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Study flow diagram.
Figuras y tablas -
Figure 1

Study flow diagram.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 2

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

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 1 Pain crises.
Figuras y tablas -
Analysis 1.1

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

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 2 Proportion experiencing pain.
Figuras y tablas -
Analysis 1.2

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

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 3 Proportion experiencing life threatening events during study.
Figuras y tablas -
Analysis 1.3

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

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 4 Number of life‐threatening events during study.
Figuras y tablas -
Analysis 1.4

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

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 5 Deaths during the study.
Figuras y tablas -
Analysis 1.5

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

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 6 Change from baseline in fetal haemoglobin (HbF %).
Figuras y tablas -
Analysis 1.6

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

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 7 Fetal haemoglobin (HbF %) after treatment.
Figuras y tablas -
Analysis 1.7

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 7 Fetal haemoglobin (HbF %) after treatment.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 8 Change from baseline in absolute neutrophil count (x10³ per μL).
Figuras y tablas -
Analysis 1.8

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 8 Change from baseline in absolute neutrophil count (x10³ per μL).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 9 Neutrophil response (10⁹/L) after treatment.
Figuras y tablas -
Analysis 1.9

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 9 Neutrophil response (10⁹/L) after treatment.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 10 Change from baseline in haemoglobin (g/L).
Figuras y tablas -
Analysis 1.10

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

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 11 Change from baseline in m corpuscular volume (fL).
Figuras y tablas -
Analysis 1.11

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

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 12 Change from baseline in white blood cells (x10³ per μL).
Figuras y tablas -
Analysis 1.12

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 12 Change from baseline in white blood cells (x10³ per μL).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 13 Change from baseline in absolute reticulocyte count (x10³ per μL).
Figuras y tablas -
Analysis 1.13

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 13 Change from baseline in absolute reticulocyte count (x10³ per μL).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 14 Change from baseline in reticulocytes (%).
Figuras y tablas -
Analysis 1.14

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

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 15 Change from baseline in total bilirubin (mg/L).
Figuras y tablas -
Analysis 1.15

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 15 Change from baseline in total bilirubin (mg/L).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 16 Change from baseline in platelet count (x10³ per μL).
Figuras y tablas -
Analysis 1.16

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 16 Change from baseline in platelet count (x10³ per μL).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 17 Haemoglobin (g/dL).
Figuras y tablas -
Analysis 1.17

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 17 Haemoglobin (g/dL).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 18 Mean corpuscular volume (fL).
Figuras y tablas -
Analysis 1.18

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 18 Mean corpuscular volume (fL).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 19 Total bilirubin (mg/L).
Figuras y tablas -
Analysis 1.19

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 19 Total bilirubin (mg/L).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 20 Reticulocytes.
Figuras y tablas -
Analysis 1.20

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 20 Reticulocytes.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 21 Platelet count.
Figuras y tablas -
Analysis 1.21

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 21 Platelet count.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 22 Packed cell volume.
Figuras y tablas -
Analysis 1.22

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 22 Packed cell volume.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 23 F reticulocytes.
Figuras y tablas -
Analysis 1.23

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 23 F reticulocytes.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 24 F cells.
Figuras y tablas -
Analysis 1.24

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 24 F cells.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 25 Red blood count.
Figuras y tablas -
Analysis 1.25

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 25 Red blood count.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 26 White blood cells.
Figuras y tablas -
Analysis 1.26

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 26 White blood cells.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 27 Dense cells.
Figuras y tablas -
Analysis 1.27

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 27 Dense cells.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 28 Leucocytes.
Figuras y tablas -
Analysis 1.28

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 28 Leucocytes.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 29 Creatinine.
Figuras y tablas -
Analysis 1.29

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 29 Creatinine.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 30 Aspartate aminotransferase.
Figuras y tablas -
Analysis 1.30

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 30 Aspartate aminotransferase.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 31 Alkaline phosphatase.
Figuras y tablas -
Analysis 1.31

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 31 Alkaline phosphatase.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 32 Change from baseline in growth.
Figuras y tablas -
Analysis 1.32

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 32 Change from baseline in growth.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 33 Quality of life: general health perception.
Figuras y tablas -
Analysis 1.33

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 33 Quality of life: general health perception.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 34 Quality of life: pain recall.
Figuras y tablas -
Analysis 1.34

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 34 Quality of life: pain recall.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 35 Quality of life: social function.
Figuras y tablas -
Analysis 1.35

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 35 Quality of life: social function.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 36 Changes in 'Ladder of Life'.
Figuras y tablas -
Analysis 1.36

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 36 Changes in 'Ladder of Life'.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 37 Proportion of participants with signs of organ damage.
Figuras y tablas -
Analysis 1.37

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 37 Proportion of participants with signs of organ damage.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 38 Signs of organ damage ‐ change from baseline in DTPA GFR.
Figuras y tablas -
Analysis 1.38

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 38 Signs of organ damage ‐ change from baseline in DTPA GFR.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 39 Signs of organ damage ‐ change from baseline in Howell‐Jolley body (per 106 red blood cells).
Figuras y tablas -
Analysis 1.39

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 39 Signs of organ damage ‐ change from baseline in Howell‐Jolley body (per 106 red blood cells).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 40 Signs of organ damage ‐ change from baseline in pitted cells (%).
Figuras y tablas -
Analysis 1.40

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 40 Signs of organ damage ‐ change from baseline in pitted cells (%).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 41 Signs of organ damage ‐ change from baseline in spleen: liver ratio of counts.
Figuras y tablas -
Analysis 1.41

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 41 Signs of organ damage ‐ change from baseline in spleen: liver ratio of counts.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 42 Signs of organ damage ‐ change from baseline in spleen volume (cm3).
Figuras y tablas -
Analysis 1.42

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 42 Signs of organ damage ‐ change from baseline in spleen volume (cm3).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 43 Signs of organ damage ‐ change from baseline in creatinine (mg/L).
Figuras y tablas -
Analysis 1.43

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 43 Signs of organ damage ‐ change from baseline in creatinine (mg/L).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 44 Signs of organ damage ‐ change from baseline in Schwartz GFR.
Figuras y tablas -
Analysis 1.44

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 44 Signs of organ damage ‐ change from baseline in Schwartz GFR.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 45 Signs of organ damage ‐ change from baseline in cystatin C.
Figuras y tablas -
Analysis 1.45

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 45 Signs of organ damage ‐ change from baseline in cystatin C.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 46 Signs of organ damage ‐ change from baseline in urine osmolality.
Figuras y tablas -
Analysis 1.46

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 46 Signs of organ damage ‐ change from baseline in urine osmolality.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 47 Signs of organ damage ‐ change from baseline in urine pH.
Figuras y tablas -
Analysis 1.47

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 47 Signs of organ damage ‐ change from baseline in urine pH.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 48 Signs of organ damage ‐ change from baseline in urine‐specific gravity.
Figuras y tablas -
Analysis 1.48

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 48 Signs of organ damage ‐ change from baseline in urine‐specific gravity.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 49 Signs of organ damage ‐ change from baseline in total kidney volume.
Figuras y tablas -
Analysis 1.49

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 49 Signs of organ damage ‐ change from baseline in total kidney volume.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 50 Signs of organ damage ‐ change from baseline in TCD ultrasound velocity (time‐averaged mean maximum velocity).
Figuras y tablas -
Analysis 1.50

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 50 Signs of organ damage ‐ change from baseline in TCD ultrasound velocity (time‐averaged mean maximum velocity).

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 51 Signs of organ damage ‐ change from baseline in CNS measures.
Figuras y tablas -
Analysis 1.51

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 51 Signs of organ damage ‐ change from baseline in CNS measures.

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Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 52 Proportion of participants experiencing adverse events and toxicity.
Figuras y tablas -
Analysis 1.52

Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 52 Proportion of participants experiencing adverse events and toxicity.

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Comparison 2 Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 1 Proportion experiencing pain.
Figuras y tablas -
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.

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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.
Figuras y tablas -
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.

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Comparison 2 Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 3 Deaths during the study.
Figuras y tablas -
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.

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Comparison 2 Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 4 Change from baseline in fetal haemoglobin (HbF %).
Figuras y tablas -
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 fetal haemoglobin (HbF %).

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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).
Figuras y tablas -
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).

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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).
Figuras y tablas -
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).

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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 (%).
Figuras y tablas -
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 (%).

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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).
Figuras y tablas -
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).

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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).
Figuras y tablas -
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).

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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).
Figuras y tablas -
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).

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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).
Figuras y tablas -
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).

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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).
Figuras y tablas -
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).

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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.
Figuras y tablas -
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.

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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).
Figuras y tablas -
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).

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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).
Figuras y tablas -
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).

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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.
Figuras y tablas -
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.

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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.
Figuras y tablas -
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.

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

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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.
Figuras y tablas -
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.

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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.
Figuras y tablas -
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.

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Comparison 3 Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 4 Adverse events and toxicity.
Figuras y tablas -
Analysis 3.4

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

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Summary of findings for the main comparison. Summary of findings ‐ Hydroxyurea compared with placebo for sickle cell disease

Hydroxyurea compared with placebo for sickle cell disease

Patient or population: adults and children with sickle cell disease

Settings: outpatients

Intervention: hydroxyurea

Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Hydroxyurea

Pain alteration1

Follow‐up: 6 ‐ 24 months

See comment

See comment

NA

577

(4 studies)2

⊕⊕⊕⊝
moderate5

All studies showed a significant advantage to hydroxyurea compared to placebo (different measures of pain alteration presented)1.

Life‐threatening illness

Follow‐up: 6 ‐ 24 months

See comment

See comment

NA

552

(3 studies)

⊕⊕⊕⊝
moderate5

Significantly fewer occurrences of ACS (2 studies) and transfusions (3 studies) on hydroxyurea compared to placebo. No significant differences in terms of stroke, hepatic or splenic sequestration (two studies).

Death during the study (all deaths)

Follow‐up: 6 ‐ 24 months

26 per 1000

10 per 1000

(0 to 51 per 1000)

RR 0.39 (0.08 to 1.96)

577

(4 studies)2

⊕⊕⊕⊝
moderate5

There was also no significant difference between groups in terms of deaths related to SCD.

Measures of HbF (%)

Follow‐up: 6 ‐ 24 months

See comment

See comment

NA

577

(4 studies)2

⊕⊕⊕⊝
moderate5

There was a significant increase in HbF(%) in the hydroxyurea group compared to the placebo group in all studies (different measures presented)3.

Measures of ANC

Follow‐up: 6 ‐ 24 months

See comment

See comment

NA

517

(3 studies)2

⊕⊕⊕⊝
moderate5

There was a significant decrease in ANC in the hydroxyurea group compared to the placebo group in all studies (different measures presented)3.

Quality of life: 'Health Status Survey' the 'Profile of Mood States' and the 'Ladder of Life'

Follow‐up: 24 months

See comment

See comment

NA

up to 277

(1 study)

⊕⊕⊝⊝

low5,6

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)4.

Adverse events or toxicity: differences in rates of specific adverse events

Follow‐up: 6 ‐ 24 months

See comment

See comment

NA

577

(4 studies)2

⊕⊕⊝⊝

low5,7

Significantly fewer events of dactylitis and gastroenteritis on hydroxyurea compared to placebo.

No significant differences between groups in terms of all other events.

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: fetal haemoglobin; MD: mean difference;NA: not applicable; RR: risk ratio; 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.

  1. Pain alteration measured by mean annual pain crisis rate, time to initiation of treatment to first, second or third crisis, number of vaso‐occlusive crises, proportion of participants experiencing pain, proportion of hospitalisation for painful episodes.

  2. One study of 25 participants is of a cross‐over design (Belgian Study 1996). Participants are counted only once in this total.

  3. Different measures presented ‐ change from baseline or post intervention measures ‐ therefore, data from all studies could not be pooled.

  4. 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 not interpreted as significant in the study publication.

  5. Downgraded once due to applicability: only individuals with HbSS or HbSβº‐thalassemia genotypes were included therefore results are not applicable to individuals with HbSC genotype.

  6. 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.

  7. 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.

Figuras y tablas -
Summary of findings for the main comparison. Summary of findings ‐ Hydroxyurea compared with placebo for sickle cell disease
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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

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

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

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)

⊕⊕⊝⊝

low4,5

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 ‐ 30 months

See comment

See comment

NA

254

(2 studies)

⊕⊕⊕⊝
moderate4

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.

Death during the study (all deaths)

Follow‐up: 24 ‐ 30 months

1 death occurred in the transfusion and chelation group of 1 study1.

1 death occurred in the hydroxyurea and phlebotomy group of 1 study1.

RR 0.99 (95% CI 0.06 to 15.42)

254

(2 studies)

⊕⊕⊝⊝

low4,5

Measures of HbF (%)

Follow‐up: 24 to 30 months

See comment

See comment

NA

254

(2 studies)

⊕⊕⊕⊝
moderate4

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)2.

Measures of ANC

Follow‐up: 24 to 30 months

See comment

See comment

NA

254

(2 studies)

⊕⊕⊕⊝
moderate4

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)2.

Quality of life

Outcome not reported3

NA

Adverse events or toxicity: differences in rates of specific adverse events

See comment

See comment

NA

254

(2 studies)

⊕⊕⊝⊝

low4,6

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.

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: fetal 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.

1. Absolute data presented for number of deaths as the confidence interval of the relative effect very large due to the small number of events.
2. Different measures presented ‐ mean or median change from baseline ‐ therefore data from all studies could not be pooled.
3. Quality of life data was collected in TWiTCH 2016; to date, primary results of this study have been published but not quality of life data. When available, quality of life data will be included in an update of this review.
4. Downgraded once due to applicability: only children with HbSS or HbSβº‐thalassemia were included therefore results are not applicable to adults or individuals with HbSC genotype.
5. Downgraded once due to imprecision: small number of events and large CI around the relative effect.
6. 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.

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

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

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Observation

Hydroxyurea

Pain alteration

Follow‐up: NA

Outcome not reported

NA

Life‐threatening illness

Follow‐up: 15 months

See comment

See comment

NA

22

(1 study)

⊕⊝⊝⊝
very low3,4

No significant differences between groups in terms of ACS, blood transfusions required or acute splenic sequestration.

Death during the study

Follow‐up: 15 months

No deaths occurred

No deaths occurred

NA

22

(1 study)

⊕⊝⊝⊝
very low3,4

Measures of HbF

Follow‐up: 15 months

See comment

See comment

NA

22

(1 study)

⊕⊝⊝⊝
very low3,4

There was a significant increase in HbF in the hydroxyurea group compared to the observation group1.

Measures of ANC

Follow‐up: 15 months

See comment

See comment

NA

22

(1 study)

⊕⊝⊝⊝
very low3,4

There was a significant decrease in ANC in the hydroxyurea group compared to the observation group1.

Quality of Life

Follow‐up: NA

Outcome not reported2

NA

Adverse events or toxicity: differences in rates of specific adverse events

Follow‐up: 15 months

See comment

See comment

NA

22

(1 study)

⊕⊝⊝⊝
very low3,4

No significant differences between groups in terms of transient neutropenia, reticulocytopenia, parasite infestation, headache and dizziness.

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: fetal 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.

1. Median values reported so data cannot be entered into analysis.
2. Outcome was not collected or presented due to early termination of study.
3. Downgraded 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.
4. Downgraded once due to applicability: only children with HbSS or HbSβº‐thalassemia were included therefore results are not applicable to adults or individuals with HbSC genotype.

Figuras y tablas -
Summary of findings 3. Summary of findings ‐ Hydroxyurea compared with observation for people with sickle cell disease and an increased risk of stroke
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Summary of findings 4. Summary of findings ‐ Hydroxyurea compared with no hydroxyurea for people with sickle cell disease

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

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

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

⊕⊝⊝⊝
very low2,3,4

Measures of HbF

Follow‐up: 24 weeks

See comment

See comment

NA

up to 44

(1 study)1

⊕⊝⊝⊝
very low2,3,4

There was a significant increase in HbF in the hydroxyurea group compared to the no hydroxyurea group1.

Measures of ANC

Follow‐up: 24 weeks

See comment

See comment

NA

up to 44

(1 study)1

⊕⊝⊝⊝
very low2,3,4

There was no significant difference in ANC between treatment groups1.

Quality of life

Follow‐up: NA

Outcome not reported

NA

Adverse events or toxicity

Follow‐up: 11 months

See comment

See comment

NA

up to 44

(1 study)1

⊕⊝⊝⊝
very low2,3,4

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).

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: fetal 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.

1. 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), results are not entered into analysis. All results of this trial are considered exploratory (CHAMPS 2011).
2. Downgraded once due to indirectness: factorial design of the study makes comparison of hydroxyurea to no hydroxyurea indirect.
3. Downgraded once due to imprecision and risk of bias: study was terminated early with only 44 out of 188 participants recruited and outcome data is presented for only those who completed each follow‐up time.
4. Downgraded once due to applicability: participants with HbSC were included therefore results are not applicable to individuals with HbSS or HbSβº‐thalassemia genotypes.

Figuras y tablas -
Summary of findings 4. Summary of findings ‐ Hydroxyurea compared with no hydroxyurea for people with sickle cell disease
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Table 1. Clinical events and markers of response in Jain 2012

Hydroxyurea

Placebo

P value

Baseline

18 months

Baseline

18 months

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: fetal haemoglobin
RBC: red blood count
VOC: vaso‐occlusive crises
WBC: white blood count

Figuras y tablas -
Table 1. Clinical events and markers of response in Jain 2012
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Table 2. Laboratory measurements from MSH 1995

Baseline

Hyrdoxyurea

Placebo

P value

2 years

Baseline

2 years

2 years

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: fetal haemoglobin
MCV: mean corpuscular volume
PCV: packed cell volume
WBC: white blood count

Figuras y tablas -
Table 2. Laboratory measurements from MSH 1995
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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: fetal 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.

Figuras y tablas -
Table 3. Laboratory evaluations from the SWiTCH trial
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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: fetal 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.

Figuras y tablas -
Table 4. Laboratory evaluations from the SCATE trial
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Table 5. Pregnancies in the MSH Study

Pregnancy

Hydroxyurea

Placebo

Patients

Normal full‐term delivery

1

2

Elective termination

2

1

Partners of patients

Normal full‐term delivery

2

0

Spontaneous abortion

1

0

Still pregnant

0

1

TOTAL

6

4

Figuras y tablas -
Table 5. Pregnancies in the MSH Study
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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 Pain crises Show forest plot

2

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

1.1 Mean annual crisis rate at 2 years (all crises)

1

Mean Difference (IV, Fixed, 95% CI)

‐2.80 [‐4.74, ‐0.86]

1.2 Mean annual crisis rate at 2 years (all crises requiring hospitalisation)

1

Mean Difference (IV, Fixed, 95% CI)

‐1.50 [‐2.58, ‐0.42]

1.3 Number of vaso‐occlusive crises after 18 months of treatment

1

Mean Difference (IV, Fixed, 95% CI)

‐9.6 [‐10.86, ‐8.34]

2 Proportion experiencing pain Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3 Proportion experiencing life threatening events during study Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Acute chest syndrome

2

492

Risk Ratio (M‐H, Fixed, 95% CI)

0.43 [0.29, 0.63]

3.2 Hepatic sequestration

1

299

Risk Ratio (M‐H, Fixed, 95% CI)

0.32 [0.03, 3.06]

3.3 Stroke

2

492

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.12, 2.53]

3.4 Patients transfused

2

492

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.52, 0.82]

3.5 Splenic sequestration

1

193

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.36, 2.23]

4 Number of life‐threatening events during study Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

4.1 Blood transfusions

1

Mean Difference (IV, Fixed, 95% CI)

‐1.85 [‐2.18, ‐1.52]

4.2 Hospitalisations

1

Mean Difference (IV, Fixed, 95% CI)

‐8.89 [‐10.04, ‐7.74]

4.3 Duration of hospitalisation (days)

1

Mean Difference (IV, Fixed, 95% CI)

‐2.00 [‐4.87, ‐3.13]

5 Deaths during the study Show forest plot

3

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

5.1 All deaths

3

552

Risk Ratio (M‐H, Fixed, 95% CI)

0.39 [0.08, 1.96]

5.2 Deaths related to SCD

3

552

Risk Ratio (M‐H, Fixed, 95% CI)

0.48 [0.09, 2.60]

6 Change from baseline in fetal haemoglobin (HbF %) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

7 Fetal haemoglobin (HbF %) after treatment Show forest plot

2

359

Mean Difference (IV, Fixed, 95% CI)

4.07 [2.95, 5.18]

8 Change from baseline in absolute neutrophil count (x10³ per μL) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

9 Neutrophil response (10⁹/L) after treatment Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

9.1 Neutrophils (x10 9/l) at 10 weeks

1

Mean Difference (IV, Fixed, 95% CI)

‐1.90 [‐2.51, ‐1.29]

9.2 Neutrophils (x10 9/l) at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

‐1.50 [‐2.01, ‐0.99]

10 Change from baseline in haemoglobin (g/L) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

11 Change from baseline in m corpuscular volume (fL) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

12 Change from baseline in white blood cells (x10³ per μL) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

13 Change from baseline in absolute reticulocyte count (x10³ per μL) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

14 Change from baseline in reticulocytes (%) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

15 Change from baseline in total bilirubin (mg/L) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

16 Change from baseline in platelet count (x10³ per μL) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

17 Haemoglobin (g/dL) Show forest plot

2

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

17.1 At 10 weeks

1

299

Mean Difference (IV, Fixed, 95% CI)

0.5 [0.19, 0.81]

17.2 At the end of the study

2

359

Mean Difference (IV, Fixed, 95% CI)

1.04 [0.82, 1.25]

18 Mean corpuscular volume (fL) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

18.1 At 10 weeks

1

Mean Difference (IV, Fixed, 95% CI)

12.30 [9.69, 14.91]

18.2 At 2 years

1

Mean Difference (IV, Fixed, 95% CI)

10.0 [7.34, 12.66]

19 Total bilirubin (mg/L) Show forest plot

2

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

19.1 At the end of the study

2

359

Mean Difference (IV, Fixed, 95% CI)

‐1.56 [‐1.90, ‐1.23]

20 Reticulocytes Show forest plot

2

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

20.1 Reticulocytes (10⁵/mm³) at 18 months

1

Mean Difference (IV, Fixed, 95% CI)

‐0.66 [‐0.90, ‐0.42]

20.2 Reticulocytes (10⁹/L) at 10 weeks

1

Mean Difference (IV, Fixed, 95% CI)

‐130.0 [‐152.17, ‐107.83]

20.3 Reticulocytes (10⁹/L) at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

‐69.0 [‐91.56, ‐46.44]

21 Platelet count Show forest plot

2

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

21.1 Platelet count (10³/mm³) at 18 months

1

Mean Difference (IV, Fixed, 95% CI)

‐0.05 [‐0.16, 0.06]

21.2 Platelet count (x10⁹/L) at 10 weeks

1

Mean Difference (IV, Fixed, 95% CI)

‐35.0 [‐75.19, 5.19]

21.3 Platelet count (x10⁹/L) at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

‐24.0 [‐51.88, 3.88]

22 Packed cell volume Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

22.1 Packed cell volume (%) at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

1.90 [0.85, 2.95]

23 F reticulocytes Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

23.1 F reticulocytes at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

2.0 [0.18, 3.82]

24 F cells Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

24.1 F cells (%) at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

13.0 [8.33, 17.67]

25 Red blood count Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

25.1 Red blood count (10⁶/mm³) at 18 months

1

Mean Difference (IV, Fixed, 95% CI)

‐1.13 [‐1.24, ‐1.02]

26 White blood cells Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

26.1 White blood cells (109/L) at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

‐2.30 [‐2.97, ‐1.63]

27 Dense cells Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

27.1 Dense cells (%) at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

‐2.0 [‐3.48, ‐0.52]

28 Leucocytes Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

28.1 Leucocytes (10³/mm³) at 18 months

1

Mean Difference (IV, Fixed, 95% CI)

‐0.84 [‐3.07, 1.39]

29 Creatinine Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

29.1 Creatinine (mg/dL) at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [‐0.11, 0.11]

30 Aspartate aminotransferase Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

30.1 Aspartate aminotransferase at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

‐4.0 [‐9.40, 1.40]

31 Alkaline phosphatase Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

31.1 Alkaline phosphatase at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

‐2.0 [‐15.78, 11.78]

32 Change from baseline in growth Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

32.1 Height (cm)

1

Mean Difference (Fixed, 95% CI)

‐0.2 [1.00, 0.60]

32.2 Weight (kg)

1

Mean Difference (Fixed, 95% CI)

0.10 [‐0.20, 0.40]

32.3 Head circumference (cm)

1

Mean Difference (Fixed, 95% CI)

‐0.2 [‐0.60, 0.20]

33 Quality of life: general health perception Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

33.1 General health perception at 6 months

1

Mean Difference (IV, Fixed, 95% CI)

0.30 [‐0.54, 1.14]

33.2 General health perception at 1 year

1

Mean Difference (IV, Fixed, 95% CI)

0.60 [‐0.18, 1.38]

33.3 General health perception at 18 months

1

Mean Difference (IV, Fixed, 95% CI)

0.9 [0.08, 1.72]

33.4 General health perception at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

0.4 [‐0.51, 1.31]

34 Quality of life: pain recall Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

34.1 Pain recall at 6 months

1

Mean Difference (IV, Fixed, 95% CI)

0.40 [‐0.13, 0.93]

34.2 Pain recall at 1 year

1

Mean Difference (IV, Fixed, 95% CI)

0.40 [‐0.18, 0.98]

34.3 Pain recall at 18 months

1

Mean Difference (IV, Fixed, 95% CI)

0.70 [0.11, 1.29]

34.4 Pain recall at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

0.3 [‐0.30, 0.90]

35 Quality of life: social function Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

35.1 Social function at 6 months

1

Mean Difference (IV, Fixed, 95% CI)

0.4 [‐0.15, 0.95]

35.2 Social function at 1 year

1

Mean Difference (IV, Fixed, 95% CI)

0.2 [‐0.36, 0.76]

35.3 Social function at 18 months

1

Mean Difference (IV, Fixed, 95% CI)

0.40 [‐0.21, 1.01]

35.4 Social function at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

0.3 [‐0.31, 0.91]

36 Changes in 'Ladder of Life' Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

36.1 Changes in 'Ladder of Life' at 6 months

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [‐0.52, 0.52]

36.2 Changes in 'Ladder of Life' at 1 year

1

Mean Difference (IV, Fixed, 95% CI)

0.4 [‐0.15, 0.95]

36.3 Changes in 'Ladder of Life' at 18 months

1

Mean Difference (IV, Fixed, 95% CI)

0.30 [‐0.22, 0.82]

36.4 Changes in 'Ladder of Life' at 2 years

1

Mean Difference (IV, Fixed, 95% CI)

0.3 [‐0.23, 0.83]

37 Proportion of participants with signs of organ damage Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

37.1 New leg ulcers

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.44, 1.64]

37.2 Aseptic necrosis (humerus or femur)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.39, 2.37]

37.3 Decreased spleen function at exit (compared to baseline)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.72 [0.44, 1.16]

38 Signs of organ damage ‐ change from baseline in DTPA GFR Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

39 Signs of organ damage ‐ change from baseline in Howell‐Jolley body (per 106 red blood cells) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

40 Signs of organ damage ‐ change from baseline in pitted cells (%) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

41 Signs of organ damage ‐ change from baseline in spleen: liver ratio of counts Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

42 Signs of organ damage ‐ change from baseline in spleen volume (cm3) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

43 Signs of organ damage ‐ change from baseline in creatinine (mg/L) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

44 Signs of organ damage ‐ change from baseline in Schwartz GFR Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

44.1 Schwartz glomerular filtration rate (mL/min per 1.73m2)

1

Mean Difference (Fixed, 95% CI)

‐8.0 [‐35.00, 21.00]

45 Signs of organ damage ‐ change from baseline in cystatin C Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

46 Signs of organ damage ‐ change from baseline in urine osmolality Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

47 Signs of organ damage ‐ change from baseline in urine pH Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

48 Signs of organ damage ‐ change from baseline in urine‐specific gravity Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

49 Signs of organ damage ‐ change from baseline in total kidney volume Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

50 Signs of organ damage ‐ change from baseline in TCD ultrasound velocity (time‐averaged mean maximum velocity) Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

51 Signs of organ damage ‐ change from baseline in CNS measures Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

51.1 Bayley Mental Development Index

1

Mean Difference (Fixed, 95% CI)

3.0 [0.00, 8.00]

51.2 Bayley motor performance development index

1

Mean Difference (Fixed, 95% CI)

2.0 [‐1.00, 7.00]

52 Proportion of participants experiencing adverse events and toxicity Show forest plot

3

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

52.1 hair loss at 1 or 2 visits

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.25 [0.69, 2.26]

52.2 hair loss at 3 or more visits

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.61 [0.31, 1.21]

52.3 skin rash at 1 or 2 visits

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.62, 1.51]

52.4 skin rash at 3 or more visits

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.58, 1.60]

52.5 fever at 1 or 2 visits

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.55, 1.69]

52.6 fever at 3 or more visits

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.68, 1.17]

52.7 Gastroinestinal disturbance at 1 or 2 visits

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.50, 1.36]

52.8 Gastrointestinal disturbance at 3 or more visits

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.74, 1.31]

52.9 Other abnormalities at 1 or 2 visits

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.60 [0.33, 1.11]

52.10 Other abnormalities at 3 or more visits

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.83, 1.40]

52.11 Hospitalisation (for any reason)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.72, 0.96]

52.12 Dactylitis

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.20, 0.58]

52.13 Priapism

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.52 [0.26, 8.87]

52.14 Sepsis or bacteraemia

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.40 [0.08, 2.03]

52.15 Splenomegaly

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.61, 1.32]

52.16 Absolute Neutrophil Count < 500

1

Risk Ratio (M‐H, Fixed, 95% CI)

2.53 [0.50, 12.71]

52.17 Absolute Neutrophil 500 ‐ 1250

1

Risk Ratio (M‐H, Fixed, 95% CI)

2.53 [1.58, 4.03]

52.18 Thrombocytopaenia

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.59 [0.64, 3.92]

52.19 Alanine transaminase > 150 U/L

1

Risk Ratio (M‐H, Fixed, 95% CI)

2.02 [0.19, 21.92]

52.20 Severe anaemia

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.51 [0.05, 5.48]

52.21 Bilirubin

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.01, 8.17]

52.22 Creatinine

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

52.23 Skin and subcutaneous disorders

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.75, 1.10]

52.24 Splenic sequestration

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.36, 2.23]

52.25 Gastroenteritis

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.44 [0.28, 0.71]

52.26 Nausea

1

Risk Ratio (M‐H, Fixed, 95% CI)

5.0 [0.25, 99.95]

52.27 Skin Rash

1

Risk Ratio (M‐H, Fixed, 95% CI)

7.0 [0.38, 129.93]
Figuras y tablas -
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

1 Proportion experiencing pain Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

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]

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 Proportion experiencing life‐threatening events during study Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Stroke (secondary)

1

133

Risk Ratio (M‐H, Fixed, 95% CI)

14.78 [0.86, 253.66]

2.2 Transient ischaemic attack (primary)

1

121

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.21, 4.84]

2.3 Transient ischaemic attack (secondary)

1

133

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.25, 1.74]

2.4 Other neurological event (primary)

1

121

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.07, 15.88]

2.5 Acute chest syndrome

2

254

Risk Ratio (M‐H, Fixed, 95% CI)

2.84 [1.25, 6.42]

2.6 Infections and Infestations

2

254

Risk Ratio (M‐H, Fixed, 95% CI)

3.65 [1.05, 12.76]

2.7 Splenic sequestration or splenectomy

2

254

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.01, 8.16]

2.8 Hepatobiliary disease

1

121

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.07, 15.88]

2.9 Total with serious adverse events

2

254

Risk Ratio (M‐H, Fixed, 95% CI)

1.93 [1.17, 3.20]

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]

3 Deaths during the study Show forest plot

2

254

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.06, 15.42]

4 Change from baseline in fetal haemoglobin (HbF %) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

5 Change from baseline in absolute neutrophil count (x10⁹/L) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

6 Change from baseline in mean corpuscular volume (fL) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

7 Change from baseline in sickle haemoglobin (%) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

8 Change from baseline in haemoglobin (g/L) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

9 Change from baseline in absolute reticulocyte count (10⁹ / L) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

10 Change from baseline in white blood count (10⁹ / L) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

11 Change from baseline in platelets (10⁹ / L) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

12 Change from baseline in total bilirubin (mg/L) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

13 Change from baseline in liver iron concentration Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

14 Change from baseline in serum ferritin (ng/mL) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

15 Change from baseline in lactate dehydrogenase (U/L) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

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

16.1 Final TCD ultrasound velocity

1

Mean Difference (IV, Fixed, 95% CI)

‐5.0 [‐9.16, ‐0.84]

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

17.1 Infections and infestations

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.24 [0.89, 1.72]

17.2 Gastrointestinal disorders

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.16 [0.74, 1.80]

17.3 Fever

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.66, 1.75]

17.4 Musculoskelatal disorders

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [0.59, 2.20]

17.5 Immune system disorders

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.12 [0.02, 0.96]

17.6 Cholelithiasis

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.17, 3.17]

17.7 Cholecystitis

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.97 [0.18, 21.21]

17.8 Asthma

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.17, 3.17]

17.9 Acute chest syndrome

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.72 [0.53, 5.61]

17.10 Renal or urinary disorder

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.11, 3.80]

17.11 Priapism

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.97 [0.18, 21.21]

17.12 Cathether‐related complications

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.48 [0.26, 8.56]

17.13 Cardiac disorder

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.06, 15.42]

17.14 Hyderbilirubianemia

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.49 [0.24, 1.02]

17.15 Alanine transaminase increase

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.06 [0.55, 2.01]

17.16 Aspartate transaminase increase

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.38 [0.66, 2.88]

17.17 Serum creatinine increase

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.97 [0.51, 7.55]

17.18 Thrombocytopenia

1

Risk Ratio (M‐H, Fixed, 95% CI)

6.90 [0.87, 54.51]

17.19 Reticuloctopenia

1

Risk Ratio (M‐H, Fixed, 95% CI)

6.90 [2.16, 22.02]

17.20 Neutropenia

1

Risk Ratio (M‐H, Fixed, 95% CI)

9.85 [1.30, 74.80]

17.21 Anaemia

1

Risk Ratio (M‐H, Fixed, 95% CI)

6.57 [2.05, 21.05]

17.22 Sickle cell pain

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.29 [0.92, 1.82]

17.23 Sickle cell‐related events

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.81, 1.30]

17.24 All adverse events

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.92, 1.05]
Figuras y tablas -
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

1 Proportion experiencing life‐threatening events during the study Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Vaso‐occlusive events

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.4 [0.10, 1.64]

1.2 Acute splenic sequestration

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.07, 14.05]

1.3 Blood transfusions required

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.04, 2.73]

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

2.1 Participants converting from conditional to abnormal TCD ultrasound velocity

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.2 [0.03, 1.45]

3 Signs of organ damage ‐ change from baseline in CNS measures Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

3.1 TCD ultrasound velocity (time‐averaged mean maximum velocity)

1

Mean Difference (IV, Fixed, 95% CI)

‐25.7 [‐45.38, ‐6.02]

4 Adverse events and toxicity Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.1 Dizziness

1

Risk Ratio (M‐H, Fixed, 95% CI)

3.0 [0.14, 66.53]

4.2 Headaches

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.07, 14.05]

4.3 Transient neutropenia

1

Risk Ratio (M‐H, Fixed, 95% CI)

3.0 [0.14, 66.53]

4.4 Reticulocytopenia

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.07, 14.05]

4.5 Parasite infection

1

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.07, 14.05]
Figuras y tablas -
Comparison 3. Hydroxyurea compared to observation for participants with SCD and risk of stroke
Ir a la tabla de la revisión