Hidroxiurea (hidroxicarbamida) para la drepanocitosis
Referencias
Referencias de los estudios incluidos en esta revisión
Referencias de los estudios excluidos de esta revisión
Referencias de los estudios en curso
Referencias adicionales
Referencias de otras versiones publicadas de esta revisión
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Study characteristics | ||
| Methods | Randomised, double‐blind (participant, investigator), placebo‐controlled, parallel assignment, efficacy study conducted at 13 centres in the USA | |
| Participants | Children aged 9 months to 18 months with SCD (HbSS or HbSߺ‐thalassaemia) irrespective of clinical severity. Exclusion criteria were transfusion within 2 months, height, weight or head circumference below the 5th percentile, mental development index less than 70 or abnormal TCD ultrasound velocity. 193 randomised: 96 participants to hydroxyurea and 97 to placebo Mean (SD) age: hydroxyurea group: 13.6 (2.7) months, placebo group: 13.5 (2.8) months 187 (97%) with HbSS genotype, 109 (56%) females | |
| Interventions | Hydroxyurea (20 mg/kg/day) versus placebo for 24 months | |
| Outcomes | Primary outcomes: spleen function (decline in splenic uptake); glomerular filtration rate with 99mTc‐diethyl‐enetriaminepentaacetic acid plasma clearance Secondary outcomes: ratio of nuclear decay counts in the spleen and liver; proportion of red blood cells containing pits or Howell‐Jolly bodies; renal function; growth; development (including neuro‐developmental assessment) | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | The telephone randomisation schedule was developed by the medical co‐ordinating centre. |
| Allocation concealment (selection bias) | Low risk | Centralised telephone randomisation was used. |
| Incomplete outcome data (attrition bias) | Low risk | Some secondary outcomes reported for only the individuals who completed the study but ITT approach taken for primary outcomes (via multiple imputation) and safety outcomes so risk of bias judged to be low. |
| Selective reporting (reporting bias) | Low risk | All outcomes well defined in the methods and reported well in the results. |
| Other bias | Low risk | None identified. |
| Blinding of participants and personnel (performance bias) | Low risk | Participants, caregivers and medical co‐ordinating centre staff were masked to treatment allocation via packaging and treatment of the same appearance. |
| Blinding of outcome assessment (detection bias) | Low risk | An unmasked "primary endpoint person" monitored laboratory values and assisted clinical management. Other outcome assessors (e.g. those reading the liver‐spleen scans). |
| Study characteristics | ||
| Methods | Randomised, placebo‐controlled, cross‐over study conducted in a single centre in Belgium | |
| Participants | 25 children with HbSS genotype, aged 2 to 22 years (median 9 years) with > 3 vaso‐occlusive events reported in preceding 12 months and/or history of CVA off transfusion (severe alloimmunisation or compliance), ACS, ASS | |
| Interventions | Hydroxyurea 20 mg/kg/day rising to 25 mg/kg/day (unless toxic cytopenia) versus placebo Treatment period was for 6 months | |
| Outcomes | Number of hospitalisations | |
| Notes | Data are not presented in a way that can be included in the review so the results are presented narratively | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Described as "drawing sealed envelopes, patients were randomly allocated to one of the following treatment sequences", therefore the generation of the treatment sequence is not clear from this statement. |
| Allocation concealment (selection bias) | Unclear risk | Described as "drawing sealed envelopes, patients were randomly allocated to one of the following treatment sequences", therefore the allocation of the treatment sequence is not clear from this statement. |
| Incomplete outcome data (attrition bias) | Unclear risk | 3 participants were excluded from the analysis due to their failure to attend the monthly evaluation at 4 to 5 months. There was no discussion of whether or not an ITT analysis was used so the risk is unclear. |
| Selective reporting (reporting bias) | High risk | A planned outcome (number of days in pain) was dropped from analysis due to difficulty in obtaining information to inform this analysis from participants. |
| Other bias | Low risk | Unclear if a washout period was used in this cross‐over study but tests for period effects and carry‐over effects were not significant so the risk of bias in the cross‐over design is low. |
| Blinding of participants and personnel (performance bias) | Unclear risk | The hospital pharmacy provided the treatment and placebo for each participant and both were described as "indistinguishable", however the physician was aware of the treatment schedule because of the difficulty of blinding the attending physician to the treatment received. Unclear if this could have influenced the results. |
| Blinding of outcome assessment (detection bias) | Unclear risk | No information provided. |
| Study characteristics | ||
| Methods | Randomised, multicentre, phase II, double‐blind, placebo‐controlled study | |
| Participants | Eligible participants over the age of 5 years with HbSC and at least 1 vaso‐occlusive event in the previous 12 months (but none in the 4 weeks prior to study entry) 44 participants randomised; 11 to each treatment group (see 'Interventions') Mean age: 13.6 years (range 5 to 53 years), 43% females | |
| Interventions | Participants randomised to 1 of 4 arms in a factorial design: 1. hydroxyurea (20 mg/kg/day) and magnesium (0.6 mmol/kg/day in 2 doses); 2. hydroxyurea (20 mg/kg/day) and placebo; 3. placebo and magnesium (0.6 mmol/kg/day in 2 doses); 4. placebo and placebo. | |
| Outcomes | Primary outcome: proportion of hyperdense red blood cells at 8 weeks Secondary outcomes: central laboratory evaluations (including measurements of red cell density, HbF, red cell cation content, KCl co‐transport and Gardos channel activity, cell adhesion to endothelial cells and laminin, and erythrocyte membrane phosphatidyl serine (PS exposure)) at baseline (twice) and weeks 8, 16, 24 and 44 Participants were evaluated at 2‐ or 4‐week intervals for 11 months (15 visits) | |
| Notes | The study was not designed to measure efficacy and all analyses were considered exploratory. The study was terminated early due to low enrolment after 44 participants had been randomised (target 188). Due to the factorial design, no data can be entered into analysis and the results for hydroxyurea groups (groups 1 and 2) compared to no hydroxyurea groups are summarised narratively. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | A sequential allocation algorithm (i.e. minimisation) was used due to small numbers within each strata (site and age group). |
| Allocation concealment (selection bias) | Unclear risk | No information provided. |
| Incomplete outcome data (attrition bias) | High risk | 36 out of 44 participants completed 8 weeks and 22 out of 44 completed 44 weeks. Only those who completed the follow‐up time were included in analysis (8 weeks for primary endpoint and 44 weeks for secondary endpoints). This is not an ITT approach. |
| Selective reporting (reporting bias) | Low risk | Outcome defined in the methods section are well described in the results section. Study was not designed to measure efficacy. |
| Other bias | Low risk | Study terminated early after only 44 of the planned sample size of 188 were recruited. However, the study was not designed to measure efficacy and performed only exploratory analyses therefore the early termination is unlikely to have introduced bias. |
| Blinding of participants and personnel (performance bias) | Low risk | All tablets were 'over‐capsulated' to disguise appearance. |
| Blinding of outcome assessment (detection bias) | Unclear risk | No information provided. |
| Study characteristics | ||
| Methods | Double‐blind, randomised, controlled study conducted in a tertiary hospital in Nagpur City, India | |
| Participants | Indian children between the ages of 5 and 18 years with severe manifestations (defined as 3 or more blood transfusions or VOC requiring hospitalisation per year) despite high HbF Exclusion criteria included seropositivity for HIV or chronic illness 60 participants randomised; 30 to each treatment group 53% females (16 females per group) Mean (SD) age ‐ hydroxyurea group: 12.73 (4.4) years, placebo group: 11.73 (4.08) years | |
| Interventions | Hydroxyurea (fixed dose 10 mg/mg/day) compared to placebo for 18 months | |
| Outcomes | Primary outcome: frequency of VOC per participant per year Secondary outcomes: frequency of blood transfusions, hospitalisations and HbF levels | |
| Notes | — | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Participants were randomised using randomisation tables. |
| Allocation concealment (selection bias) | Unclear risk | No information provided. |
| Incomplete outcome data (attrition bias) | Low risk | All participants completed 18‐month follow‐up and were included in analysis. |
| Selective reporting (reporting bias) | Low risk | No protocol available; outcomes defined in the methods reported well in the results. |
| Other bias | Low risk | None identified. |
| Blinding of participants and personnel (performance bias) | Low risk | Participants were blinded with placebo tablets of identical appearance. The clinician who assessed participants was not aware of treatment arm. |
| Blinding of outcome assessment (detection bias) | Low risk | The laboratory technician and the clinician who assessed participants were not aware of treatment arm. |
| Study characteristics | ||
| Methods | Randomised, multicentre, parallel, double‐blind, placebo‐controlled study conducted in the USA and Canada across 21 sites | |
| Participants | Adults over 18 years of age with HbSS genotype who had reported more than 3 'crises' to treating physician in the preceding 12 months and who had < 15% HbA Exclusions included: HbA > 15%, pregnancy, opiate addiction, other potent anti‐sickling agents, cytopenia, CVA in the preceding 6 years, HIV antibody +, prior hydroxyurea therapy 152 randomised to hydroxyurea and 147 randomised to placebo | |
| Interventions | Hydroxyurea starting at 15 mg/kg/day rising 12‐weekly by 5 mg/kg/day unless marrow depression (then cessation of drug until recovery and restarted at 2.5 mg/kg/day lower, i.e. MTD) compared to placebo for 2 years | |
| Outcomes | Primary outcome: pain events ‐ attending hospital > 4 hours and parenteral opiate treatment | |
| Notes | 93% follow‐up at 2 years, treatment stopped in 14 hydroxyurea and 6 placebo participants. Due to beneficial treatment effects, the study was stopped at a mean follow‐up of 21 months, before the planned 24 months of treatment had been completed for all participants. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Treatment assignments were made centrally using a computer program to generate separate, randomised block assignment schedules for each clinic. |
| Allocation concealment (selection bias) | Unclear risk | There was no clear discussion of allocation concealment. |
| Incomplete outcome data (attrition bias) | Low risk | Withdrawals from the study were well documented; all participants included in analysis in an ITT approach in the primary publications but later reported outcomes (such as quality of life) reported only for those who contributed data. |
| Selective reporting (reporting bias) | Low risk | All outcomes well defined in the methods and reported well in the results. |
| Other bias | Low risk | None identified. |
| Blinding of participants and personnel (performance bias) | Low risk | Stated to be double‐blind (physician and participant), where treatment was assigned in combinations of identically appearing capsules. |
| Blinding of outcome assessment (detection bias) | Unclear risk | There was no clear discussion of blinding of outcome assessors. |
| Study characteristics | ||
| Methods | Prospective, randomised, placebo‐controlled, double‐blind phase III trial (NOHARM trial) | |
| Participants | Study participants were recruited from the Mulago Hospital Sickle Cell Clinic (MHSCC) in Kampala, Uganda Children aged 1 to 4 years with documented HbSS living in an area of meso‐endemic malaria transmission Exclusion criteria included severe malnutrition, known chronic medical conditions, current hydroxyurea treatment or blood transfusion in the previous 30 days 208 participants randomised; 104 randomised to either hydroxyurea or placebo; 1 randomised participant in the placebo group later found to be ineligible so excluded from the study Mean (SD) age: hydroxyurea group: 2.2 (0.9) years, placebo group: 2.3 (0.9) years Females: hydroxyurea group: 49 (47%), placebo group: 46 (45%) | |
| Interventions | Hydroxyurea 20 ± 2.5 mg/kg/day compared to placebo | |
| Outcomes | Primary outcome: malaria incidence, defined as episodes of clinical malaria occurring over the 1‐year randomised study treatment period Secondary outcomes: a composite of 1 or more SCA‐related adverse events (pain, dactylitis, acute chest syndrome, splenic sequestration or transfusion); clinical adverse events and dose‐limiting toxicities; laboratory characteristics (e.g. HbF) | |
| Notes | Summary of primary outcome results (not a pre‐specified outcome of this review): there were 12 episodes of malaria during the study; 5 episodes in 3 children in the hydroxyurea group and 7 episodes in 7 children in the placebo group. Malaria incidence did not differ between children prescribed hydroxyurea (0.05 episodes per child per year, 95% CI 0.02 to 0.13) versus placebo (0.07 episodes per child per year, 95% CI 0.03 to 0.16). Time to malaria infection also did not differ significantly between hydroxyurea and placebo. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomisation was conducted using computer‐generated block randomisation. |
| Allocation concealment (selection bias) | Low risk | Randomisation was performed centrally and (quote) "... all but two members of the Data Coordinating Center were masked to treatment allocation". |
| Incomplete outcome data (attrition bias) | Unclear risk | Attrition clearly described in a study flow diagram with reasons for treatment discontinuation provided. Analysis conducted using an ITT approach. |
| Selective reporting (reporting bias) | Low risk | Published protocol available. All pre‐specified outcomes reported. |
| Other bias | Low risk | None identified. |
| Blinding of participants and personnel (performance bias) | Low risk | Double‐blinding was achieved with placebo tablets of identical size and appearance and all but 2 members of the Data Coordinating Center were masked to treatment allocation |
| Blinding of outcome assessment (detection bias) | Low risk | Double‐blinding was achieved with placebo tablets of identical size and appearance and all but 2 members of the Data Coordinating Center were masked to treatment allocation. |
| Study characteristics | ||
| Methods | Phase III, randomised, partially masked (outcome assessors), multicentre study conducted in 3 centres in the USA, Jamaica and Brazil between May 2012 and August 2013 | |
| Participants | Children with SCA and conditional TCD ultrasound velocities (170 cm to 199 cm per second). Exclusion criteria were prior abnormal TCD velocities or clinical stroke, red blood cell transfusion within 2 months of enrolment, concurrent use of another anti‐sickling medication or contraindication to hydroxyurea therapy (allergy, pregnancy, renal insufficiency) 22 participants randomised, 11 to each treatment group Mean age (SD): hydroxyurea group: 6.2 (2.4) years, observation group: 6.6 (1.5) years 64% females, 7 per group. 21 participants with HbSS and 1 with HbSβº‐thalassaemia | |
| Interventions | Hydroxyurea (starting at 20 mg/kg/day escalated to a maximum of 35 mg/kg/day) compared to standard treatment (observation) | |
| Outcomes | Primary outcome: conversion to abnormal maximum abnormal TAMV Secondary outcomes: changes in serial TCD velocities Incidence of acute events including stroke Health‐related quality of life (planned but not recorded, see 'Selective reporting' below) | |
| Notes | The planned length of follow‐up was 30 months but the study was terminated early after 15 months of follow‐up due to slow participant accrual and the unlikelihood of meeting the trial recruitment target (100) and the primary endpoint. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomisation was performed using an adaptive blocked algorithm. |
| Allocation concealment (selection bias) | Low risk | Central pharmacy distribution of allocations. |
| Incomplete outcome data (attrition bias) | Low risk | Numbers screened, randomised and number receiving randomised treatment reported. Analysis conducted using an ITT approach. |
| Selective reporting (reporting bias) | High risk | A planned outcome (health‐related quality of life) was not analysed or presented as the outcome was not sufficiently collected due to early study termination. |
| Other bias | High risk | Study terminated early after only 22 of planned sample size of 100 were recruited therefore study is likely to be statistically underpowered. |
| Blinding of participants and personnel (performance bias) | Low risk | Participants and personnel could not be masked to treatment allocation by design (hydroxyurea compared to observation only). The primary outcome (conversion to abnormal TAMV) was objective and determined by masked outcome assessors so lack of blinding of participants and personnel is unlikely to have affected results. |
| Blinding of outcome assessment (detection bias) | Low risk | All TCD site examiners and central reviewers were masked, and site clinicians were masked to participants' TCD results. |
| Study characteristics | ||
| Methods | Phase III, multicentre, single‐masked (outcome assessors), non‐inferiority study conducted across 26 paediatric sites in the USA | |
| Participants | Participants with previous clinical stroke, aged 7 to 17 years, PRBC transfusions for at least 18 months and transfusional iron overload No specific exclusion criteria stated 133 participants were randomised; 67 randomised to hydroxyurea treatment and 66 to standard treatment Mean (SD) age at study enrolment in years: hydroxyurea group 13.0 (4.0) years, standard treatment group 13.3 (3.8) years 132 out of 133 participants with HbSS genotype, 61 females (46%) | |
| Interventions | Hydroxyurea starting at 20 mg/kg/day escalated to MTD and phlebotomy compared to standard treatment (transfusions and chelation) for 30 months | |
| Outcomes | The primary outcome of the trial was a composite outcome. This involved occurrence of a secondary stroke and quantitative liver iron level change from baseline. Secondary outcomes included quality of life, non‐stroke neurological events, other SCD‐related events, growth and development, functional evaluations, neurocognitive evaluations, transfusion‐related complications, chelation‐related complications, hydroxyurea‐related complications, phlebotomy‐related complications, liver biopsy‐related complications and adverse and serious adverse events | |
| Notes | Numerous secondary outcomes were not reported in the main paper or any subsequent papers | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Study described as randomised, no further details given. |
| Allocation concealment (selection bias) | Unclear risk | No details were given on allocation concealment. |
| Incomplete outcome data (attrition bias) | Low risk | Withdrawals from treatment reported, all individuals included in analysis in an ITT approach. |
| Selective reporting (reporting bias) | High risk | Many of the secondary outcomes (such as growth and development, functional evaluations, neurocognitive evaluations) have not yet been reported. If these results can be included at a later date then this judgement will be reconsidered. |
| Other bias | Low risk | None identified. |
| Blinding of participants and personnel (performance bias) | Low risk | Participants and personnel could not be masked to treatment allocation by design (hydroxyurea compared to transfusion). The primary outcome (secondary stroke and quantitative liver iron level change from baseline) was objective and determined by masked outcome assessors so lack of blinding of participants and personnel is unlikely to have affected results. |
| Blinding of outcome assessment (detection bias) | Low risk | The primary outcome (secondary stroke and quantitative liver iron level change from baseline) were determined by a group of treatment‐masked neurologists and neuroradiologists. |
| Study characteristics | ||
| Methods | Multicentre, phase III, randomised, open‐label (partially masked) non‐inferiority study conducted at 26 paediatric hospitals and health centres in the USA and Canada | |
| Participants | Children aged 4 to 16 years with SCA and abnormal TCD ultrasound velocities (> 200 cm per second) if they had received 12 months of chronic transfusions Exclusion criteria were documented clinical stroke, TIA or severe vasculopathy 121 participants were randomised; 60 randomised to hydroxyurea treatment and 61 to standard treatment Mean (SD) age at study enrolment in years: hydroxyurea group 9.5 (2.6) years, standard treatment group 9.7 (3.2) years 119 out of 121 participants with HbSS genotype, 73 females (60%) | |
| Interventions | Hydroxyurea starting at 20 mg/kg/day escalated to MTD and phlebotomy compared to standard treatment (transfusions and chelation) for 24 months | |
| Outcomes | Primary outcome: maximum TCD time averaged mean velocity on the index side (i.e. the cerebral hemisphere with the higher mean arterial velocity at baseline assessment) Secondary outcomes: TCD velocity on the non‐index side, neurological events, new brain lesions, hepatic iron overload, SCD‐related events, treatment‐related complications (reported in this publication), neuropsychological status, quality of life and growth (to be reported in future publications) | |
| Notes | Study was terminated early at the first interim analysis when non‐inferiority was demonstrated; target sample size was met at early termination | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Centralised block randomisation with block size four, with stratification by site and balanced by baseline age and TCD velocity. |
| Allocation concealment (selection bias) | Low risk | Central randomisation and treatment allocation. |
| Incomplete outcome data (attrition bias) | Low risk | Numbers discontinuing the interventions stated, all participants included in an ITT analysis. |
| Selective reporting (reporting bias) | High risk | Outcomes of neuropsychological status, quality of life and growth were measured but results are not yet published. If these results can be included at a later date then this judgement will be reconsidered. |
| Other bias | Low risk | Study was terminated early at the first interim analysis when non‐inferiority was demonstrated; target sample size was met at early termination so the study is adequately powered to detect differences. |
| Blinding of participants and personnel (performance bias) | Low risk | Participants and personnel could not be masked to treatment allocation by design (hydroxyurea compared to transfusion). The primary outcome (maximum TCD time averaged mean velocity) was objective and determined by masked outcome assessors so lack of blinding of participants and personnel is unlikely to have affected results. |
| Blinding of outcome assessment (detection bias) | Low risk | All TCD examinations were read centrally by observers blinded to treatment allocation and previous TCD results. |
ACS: acute chest syndrome
ASS: acute splenic sequestration
CI: confidence interval
CVA: cerebrovascular accident
Cytopenia: refers to either neutropenia or thrombocytopenia; anaemia is also a risk but was not reported
FBC: full blood count
HbA: adult haemoglobin
HbF: foetal haemoglobin
HbSβº: haemoglobin Sβºthalassaemia genotype
HbSC: haemoglobin SC genotype
HbSS: haemoglobin SS genotype
ITT: intention‐to‐treat
KCl: potassium chloride
MTD: maximum tolerated dose
PRBC: packed red blood cells
SCA: sickle cell anaemia
SCD: sickle cell disease
SD: standard deviation
TAMV: time averaged mean velocity
TCD: transcranial Doppler
TIA: transient ischaemic attack
VOC: vaso‐occlusive crisis
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| Participants randomised to low‐ or moderate‐dose hydroxyurea and does not include a placebo or standard therapy arm as a comparator. | |
| Participants randomised to fixed low‐ or moderate‐dose hydroxyurea and no comparison to placebo or standard care. This study documents the rationale and design of a phase III randomised clinical trial (translation of research into practice for stroke prevention in sickle cell anaemia) and examines whether low educational level of head of household, a proxy for poverty, is associated with severe anaemia. | |
| This is not a randomised study. | |
| This does not make a randomised comparison of hydroxyurea and placebo or standard treatment; participants are randomised to PF‐04447943 or placebo and randomisation is stratified by use of hydroxyurea (yes or no). | |
| Hydroxyurea was given at 30 mg/kg to 45 mg/kg hydroxyurea upon study inclusion. 2 more daily hydroxyurea doses were given if the participant was still hospitalised. This study therefore did not compare hydroxyurea to placebo or standard care for periods of 1 month or longer. | |
| Participants randomised to low‐ or standard‐dose hydroxyurea and does not include a placebo or standard therapy arm as a comparator. | |
| This study does not fulfil the inclusion criteria. The length of treatment was 8 days; the inclusion criteria state that treatment should be at least 1 month. | |
| This is not a randomised study. | |
| No randomised comparison of hydroxyurea to placebo or standard treatment; all participants received hydroxyurea and were randomised to arginine or placebo. | |
| No randomised comparison of hydroxyurea and placebo or standard treatment. | |
| Participants randomised to hydroxyurea treatment in both arms of this study (moderate‐ versus low‐dose). Hence there is no randomised comparison of hydroxyurea to placebo or standard treatment. | |
| This registry entry outlines the methodology of the study: "Hydroxyurea optimization through precision study (HOPS): a prospective, multi‐center, randomised trial of personalized, pharmacokinetics‐guided dosing of hydroxyurea versus standard weight‐based dosing for children with sickle cell anemia." Primary results are not yet published at the time of writing. Additionally, participants will be randomised to receive hydroxyurea at different doses either using a starting dose of 20 mg/kg/day (standard arm) or a pharmacokinetic‐guided dose (alternative arm) not to placebo or another modality considered as standard of care, as required for inclusion. | |
| This study does not fulfil the inclusion criteria. The length of treatment was 7 days, but the inclusion criteria state that treatment should be at least 1 month. Additionally, participants were randomised to hydroxyurea or either of two doses of the investigational product, which for the purposes of this study is neither placebo nor standard of care. | |
| This is not a randomised study. | |
| This is not a randomised study. | |
| No randomised comparison of hydroxyurea to placebo or standard treatment. | |
| Hydroxyurea treatment not compared to placebo or standard care. The study aims to determine whether viewing the peripheral blood smear of individuals with poor adherence to hydroxyurea compared to a blood smear of someone on hydroxyurea could be used to improve adherence. | |
| Observational study of participants who had already completed BABY HUG. | |
| Study terminated early with no participants recruited. | |
| This is not an appropriate design to measure the effectiveness of hydroxyurea (cross‐over design of low‐dose hydroxyurea compared to no treatment to monitor those at increased risk of infection). | |
| Participants randomised to hydroxyurea plus a nutritional supplement or a nutritional supplement alone. Effect of hydroxyurea cannot be determined. | |
| Terminated early due to challenges with recruitment during the COVID pandemic. | |
| There is no placebo or comparator arm in relation to hydroxyurea treatment. | |
| This study was excluded as it includes another investigational drug apart from hydroxyurea. | |
| No randomised comparison of hydroxyurea to placebo or standard treatment (the randomised comparison is dosing schedules of hydroxyurea). | |
| The study compared participants randomised to hydroxyurea treatment either at a fixed dose or with dose escalation. The study did not compare hydroxyurea to a placebo or another standard treatment (no placebo). | |
| This is not a randomised study. | |
| This is not a randomised study. | |
| This is not a randomised study. | |
| No comparison of hydroxyurea to placebo or standard care. Participants were all treated with hydroxyurea and randomised to standard care (specialist care only) or the experimental arm where they received case management and education from 'Patient navigators'. | |
| No randomised comparison of hydroxyurea to placebo or standard treatment; participants are randomised to crizanlizumab or placebo and randomisation is stratified by use of hydroxyurea (yes or no). | |
| No randomised comparison of hydroxyurea to placebo or standard treatment; participants are randomised to crizanlizumab or placebo and participants may already be receiving hydroxyurea as standard of care. | |
| No randomised comparison of hydroxyurea to placebo or standard treatment; participants are randomised to crizanlizumab or placebo and randomisation is stratified by use of hydroxyurea (yes or no). | |
| This does not make a randomised comparison of hydroxyurea and placebo or standard treatment. | |
| This is not a randomised study. |
Characteristics of ongoing studies [ordered by study ID]
| Study name | NCT01389024: Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease (HUPrevent) |
| Methods | Randomised, double‐blind, parallel design, phase II study |
| Participants | Participants with HbSS or HbSβº‐thalassaemia aged between 9 and 48 months of age, with or without central nervous system complications |
| Interventions | Hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day Placebo (sucrose) 0.2 mL/kg/day increased to max of 0.35 mL/kg/day |
| Outcomes | Primary outcome: central nervous system complications (a composite of abnormally elevated cerebral blood flow velocity as measured by TCD ultrasound, SCI or stroke) Secondary outcome: proportion of participants with severe adverse events attributed to study procedures |
| Starting date | October 2011 |
| Contact information | Johns Hopkins University Diane Weiss, BA ([email protected]) James F. Casella, MD ([email protected]) |
| Notes | Listed as active but not recruiting. Estimated completion date 30 November 2022 (final data collection date for primary outcome measure). |
| Study name | SIKAMIC (SIklos on Kidney Function and AlbuMInuria Clinical Trial) (SIKAMIC) |
| Methods | Multicentre, phase II, randomised, double‐blind, placebo‐controlled study |
| Participants | Adults aged above 18 years with HbSS or HbSβº genotype and with a value of albuminuria, assessed by ACR, over 3 mg/mmol and inferior to 100 mg/mmol confirmed by 3 positive urine samples taken 1 day apart |
| Interventions | Hydroxycarbamide or placebo (15 mg/kg/day and will be administered for 12 months) |
| Outcomes | Primary outcome: Proportion of patients achieving at least a 30% decrease in ACR baseline value (time frame: 12 months) Secondary outcomes:
|
| Starting date | February 2019 |
| Contact information | Sponsor: ADDMEDICA SASA Contact: Corinne Duguet, MD ([email protected]) Contact: Laura Thomas‐bourgneuf (laura.thomas‐[email protected]) |
| Notes | Listed as recruiting. Estimated completion date: March 2023 (final data collection date for primary outcome measure). |
ACR: albumin‐to‐creatinine ratio
eGFR: estimated glomerular filtration rate
HbSβº:haemoglobin Sβºthalassaemia genotype
HbSC: haemoglobin SC genotype
HbSS: haemoglobin SS genotype
SCI: silent cerebral infarct
TCD: transcranial Doppler
Data and analyses
| 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 | |
| Analysis 1.1  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 1: Pain crises | ||||
| 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 | |
| Analysis 1.2  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 2: Proportion experiencing pain | ||||
| 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 | |
| Analysis 1.3  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 3: Proportion experiencing life‐threatening events during study | ||||
| 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 | |
| Analysis 1.4  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 4: Number of life‐threatening events during study | ||||
| 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 | |
| Analysis 1.5  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 5: Deaths during the study | ||||
| 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] |
| Analysis 1.6  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 6: Change from baseline in foetal haemoglobin (HbF%) | ||||
| 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] |
| 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) | ||||
| 1.8 Foetal haemoglobin (HbF%) after treatment Show forest plot | 3 | 566 | Mean Difference (IV, Fixed, 95% CI) | 6.24 [5.28, 7.20] |
| Analysis 1.8  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 8: Foetal haemoglobin (HbF%) after treatment | ||||
| 1.9 Neutrophil response (x10⁹/L) after treatment Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.9  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 9: Neutrophil response (x10⁹/L) after treatment | ||||
| 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] |
| Analysis 1.10  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 10: Change from baseline in haemoglobin (g/L) | ||||
| 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] |
| Analysis 1.11  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 11: Change from baseline in mean corpuscular volume (fL) | ||||
| 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] |
| 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) | ||||
| 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] |
| 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) | ||||
| 1.14 Change from baseline in reticulocytes (%) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.14  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 14: Change from baseline in reticulocytes (%) | ||||
| 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] |
| Analysis 1.15  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 15: Change from baseline in platelet count (10⁹/L) | ||||
| 1.16 Change from baseline in creatinine (mg/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.16  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 16: Change from baseline in creatinine (mg/dL) | ||||
| 1.17 Change from baseline in total bilirubin (mg/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.17  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 17: Change from baseline in total bilirubin (mg/L) | ||||
| 1.18 Change from baseline in alanine transferase (ALT) (U/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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) | ||||
| 1.19 Haemoglobin (g/dL) Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.19  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 19: Haemoglobin (g/dL) | ||||
| 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 | |
| Analysis 1.20  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 20: Mean corpuscular volume (fL) | ||||
| 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] |
| 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 | ||||
| 1.22 Reticulocytes (10⁹/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.22  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 22: Reticulocytes (10⁹/L) | ||||
| 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] |
| Analysis 1.23  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 23: Reticulocytes (10⁵/mm³) at 18 months | ||||
| 1.24 Total bilirubin (mg/L) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.24  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 24: Total bilirubin (mg/L) | ||||
| 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 | |
| Analysis 1.25  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 25: Platelet count (10⁹/L) | ||||
| 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] |
| Analysis 1.26  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 26: Platelet count (10³/mm³) at 18 months | ||||
| 1.27 Packed cell volume Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.27  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 27: Packed cell volume | ||||
| 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 | |
| Analysis 1.28  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 28: F reticulocytes | ||||
| 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 | |
| Analysis 1.29  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 29: F cells | ||||
| 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 | |
| Analysis 1.30  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 30: Red blood count | ||||
| 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 | |
| Analysis 1.31  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 31: Dense cells | ||||
| 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 | |
| Analysis 1.32  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 32: Leucocytes | ||||
| 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 | |
| Analysis 1.33  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 33: Alanine transferase (ALT) (U/L) | ||||
| 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] |
| 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 | ||||
| 1.35 Aspartate aminotransferase Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.35  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 35: Aspartate aminotransferase | ||||
| 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 | |
| Analysis 1.36  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 36: Alkaline phosphatase | ||||
| 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 | |
| Analysis 1.37  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 37: Change from baseline in growth | ||||
| 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 | |
| Analysis 1.38  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 38: Quality of life: general health perception | ||||
| 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 | |
| Analysis 1.39  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 39: Quality of life: pain recall | ||||
| 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 | |
| Analysis 1.40  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 40: Quality of life: social function | ||||
| 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 | |
| Analysis 1.41  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 41: Changes in 'Ladder of Life' | ||||
| 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 | |
| Analysis 1.42  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 42: Proportion of participants with signs of organ damage | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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) | ||||
| 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 | |
| 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 (%) | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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) | ||||
| 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 | |
| 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) | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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) | ||||
| 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 | |
| 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 | ||||
| 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 | |
| Analysis 1.57  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 57: Proportion of participants experiencing adverse events and toxicity | ||||
| 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 | |
| Analysis 1.58  Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 58: Proportion with SCA‐related events (composite outcome) | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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 | ||||
| 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] |
| 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 | ||||
| 2.4 Change from baseline in foetal haemoglobin (HbF %) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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 %) | ||||
| 2.5 Change from baseline in absolute neutrophil count (x10⁹/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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) | ||||
| 2.6 Change from baseline in mean corpuscular volume (fL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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) | ||||
| 2.7 Change from baseline in sickle haemoglobin (%) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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 (%) | ||||
| 2.8 Change from baseline in haemoglobin (g/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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) | ||||
| 2.9 Change from baseline in absolute reticulocyte count (10⁹ / L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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) | ||||
| 2.10 Change from baseline in white blood count (10⁹ / L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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) | ||||
| 2.11 Change from baseline in platelets (10⁹/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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) | ||||
| 2.12 Change from baseline in total bilirubin (mg/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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) | ||||
| 2.13 Change from baseline in liver iron concentration Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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 | ||||
| 2.14 Change from baseline in serum ferritin (ng/mL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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) | ||||
| 2.15 Change from baseline in lactate dehydrogenase (U/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 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) | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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 | |
| 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 | ||||
| 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 | |
| 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 | ||||
| 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 | |
| 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 | ||||
| 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 | |
| Analysis 3.4  Comparison 3: Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 4: Adverse events and toxicity | ||||
| 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 | |
Study flow diagram for this review (2022)
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 1: Pain crises
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 2: Proportion experiencing pain
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 3: Proportion experiencing life‐threatening events during study
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 4: Number of life‐threatening events during study
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 5: Deaths during the study
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 6: Change from baseline in foetal haemoglobin (HbF%)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 7: Change from baseline in absolute neutrophil count (ANC, x10⁹/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 8: Foetal haemoglobin (HbF%) after treatment
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 9: Neutrophil response (x10⁹/L) after treatment
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 10: Change from baseline in haemoglobin (g/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 11: Change from baseline in mean corpuscular volume (fL)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 12: Change from baseline in white blood cell (WBC) count (x10⁹/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 13: Change from baseline in absolute reticulocyte count (x10⁹/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 14: Change from baseline in reticulocytes (%)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 15: Change from baseline in platelet count (10⁹/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 16: Change from baseline in creatinine (mg/dL)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 17: Change from baseline in total bilirubin (mg/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 18: Change from baseline in alanine transferase (ALT) (U/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 19: Haemoglobin (g/dL)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 20: Mean corpuscular volume (fL)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 21: White blood cells (WBC) count at the end of the study
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 22: Reticulocytes (10⁹/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 23: Reticulocytes (10⁵/mm³) at 18 months
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 24: Total bilirubin (mg/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 25: Platelet count (10⁹/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 26: Platelet count (10³/mm³) at 18 months
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 27: Packed cell volume
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 28: F reticulocytes
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 29: F cells
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 30: Red blood count
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 31: Dense cells
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 32: Leucocytes
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 33: Alanine transferase (ALT) (U/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 34: Creatinine (mg/dL) at the end of the study
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 35: Aspartate aminotransferase
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 36: Alkaline phosphatase
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 37: Change from baseline in growth
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 38: Quality of life: general health perception
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 39: Quality of life: pain recall
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 40: Quality of life: social function
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 41: Changes in 'Ladder of Life'
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 42: Proportion of participants with signs of organ damage
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 43: Signs of organ damage ‐ change from baseline in DTPA GFR
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)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 45: Signs of organ damage ‐ change from baseline in pitted cells (%)
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
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 47: Signs of organ damage ‐ change from baseline in spleen volume (cm3)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 48: Signs of organ damage ‐ change from baseline in creatinine (mg/L)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 49: Signs of organ damage ‐ change from baseline in Schwartz GFR
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 50: Signs of organ damage ‐ change from baseline in cystatin C
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 51: Signs of organ damage ‐ change from baseline in urine osmolality
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 52: Signs of organ damage ‐ change from baseline in urine pH
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 53: Signs of organ damage ‐ change from baseline in urine‐specific gravity
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 54: Signs of organ damage ‐ change from baseline in total kidney volume
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)
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 56: Signs of organ damage ‐ change from baseline in CNS measures
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 57: Proportion of participants experiencing adverse events and toxicity
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 58: Proportion with SCA‐related events (composite outcome)
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 1: Proportion experiencing pain
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
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 3: Deaths during the study
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 %)
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)
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)
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 (%)
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)
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)
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)
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)
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)
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
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)
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)
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
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
Comparison 3: Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 1: Proportion experiencing life‐threatening events during the study
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
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
Comparison 3: Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 4: Adverse events and toxicity
| 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 | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | Hydroxyurea | |||||
| Pain alterationa 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 | ⊕⊕⊕⊝ |
| |
| 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) | ⊕⊕⊕⊝ |
| |
| 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 | ⊕⊕⊕⊝ | 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 | ⊕⊕⊝⊝ lowe,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 | ⊕⊕⊕⊝ |
| |
| 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) | ⊕⊕⊝⊝ lowe,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 | ⊕⊕⊝⊝ lowe,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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 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. | ||||||
| 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 | No of participants | Quality of the evidence | 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) | ⊕⊕⊝⊝ lowd,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) | ⊕⊕⊕⊝ |
| |
| Death during the study (all deaths) Follow‐up: 24 to 30 months | 1 death occurred in the transfusion and chelation group of 1 studya . | 1 death occurred in the hydroxyurea and phlebotomy group of 1 studya . | RR 0.99 (95% CI 0.06 to 15.42) | 254 (2 studies) | ⊕⊕⊝⊝ lowd,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) | ⊕⊕⊕⊝ |
| |
| 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) | ⊕⊕⊕⊝ |
| |
| Quality of life | Outcome not reportedc . | 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) | ⊕⊕⊝⊝ lowd,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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 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. | ||||||
| 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 | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| 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) | ⊕⊝⊝⊝ |
| |
| Death during the study Follow‐up: 15 months | No deaths occurred. | No deaths occurred. | NA | 22 (1 study) | ⊕⊝⊝⊝ |
|
| Measures of HbF Follow‐up: 15 months | There was a significant increase in HbF in the hydroxyurea group compared to the observation groupa . | NA | 22 (1 study) | ⊕⊝⊝⊝ |
| |
| Measures of ANC Follow‐up: 15 months | There was a significant decrease in ANC in the hydroxyurea group compared to the observation groupa . | NA | 22 (1 study) | ⊕⊝⊝⊝ |
| |
| Quality of life Follow‐up: NA | Outcome not reportedb . | 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) | ⊕⊝⊝⊝ |
| |
| 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aMedian values reported so data cannot be entered into analysis. | ||||||
| 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 | No of participants | Quality of the evidence | 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 | ⊕⊝⊝⊝ |
|
| 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 | ⊕⊝⊝⊝ |
| |
| Measures of ANC Follow‐up: 24 weeks | There was no significant difference in ANC between treatment groupsa . | NA | Up to 44 (1 study)1 | ⊕⊝⊝⊝ |
| |
| 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 | ⊕⊝⊝⊝ |
| |
| 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). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 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). | ||||||
| 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 | |||||
| Baseline | Hydroxyurea | Placebo | P value | ||
|---|---|---|---|---|---|
| Baseline | 2 years | Baseline | 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 | |||||
| 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 Values are median change from baseline and interquartile range. P values are calculated using Wilcoxon rank sum test. | |||
| 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 Values are median change from baseline and P values are calculated using Wilcoxon rank sum test. | |||
| 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 | |
| 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 | |
| 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 | |
| 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 | |
