social function at 2 years	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.41 Changes in 'Ladder of Life' Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.41.1 Changes in 'Ladder of Life' at 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.41.2 Changes in 'Ladder of Life' at 1 year	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.41.3 Changes in 'Ladder of Life' at 18 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.41.4 Changes in 'Ladder of Life' at 2 years	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.42 Proportion of participants with signs of organ damage Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.42.1 New leg ulcers	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.42.2 Aseptic necrosis (humerus or femur)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.42.3 Decreased spleen function at exit (compared to baseline)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.43 Signs of organ damage ‐ change from baseline in DTPA GFR Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.44 Signs of organ damage ‐ change from baseline in Howell‐Jolley body (per 10⁶ red blood cells) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.45 Signs of organ damage ‐ change from baseline in pitted cells (%) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.46 Signs of organ damage ‐ change from baseline in spleen: liver ratio of counts Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.47 Signs of organ damage ‐ change from baseline in spleen volume (cm³) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.48 Signs of organ damage ‐ change from baseline in creatinine (mg/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.49 Signs of organ damage ‐ change from baseline in Schwartz GFR Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.49.1 Schwartz glomerular filtration rate (mL/min per 1.73m2)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.50 Signs of organ damage ‐ change from baseline in cystatin C Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.51 Signs of organ damage ‐ change from baseline in urine osmolality Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.52 Signs of organ damage ‐ change from baseline in urine pH Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.53 Signs of organ damage ‐ change from baseline in urine‐specific gravity Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.54 Signs of organ damage ‐ change from baseline in total kidney volume Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.55 Signs of organ damage ‐ change from baseline in TCD ultrasound velocity (time‐averaged mean maximum velocity) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.56 Signs of organ damage ‐ change from baseline in CNS measures Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.56.1 Bayley Mental Development Index	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.56.2 Bayley motor performance development index	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.57 Proportion of participants experiencing adverse events and toxicity Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.57.1 Hair loss at 1 or 2 visits	1	299	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.69, 2.26]
1.57.2 Hair loss at 3 or more visits	1	299	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.31, 1.21]
1.57.3 Skin rash at 1 or 2 visits	1	299	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.62, 1.51]
1.57.4 Skin rash at 3 or more visits	1	299	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.58, 1.60]
1.57.5 Fever at 1 or 2 visits	1	299	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.55, 1.69]
1.57.6 Fever at 3 or more visits	1	299	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.68, 1.17]
1.57.7 Gastrointestinal disturbance at 1 or 2 visits	1	299	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.50, 1.36]
1.57.8 Gastrointestinal disturbance at 3 or more visits	1	299	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.74, 1.31]
1.57.9 Other abnormalities at 1 or 2 visits	1	299	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.33, 1.11]
1.57.10 Other abnormalities at 3 or more visits	1	299	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.83, 1.40]
1.57.11 Hospitalisation (for any reason)	2	400	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.62, 0.86]
1.57.12 Dactylitis	2	400	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.39, 0.67]
1.57.13 Sepsis or bacteraemia	2	400	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.20, 0.99]
1.57.14 Anaemia	2	400	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.39, 0.88]
1.57.15 Gastroenteritis	2	400	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.44, 0.99]
1.57.16 Thrombocytopenia	2	400	Risk Ratio (M‐H, Fixed, 95% CI)	2.00 [1.00, 4.02]
1.57.17 Elevated bilirubin	2	400	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.18]
1.57.18 Priapism	1	193	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [0.26, 8.87]
1.57.19 Splenomegaly	1	193	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.61, 1.32]
1.57.20 Absolute neutrophil count < 500	1	193	Risk Ratio (M‐H, Fixed, 95% CI)	2.53 [0.50, 12.71]
1.57.21 Absolute neutrophil 500 to 1250	1	193	Risk Ratio (M‐H, Fixed, 95% CI)	2.53 [1.58, 4.03]
1.57.22 Alanine transaminase > 150 U/L	1	193	Risk Ratio (M‐H, Fixed, 95% CI)	2.02 [0.19, 21.92]
1.57.23 Skin and subcutaneous disorders	1	193	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.75, 1.10]
1.57.24 Splenic sequestration	1	193	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.36, 2.23]
1.57.25 Nausea	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	5.00 [0.25, 99.95]
1.57.26 Skin rash	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	7.00 [0.38, 129.93]
1.57.27 Neutropenia	1	207	Risk Ratio (M‐H, Fixed, 95% CI)	4.95 [0.24, 101.91]
1.57.28 Acute chest syndrome	1	207	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.52, 1.46]
1.57.29 Upper respiratory tract infection	1	207	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.68, 1.10]
1.57.30 Infections	1	207	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.21, 1.18]
1.57.31 Reticulocytopenia	1	207	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.15, 2.42]
1.57.32 Elevated AST/ALT	1	207	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.01]
1.58 Proportion with SCA‐related events (composite outcome) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 1. Hydroxyurea versus placebo for participants with sickle cell disease

Ir a la tabla de la revisión

Comparison 2. Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Proportion experiencing pain Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1.1 Vaso‐occlusive or sickle cell‐related pain (all)	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.81, 1.30]
2.1.2 Vaso‐occlusive or sickle cell‐related pain (serious)	2	254	Risk Ratio (M‐H, Fixed, 95% CI)	3.37 [1.59, 7.11]
2.2 Proportion experiencing life‐threatening events during study Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.2.1 Stroke (secondary)	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	14.78 [0.86, 253.66]
2.2.2 Transient ischaemic attack (primary)	1	121	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.21, 4.84]
2.2.3 Transient ischaemic attack (secondary)	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.25, 1.74]
2.2.4 Other neurological event (primary)	1	121	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.07, 15.88]
2.2.5 Acute chest syndrome	2	254	Risk Ratio (M‐H, Fixed, 95% CI)	2.84 [1.25, 6.42]
2.2.6 Infections and infestations	2	254	Risk Ratio (M‐H, Fixed, 95% CI)	3.65 [1.05, 12.76]
2.2.7 Splenic sequestration or splenectomy	2	254	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.16]
2.2.8 Hepatobiliary disease	1	121	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.07, 15.88]
2.2.9 Total with serious adverse events	2	254	Risk Ratio (M‐H, Fixed, 95% CI)	1.93 [1.17, 3.20]
2.2.10 Total with sickle cell related, non‐neurological adverse events	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [1.42, 6.75]
2.3 Deaths during the study Show forest plot	2	254	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.06, 15.42]

2.4 Change from baseline in foetal haemoglobin (HbF %) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.5 Change from baseline in absolute neutrophil count (x10⁹/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.6 Change from baseline in mean corpuscular volume (fL) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.7 Change from baseline in sickle haemoglobin (%) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.8 Change from baseline in haemoglobin (g/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.9 Change from baseline in absolute reticulocyte count (10⁹ / L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.10 Change from baseline in white blood count (10⁹ / L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.11 Change from baseline in platelets (10⁹/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.12 Change from baseline in total bilirubin (mg/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.13 Change from baseline in liver iron concentration Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.14 Change from baseline in serum ferritin (ng/mL) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.15 Change from baseline in lactate dehydrogenase (U/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.16 Signs of organ damage ‐ CNS measures at the end of the study Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.16.1 Final TCD ultrasound velocity	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.17 Proportion of participants experiencing non‐neurological adverse events and toxicity Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.17.1 Infections and infestations	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.2 Gastrointestinal disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.3 Fever	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.4 Musculoskeletal disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.5 Immune system disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.6 Cholelithiasis	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.7 Cholecystitis	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.8 Asthma	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.9 Acute chest syndrome	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.10 Renal or urinary disorder	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.11 Priapism	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.12 Catheter‐related complications	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.13 Cardiac disorder	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.14 Hyperbilirubinaemia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.15 Alanine transaminase increase	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.16 Aspartate transaminase increase	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.17 Serum creatinine increase	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.18 Thrombocytopenia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.19 Reticuloctopenia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.20 Neutropenia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.21 Anaemia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.22 Sickle cell pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.23 Sickle cell‐related events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.17.24 All adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke

Ir a la tabla de la revisión

Comparison 3. Hydroxyurea compared to observation for participants with SCD and risk of stroke

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Proportion experiencing life‐threatening events during the study Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1.1 Vaso‐occlusive events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.1.2 Acute splenic sequestration	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.1.3 Blood transfusions required	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.2 Signs of organ damage ‐ proportion of participants with a change in CNS measures Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.2.1 Participants converting from conditional to abnormal TCD ultrasound velocity	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.3 Signs of organ damage ‐ change from baseline in CNS measures Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.3.1 TCD ultrasound velocity (time‐averaged mean maximum velocity)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.4 Adverse events and toxicity Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.4.1 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.4.2 Headaches	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.4.3 Transient neutropenia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.4.4 Reticulocytopenia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.4.5 Parasite infection	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 3. Hydroxyurea compared to observation for participants with SCD and risk of stroke

Ir a la tabla de la revisión

	Idioma de la Revisión Cochrane Escoja su idioma de preferencia para las revisiones Cochrane y otros contenidos. Las secciones sin una traducción aparecerán en inglés.

	Idioma de la web Escoja su idioma de preferencia para la web de la Biblioteca Cochrane.

Idioma de la Revisión Cochrane

Idioma de la web

Información

Cifras del artículo

Altmetric:

Citado por:

Autores

Contributions of authors

Original review (2001)

2005 (minor) update

2010 (minor) update

2017 (major) update

2022 (minor) update

Sources of support

Internal sources

External sources

Declarations of interest

Acknowledgements

Version history

Differences between protocol and review

Notes

Information on the search results of previous versions of this review

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

PICO

PICO

Population

Intervention

Comparison

Outcome

Copiar o descargar referencia

Idioma de la Revisión Cochrane

Idioma de la web

Instituciones a las que se accedió previamente

Usuarios institucionales

Instituciones a las que se accedió previamente

Otras opciones de acceso