Hydroxyurea for sickle cell disease (Review)

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1 Jones AP, Davies SC, Olujohungbe A This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 12

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS DISCUSSION AUTHORS CONCLUSIONS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Hydroxyurea versus placebo, Outcome 1 Pain crises Analysis 1.3. Comparison 1 Hydroxyurea versus placebo, Outcome 3 Number dying or experiencing life threatening complications of SCD during study Analysis 1.4. Comparison 1 Hydroxyurea versus placebo, Outcome 4 Fetal haemoglobin Analysis 1.5. Comparison 1 Hydroxyurea versus placebo, Outcome 5 Neutrophil response Analysis 1.6. Comparison 1 Hydroxyurea versus placebo, Outcome 6 Haematological parameters as a surrogate markers of response to hydroxyurea Analysis 1.7. Comparison 1 Hydroxyurea versus placebo, Outcome 7 Haematological parameters as a surrogate marker of response to hydroxyurea Analysis 1.8. Comparison 1 Hydroxyurea versus placebo, Outcome 8 General health perception Analysis 1.9. Comparison 1 Hydroxyurea versus placebo, Outcome 9 Social function Analysis Comparison 1 Hydroxyurea versus placebo, Outcome 10 Changes in Ladder of Life Analysis Comparison 1 Hydroxyurea versus placebo, Outcome 11 Pain recall Analysis Comparison 1 Hydroxyurea versus placebo, Outcome 12 Organ damage Analysis Comparison 1 Hydroxyurea versus placebo, Outcome 13 Possible adverse effects of hydroxyurea treatment. 34 Analysis Comparison 1 Hydroxyurea versus placebo, Outcome 14 Cost-effectiveness of hydroxyurea ADDITIONAL TABLES WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS i

3 [Intervention Review] Hydroxyurea for sickle cell disease Ashley P Jones 1, Sally C Davies 2, Adebayo Olujohungbe 3 1 Institute of Child Health, University of Liverpool, Liverpool, UK. 2 Standards & Quality Business Group, Research & Development Division, Dept of Health, London, UK. 3 CancerCare Manitoba, Winnipeg, Canada Contact address: Ashley P Jones, Institute of Child Health, University of Liverpool, Alder Hey Children s NHS Foundation Trust, Eaton Road, Liverpool, Merseyside, L12 2AP, UK. Editorial group: Cochrane Cystic Fibrosis and Genetic Disorders Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 12, Review content assessed as up-to-date: 9 November Citation: Jones AP, Davies SC, Olujohungbe A. Hydroxyurea for sickle cell disease. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD DOI: / CD Background A B S T R A C T Sickle cell disease is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea, an oral chemotherapeutic drug, is expected to ameliorate some of the clinical problems of sickle cell disease, in particular that of pain, by raising fetal haemoglobin. Objectives To assess the effects of hydroxyurea therapy in people with sickle cell disease (all types), of any age, regardless of setting. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of the most recent search: 12 May Selection criteria All randomised or quasi-randomised controlled trials comparing the use of hydroxyurea for one month or longer with placebo, standard therapy or other interventions for the treatment of people with sickle cell disease. Data collection and analysis Three authors independently assessed study quality and extracted data from the two included studies. Main results Two studies found by the searches, which reported results from a total of 324 adults and children, were suitable for inclusion in the review. From the data provided in the published reports, only one study (the MSH study to the United States of America) could be analysed. This study showed marked differences in favour of hydroxyurea treatment as compared with placebo in terms of annual crisis rate, use of transfusions, and life-threatening complications (in particular, acute sickle chest syndrome). Both studies documented the expected rise in fetal haemoglobin. No serious adverse effects were reported from either study. 1

4 Authors conclusions While hydroxyurea appears both effective and safe in severely affected SS adults over a two-year period; further studies are required to elucidate its role in other patient groups and for other conditions. P L A I N L A N G U A G E S U M M A R Y Hydroxyurea for people with sickle cell disease Haemoglobin is the substance within the red blood cells that carries oxygen around the body. Sickle cell disease (SCD) is an inherited genetic disorder where there are problems with the haemoglobin. Crystals form in the red blood cells and block the blood flow. This causes pain and organ damage. Fetal haemoglobin stops crystals forming in the sickle haemoglobin within the red blood cell. So, raising the fetal haemoglobin level in people with SCD can reduce the effects of the disease. The drug hydroxyurea is used to raise fetal haemoglobin. We looked for studies which compared hydroxyurea to placebo for longer than one month. The review includes two studies with 324 people. One study is waiting to be assessed. We were only able to analyse data from one study which lasted two years. This study favoured hydroxyurea compared with placebo for the outcomes: annual crisis rate; use of transfusions; and life-threatening complications. Both studies described the expected rise in fetal haemoglobin. No serious adverse effects were reported from either study. We conclude that hydroxyurea can raise fetal haemoglobin levels in adults with SCD without any adverse effects. B A C K G R O U N D Description of the condition Haemoglobinopathies, including sickle cell disease (SCD), are the most common inherited disorders in the world. Sickle cell disease affects peoples originating from the Sub-Sahara in Africa, Arab countries, the Mediterranean, the Indian subcontinent, the Caribbean and South America, as well as Afro-Americans and descendants in other parts of the world from immigrants from the above countries. The genetic mutation gives some advantage to carriers against malaria and for this reason has persisted. Sickle cell disease is the family of recessively inherited disorders of haemoglobin which is responsible for transporting oxygen around the body packaged in red blood cells. People who inherit only one sickle gene and the normal gene for adult haemoglobin (HbA) are sickle cell carriers (sickle cell trait or AS) and are healthy. When people are homozygous because they have inherited two sickle genes (SS), they have sickle cell anaemia, which is a variable clinical condition, with the vast majority of individuals suffering some pain attacks and a reduced life expectancy. Clinically significant SCD also arises when people inherit the sickle gene from one parent and another variant haemoglobin gene from the second parent such as haemoglobin C (SC) or a beta thalassaemia gene (Sβ+ or SβO). Sickle haemoglobin, when not carrying oxygen, polymerises distorting the red blood cell into the classic sickle stage. The clinical problems arise predominantly as a result of chronic anaemia and the blockage of small blood vessels, which stops oxygen delivery to the tissues causing pain or organ damage or both. The most frequent clinical problem is pain which causes over 90% of acute hospital admissions (Brozovic 1987) and significant morbidity in the community (Fuggle 1996). While 13% die before the age of 20 years in the developed world (Leikin 1989), the median survival for SS is 42 years in men and 46 years in women and for SC is 60 years and 68 years respectively (Platt 1994). Death generally relates to sickle cell disease and is caused either by chronic organ failure consequent on the sickling process or as a result of an acute catastrophic event, such as stroke (Powars 1983), acute sickle chest syndrome, splenic sequestration (Rogers 1978) or other complications (Gray 1991). Present treatment of SCD is aimed at prevention including pneumococcal prophylaxis and avoidance of factors that precipitate crisis (including dehydration, infection and cold), with symptomatic treatment of the pain crisis when it occurs including adequate analgesia, appropriate antibiotics, rehydration and judicious use of blood transfusion (Davies 1997a; Davies 1997b; Steinberg 1999). How the intervention might work It has long been recognised that raised fetal haemoglobin (HbF) levels can ameliorate the clinical effects of SCD (Perrine 1978; Platt 1994). This is because the fetal haemoglobin interferes with the crystal formation of the sickle haemoglobin within the red blood cell. This crystallisation is the underlying pathology in SCD. 2

5 The more fetal haemoglobin there is, the greater the inhibition. Hydroxyurea was first shown to raise fetal haemoglobin levels in SCD in 1985 (Veith 1985). It is thought to have this effect as a result of the bone marrow suppression it causes. Studies in humans culminated in a Phase 3 double-blind randomised controlled trial published in 1995 (Charache 1995). Hydroxyurea is a cheap oral drug ( 15 or US$22 equivalent per month) but frequent monitoring of the individual s blood count is required. Also, there are recognised side effects such as cytopenias (low white cell or platelet counts) and occasionally nausea, as with any chemotherapy drug. Why it is important to do this review It is therefore important to examine as a whole, the body of work relating to the use of hydroxyurea in SCD, to evaluate the drug s effectiveness in adults and children, and in the different types of SCD, the dosage regimens and whether the setting appears to influence the outcome, i.e. developed versus underdeveloped countries. We set out to review any evidence relating to the impact of hydroxyurea on the natural history of SCD and life expectancy. O B J E C T I V E S The aims of this review were to determine whether the use of hydroxyurea in people with SCD: 1. alters the pattern of acute events, including pain; 2. prevents, delays or reverses organ dysfunction; 3. alters survival and quality of life; 4. is associated with adverse effects. In addition we hoped to assess whether the response to hydroxyurea in SCD varies with type of SCD, age of the individual, duration and dose of treatment and healthcare setting. M E T H O D S Criteria for considering studies for this review Types of participants This review is limited to studies of hydroxyurea in SCD only. In order to fully quantify the potential harm and toxicity of this drug, a further review may need to be undertaken in all patient groups treated with hydroxyurea. People of any age with sickle cell disease SS, SβO, SC, Sβ+ (proven by electrophoresis and sickle solubility test, with family studies or DNA tests as appropriate). Types of interventions Hydroxyurea in any formulation at all doses, compared to either placebo or standard treatment (no placebo) for periods of one month or longer. Types of outcome measures Primary outcomes 1. Pain alteration (as measured by inpatient days, outpatient or accident and emergency department visits for opiate treatment and self-reported patient scales) 2. Life threatening illness (including acute chest syndrome, stroke and acute splenic sequestration) 3. Death during the study Secondary outcomes 1. Measures of fetal haemoglobin (HbF or F cells) and neutrophil counts 2. Other surrogate markers of response (including haemoglobin, mean cell volume, platelet count and growth) 3. Quality of life, time loss to school or employment, integration into society, scales recording feeling of well-being and global function e.g. Karnofsky 4. Measures of organ damage: spleen (pitted red cells); chronic sickle lung disease (transfer factor); liver; chronic renal failure (creatinine); priapism leg ulcer; neurological damage (e.g. intelligence quotient (IQ)) 5. Any reported adverse effects or toxicity of hydroxyurea recorded 6. Cost-effectiveness of hydroxyurea The final secondary outcome (cost effectiveness of hydroxyurea) has been added at the 2005 update of this review. Types of studies All randomised or quasi-randomised trials, irrespective of language. Trials with quasi-randomised methods, such as alternation, were included if there was sufficient evidence that the treatment and control groups were similar at baseline. Search methods for identification of studies Electronic searches 3

6 Relevant studies were identified from the Cochrane Cystic Fibrosis and Genetic Disorders Group s Haemoglobinopathies Trials Register using the terms sickle cell AND hydroxyurea. The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (Clinical Trials) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE. Unpublished work is identified by searching the abstract books of five major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cystic Fibrosis and Genetic Disorders Group Module. Date of the most recent search of the Group s Haemoglobinopathies Trials Register: 12 May Searching other resources The bibliographic references of all retrieved studies and reviews were assessed for additional reports of trials. Data collection and analysis Selection of studies For the initial review, two authors (SCD and AO) independently applied inclusion criteria. For the updates of the review, the third author (AJ) also performed this task. There were no discrepancies between the authors assessments. Data extraction and management For the initial review, two authors (SCD and AO) independently extracted the data. For the updates of the review, the third author (AJ) also performed this task. There were no discrepancies between the authors assessments. We intended to group outcome data into those measured at three, six, twelve months and annually thereafter. When outcome data were recorded at other time periods, then consideration was given to examining these as well. Assessment of risk of bias in included studies For the initial review, two authors (SCD and AO) independently assessed the methodological quality of each trial. For the updates of the review, the third author (AJ) also performed these tasks. The authors assessed methodological quality on the methods of concealment and generation of randomisation sequence, blinding, whether data were available to analyse on intention-to-treat basis and whether all randomised participants were included in the analysis. There were no discrepancies between the authors assessments. Measures of treatment effect For binary outcomes, we aimed to calculate a pooled estimate of the treatment effect for each outcome across studies, (the risk of an outcome among treatment allocated participants to the corresponding risk among controls). For each study, we calculated risk ratios (RR) with 95% confidence intervals (CI) for all important, dichotomous outcomes. We present risk ratios in preference to odds ratios (OR), as odds ratios give an inflated impression of the size of effect where event rates are high, as is the case of these studies. For the continuous outcomes, we intended to calculate a pooled estimate of treatment effect, using the mean difference (MD). Unit of analysis issues One study was cross-over in design (Belgian study 1996). We planned to analyse data from this study using the approach recommended by Elbourne (Elbourne 2002). Outcomes were measured at different time points throughout the course of the MSH study. Currently there are no methods to analyse aggregate longitudinal data if individual patient data are not available, therefore in this review we have carried out analysis at each individual time point reported. Dealing with missing data In order to allow an intention-to-treat analysis, we collected data by allocated treatment groups, irrespective of compliance, later exclusion (regardless of cause) or loss to follow up. Assessment of heterogeneity We proposed to examine heterogeneity between study results using the test recommended by Higgins (Higgins 2003). Data synthesis If we had found significant heterogeneity then we would have examined it using a random-effects model and subgroup analyses. Subgroup analysis and investigation of heterogeneity Subgroup analyses would be done according to age, type of SCD, dosage regimen and setting, if possible. 4

7 Sensitivity analysis We also planned a sensitivity analysis based on the methodological quality of the studies, including and excluding quasi-randomised studies. R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies. Results of the search Nine studies were identified from the searches (Baby Hug 2007; Belgian study 1996; De Montalembert 2006; Jain 2010; MSH 1995; Silva-Pinto 2007; Voskaridou 2005; Wang 2009; Ware 2006). Two were eligible for inclusion, with a total of 324 children and adults (Belgian study 1996; MSH 1995). Four were excluded (De Montalembert 2006; Silva-Pinto 2007; Voskaridou 2005; Ware 2006); one is currently ongoing (Baby Hug 2007); and two, published in abstract form only are awaiting classification (Jain 2010; Wang 2009). Included studies Two studies were eligible for inclusion, with a total of 324 children and adults (Belgian study 1996; MSH 1995). The MSH study was a multicentre North American randomised and double-blind study, which compared hydroxyurea with placebo over two years in adults with SS with the objective of reducing pain crises (MSH 1995). A second study in children with SS was undertaken in Belgium (Belgian study 1996). This involved only 25 children and young adults with the aim of reviewing the impact on pain events, hospitalisation and also on fetal haemoglobin reactivation. As a result of the beneficial effects observed, the MSH study was stopped at a mean follow up of 21 months, before the planned 24 months of treatment had been completed for all participants (MSH 1995). In the MSH study, hydroxyurea was started at low dose (15 mg/ kg/day) and increased at 12-weekly intervals by 5 mg/kg/day until mild bone marrow depression, as judged by either neutropenia or thrombocytopenia, at that point the treatment was stopped (MSH 1995, reported in Handy 1996). Once the blood count had recovered, treatment was restarted at 2.5 mg/kg/day less than the toxic dose. The study was therefore aiming for the maximum tolerated dose (MTD) for each individual within the study. The MSH study was blinded and the study centre recorded and held the mean corpuscular volume (MCV) and fetal haemoglobin levels, which were not looked at by the caring physicians (MSH 1995). This is because the MCV and fetal haemoglobin levels rise in most people with SS taking hydroxyurea. The treatment assignments could be revealed if its knowledge would alter a participant s subsequent medical care. In addition, the National Heart, Lung and Blood Institute of the USA approved the protocol, reviewed each clinic s consent form, provided advice and oversaw participant safety and the progress of the study by appointing a board which eventually recommended the discontinuation of the study, when interim analyses showed hydroxyurea to be effective. The results of the primary end point in the MSH study (MSH 1995) (pain crises) have been published by Barton (Barton 1996). This update of the review includes data on the cost-effectiveness of hydroxyurea in SCD which have been reported by Moore (Moore 1999) as part of the MSH study (MSH 1995). The abstract reports that cost estimates were applied to all outpatient and emergency department visits and inpatient hospital stays that were classified as a crisis. The second study was in SS children in Belgium. This study was also placebo-controlled, randomised and blinded to the participant but not to the caring physician (Belgian study 1996). In addition, this was a cross-over study which started at 20 mg/kg/day and, unless cytopenia developed this was raised to a maximum of 25 mg/kg/day (Belgian study 1996). In this study the participants were randomised to either hydroxyurea or placebo for the initial six months and then crossed over to the other arm. There was no significant period or carry-over effect for the statistical tests performed on the number of hospitalisations and the number of days in hospital. Excluded studies Four studies were excluded (De Montalembert 2006; Silva-Pinto 2007; Voskaridou 2005; Ware 2006). Risk of bias in included studies Allocation For the MSH study, treatment assignments were made centrally using a computer programme to generate separate, randomised block assignment schedules for each clinic (MSH 1995). There was no clear discussion on allocation concealment and therefore this has been graded as unclear (MSH 1995). The Belgian study described the randomisation of participants as drawing sealed envelopes, patients were randomly allocated to one of the following treatment sequences, therefore the generation and the allocation of the treatment sequence are not clear from this statement. The hospital pharmacy provided the treatment and placebo for each participant and both were described as indistinguishable. 5

8 Blinding The MSH study was described as double blind (physician and participant), where treatment was assigned in combinations of identically appearing capsules (MSH 1995). The Belgian study was single-blinded (the participant was unaware of the treatment schedule but the physician was aware of the treatment schedule) because of the difficulty of blinding the attending physician to the treatment received (Belgian study 1996). Incomplete outcome data Analysis of the MSH study was by intention-to-treat and the paper stated that patients whose treatment was stopped for any reason were included in all analyses in their assigned treatment group. Withdrawals from the study were documented. Fifty-three participants had study treatment discontinued, the main reason being inactivity and pregnancy. A full list of reasons is documented within the study (MSH 1995). In the Belgian study, there were three participants who were excluded from the analysis due to their failure to attend the monthly evaluation at four to five months. There was no discussion of whether or not an intention-to-treat analysis was used (Belgian study 1996) months on placebo) and second painful crisis (6.58 months in the hydroxyurea group compared with 4.13 months on placebo) (MSH 1995). Information relating to the analgesia used by participants in the MSH study has been presented (MSH 1995), but has not been presented according to the groups to which the participants were randomised (Ballas 1996). The Belgian study showed a mean hospital stay of 5.3 days in the hydroxyurea treated group and 15.2 days in the placebo group (Belgian study 1996). 2. Life-threatening illness The MSH study reported specific data on the occurrence of acute chest syndrome, stroke, hepatic sequestration, and participants transfused (MSH 1995). Statistically significant advantages in the hydroxyurea group were the reductions in the occurrence of the acute sickle chest syndrome, RR 0.44 (95% CI 0.28 to 0.68), while fewer on hydroxyurea underwent transfusions, RR 0.67 (95% CI 0.52 to0.87). Stroke occurred in two of the treated and three of the placebo group, RR 0.64 (95% CI 0.11 to 3.80). Effects of interventions The only interim results published from the Belgian study are on mean hospital days comparing participants on treatment against self, not placebo, (Belgian study 1996). Further comparison between hydroxyurea and control group is, therefore, not possible. Significant advantages in the hydroxyurea group of the MSH study were the reduction in the occurrence of the acute sickle chest syndrome (MSH 1995). Primary outcomes 3. Death during the study The MSH study reported death and causes of death (MSH 1995). There were two deaths in the treated group and five in the placebo group including one homicide; these differences were not significant. Long-term follow up of the participants in the MSH study has continued and is reported (Steinberg 2000). The participants have now all been offered hydroxyurea therapy so that data reported after the MSH study period are uncontrolled. The results are not therefore analysed in this review. There were no deaths during the Belgian study (Belgian study 1996). 1. Pain alteration Neither study published pain alteration as defined in this review. Nor did the studies publish self-reported patient scales. The MSH study defined pain crisis as a visit to a medical facility, lasting four or more hours, requiring opiate analgesia. The MSH has published total crises, inpatient crises, annual crisis rates, and times to first, second, and third crisis (MSH 1995). The average crisis rate was 5.1 (standard deviation (SD) 7.3) in the treated group and 7.9 (SD 9.6) in the placebo group, MD (95% CI to -0.86). Both studies (Belgian study 1996; MSH 1995) showed a dramatic alteration in pain crisis in the hydroxyurea group compared with controls: the MSH study showed a reduction in hospitalisation and a reduction in median time from the initiation of treatment to both first (2.76 months in the hydroxyurea arm compared with Secondary outcomes 1. Measures of fetal haemoglobin and neutrophil counts The fetal haemoglobin (HbF) and neutrophil counts are reported at the start and finish of both studies (Belgian study 1996; MSH 1995). The MSH study showed the expected rise in HbF and F cells in the hydroxyurea group as compared with the control group. The rise in HbF on treatment was significant, MD 3.9 (95% CI 2.54 to 5.26) (MSH 1995). The neutrophil counts in the hydroxyurea arm of the MSH study were significantly lower than in the placebo arm at the end of the study, MD (95% CI to -1.29) (MSH 1995). 6

9 2. Other surrogate markers of response Both studies reported haemoglobin (Hb), mean cell volume (MCV), and platelet count (Belgian study 1996; MSH 1995). The changes on hydroxyurea treatment were as previously reported, in particular the marked rise in MCV. 3. Quality of life Neither study initially reported using measures relating to this outcome (Belgian study 1996; MSH 1995). Weight gain after two years was reported in the MSH study as a mean rise of 3% in the hydroxyurea treated group and 6% in the placebo group, which is not statistically significant (MSH 1995). The MSH study has published in abstract limited quality of life data collected at sixmonthly intervals (MSH 1995). These are presented as changes in baseline of three measures from the Health Status Survey (nine scales), the Profile of Mood States (four scales) and the Ladder of Life ; where a negative change or worsening in all measures reported means a reduction in score (Terrin 1999). At 12 months general health perception was 1.6 above baseline in the treated group and 1.0 in the placebo group, MD 0.60 (95% CI to 1.38), social function 0.4 above baseline in the treated group and 0.2 in the placebo group, MD 0.20 (95% CI to 0.76), pain recall 0.7 above baseline in the treated group and 0.3 in the placebo group, MD 0.40 (95% CI to 0.98) and the Ladder of Life -0.1 in the treated group and -0.5 in the placebo group, indicating deterioration, MD 0.40 (95% CI to 0.95). Although analyses within this review show a non-significant difference between the two groups, the analyses carried out in the study looked at the overall group treatment differences using a general estimating equations model using repeated measures. The results from these analyses were statistically significant. A later report from the MSH study reported marginal but not significant improvement in general health perception at the end of the study MD 0.4 (95% CI to 1.31) and no significant difference with a range of other measures (MSH 1995). 4. Measure of chronic organ damage The MSH study reported similar rates of new leg ulcers, RR 0.85 (95% CI 0.44 to 1.64) and avascular necrosis of femur and humerus, RR 0.97 (95% CI 0.39 to 2.37), in both groups (MSH 1995). 5. Adverse effects of hydroxyurea In the MSH study, toxicity relating to the blood count was defined as less than 2500 x 10 9 neutrophils/l, less than x 10 9 platelets/l, and haemoglobin concentration less than 5.3 g/ dl (MSH 1995). Using these definitions 120 of the hydroxyureatreated participants (79%) and 54 placebo participants (37%) became toxic at least once, resulting in a dose modification. Importantly, no infections were related to neutropenia and no bleeding episode could be related to thrombocytopenia. The possible adverse effects of hydroxyurea studied by the MSH study are hair loss, skin rash, fever, gastro-intestinal disturbance, and other reported events. There was no significant difference between the groups with these measures (MSH 1995). No adverse effects are reported in the Belgian study (Belgian study 1996). 6. Cost-effectiveness of hydroxyurea Hospitalisation for painful crisis accounted for the majority of costs (MSH 1995 reported by Moore 1999). The difference in means was statistically significant, US$5130 (95% CI US$60 to US$10200). Chest syndrome was the next largest cost with a mean difference of US$830 (95% CI -US$340 to US$2000). It was also reported within the abstract that the hydroxyurea arm was associated with lower costs for emergency department visits, transfusion and use of opiate analgesics, although no data were reported on these outcomes (Moore 1999). Overall the average annual cost for an individual receiving hydroxyurea was US$16,810 (95% CI %13,350 to $20,270) and the annual average cost for an individual receiving placebo was US$22,020 (95% CI US$17,340 to US$26,710). The difference in means was $5210 (95% CI -$610 to $11,030). This was not statistically significant. D I S C U S S I O N The MSH study is a well-conducted study that included 299 participants. It demonstrated significant advantage for those participants with three or more painful crises a year in terms of reduction of painful crisis, reduction in the acute sickle chest syndrome and the use of blood transfusion in adults with SS treated with hydroxyurea (MSH 1995). The Belgian study appears to support these findings and, despite being a small study suggests that the results are likely to be similar for pain crises in children and adolescents with SS treated with hydroxyurea (Belgian study 1996). However, full data for comparison are not yet available. Moreover, for drugs that alter the natural history of a disease, as hydroxyurea does in SCD, a cross-over study is not the best study design. In addition, as the participant numbers entered into this study are small, further randomised controlled trials are needed in children. Such trials in children need to address the impact of hydroxyurea on brain development, IQ, growth and development, the prevention and management of chronic organ damage as well as the outcome measures sought in this review. The MSH study did not show a relationship between baseline characteristics and outcome for the following parameters: gender; age; alpha globin gene number; number of high FCP genes; and 7

10 beta globin haplotype (MSH 1995). One of the modes of action of hydroxyurea is through the raised HbF level in treated participants (Charache 1991; Charache 1992; Rodgers 1990) while the MSH study additionally showed that, among the hydroxyurea-treated participants, those with the lower crisis rates had lower neutrophil counts, while those with higher crisis rates had higher neutrophil counts (MSH 1995). The MSH was not designed to detect any specific levels of effect in health-related quality of life. Therefore, no firm conclusions can be drawn from the reported results in this area (Terrin 1999). However, the modest levels of improvement in all four measures reported are consistent with the primary end-point of reduction in crisis. The MSH participants continue long-term follow up, which is welcomed (MSH 1995). While it was not possible within the design of the MSH to continue long-term follow up within the randomised treatment groups, such data will be invaluable, for instance after eight years of follow up the only malignancy reported is one case of carcinoma in situ of the cervix, which is unlikely to be related (Steinberg 2000). Laboratory values of MSH participants at eight years are also published (Kutlar 2000). The report by Steinberg reported on the effect of hydroxyurea on mortality and morbidity up to nine years of treatment (Steinberg 1999). During this study period (1996 to 2001) participants were allowed to continue, stop or start hydroxyurea. The study had follow up data on 233 people. Seventy-five people died during the study period or follow-up period of this study, 21 of these were due to pulmonary disease. Based on an intention-to-treat approach, mortality was similar in the original two treatment groups (P = 0.35), but the study reported that the overall reduction in mortality up to nine years of observation was 40%. This result should be treated very cautiously as the participants were no longer randomised and the analysis of mortality in an observational study is more complex. Hydroxyurea is a chemotherapeutic agent that blocks synthesis of deoxyribose nucleic acid (DNA) by inhibiting ribonucleotide reductase. Cytopenias are therefore to be expected as the dose of the drug is raised. Clearly, with careful laboratory monitoring and appropriate patient education, cytopenia should rarely represent a major issue as demonstrated by the two included studies (Belgian study 1996; MSH 1995), despite the cautionary note sounded by Vichinsky (Vichinsky 1994). As a chemotherapeutic agent, the cytostatic effects of hydroxyurea are different from those of radiation, alkylating agents and other anti-cancer drugs, many of which are known to increase the risk of development of either leukaemia or cancer. Long-term follow up of people taking hydroxyurea for other diagnoses, including polycythaemia rubra vera (Berk 1995; Fruchtman 1994; Najean 1997), essential thrombocythaemia (Sterkers 1998) and cyanotic heart disease (Triadou 1994), has shown no increase in malignancies in those with normal bone marrows and no significant increase in the other groups. Other toxicity often related to chemotheraputic agents such as hair loss, skin rash, gastro-intestinal (GI) disturbance and fever have also been shown by the MSH study not to be significantly more frequent in the hydroxyurea-treated group as compared with the placebo group (MSH 1995). Preliminary studies using hydroxyurea in SCD suggested that weight gain attributed to the general improvement in patients health and decrease in bone marrow activity while on hydroxyurea. This has not been confirmed in the MSH study, which reported an overall weight gain of 3% in the treated arm and 6% in the placebo arm at two years (MSH 1995). The safety of the hydroxyurea therapy in pregnancy remains unclear. Three babies born to parents on hydroxyurea during the MSH study showed no evidence of birth defects or developmental abnormalities during early follow up, these data are presented in an additional table (Table 1). It is important however, that every attempt should be made to prevent pregnancy in both women being treated with hydroxyurea and their partners as the magnitude of the risk is unknown. A number of the studies considered for this review, but excluded for methodological reasons, are from the developing world (El Alfy 2000; El-Hazmi 2000; Lima 1997). Their results suggest that participants responses may be no different from those reported in the two included studies. The issues that might impact on participant responses include poor nutrition and the presence of a co-existing disease in particular infection such as malaria and HIV. Access both to hydroxyurea and medical services can be limited by either geography or financial circumstances, giving rise to concerns about the safety of the drug if inadequately monitored. However, it is likely that doses lower than the maximum-tolerated dose (MTD) aimed for in the MSH study also produce clinically significant responses, while providing a margin of safety (MSH 1995). The MSH study aimed for MTD of hydroxyurea, with similar doses (20 mg to 25 mg/kg/day) in the Belgian study (Belgian study 1996; MSH 1995). Yet, depending on which underlying mechanisms of action of hydroxyurea are the most important for clinical response - lower doses not only offer greater safety and cost savings but may also be clinically effective. Indeed, in ten participants during a dose escalation study, Lima showed a trend in increase of Hb, MCV and HbF with increasing hydroxyurea dosage from 10 mg to 15 mg/kg/day with a non-significant fall in neutrophils and reticulocytes as the dose was raised from 15 mg to 20 mg/kg/day (Lima 1997). Cost effectiveness was not an original outcome considered within this review. However, recent publications from the MSH study team (MSH 1995) address this and show that hospitalisation 8

11 for painful crisis accounted for the majority of costs in both arms of the study and calculated annualised differential costs between hydroxyurea and placebo, annual mean US$12,160 (95% CI US$49,440 to US$414,880) for hydroxyurea and US$17,290 (95%CI US$13,010 to US$21,570) for placebo (Moore 1999; Moore 2000). Hydroxyurea may prevent chronic organ dysfunction or treat it effectively. Unfortunately, no data are available from randomised controlled trials. An important area for future investigation is that of stroke in SCD. There are a number of reports of people with SCD suffering strokes while being treated with hydroxyurea (Kutlar 2000; Steinberg 2000). While Ware and colleagues have reported results from 16 children with SCD treated to prevent stroke recurrence, only three of these children had a recurrent stroke early in their hydroxyurea treatment schedule, suggesting there may be a role for hydroxyurea in treating such children (Ware 1999). A randomised controlled trial is indicated, which addresses stroke as a primary end point, but also considers other management issues such as haematocit in the therapeutic regimen. It is important to recognise that the participants eligible for both the MSH and Belgian studies had suffered three or more crises during the preceding 12 months, which represents only a small proportion (8.3%) of people with sickle cell anaemia when compared with the crisis rate of participants entered into the National Co-operative Study of Sickle Cell Disease in the USA (Platt 1991). Other more mildly affected people with SS may well benefit from hydroxyurea but the crucial randomised control trials remain to be undertaken. Other genotypes of SCD other than SS have been treated with hydroxyurea. People with Sβo appear to respond well (Voskaridou 1995), while those reported with Sβ+ are insufficient to make a judgement. The single small study of six individuals with SC found on searching (Steinberg 1997 (SC)), suggests small effects on haematological parameters in most participants with a potentially significant rise in HbF in only one participant on daily doses of 1000 mg of hydroxyurea. A U T H O R S C O N C L U S I O N S Implications for practice Hydroxyurea appears to be effective in severely affected SS adults. However, this conclusion is based on two studies involving a small number of participants. In the future it may well prove to have an important role for the less severely affected adults as well as in children. However, its use in SCD is not licensed in Europe and licensing by the Federal Drug Authority in the USA is only for SS adults. Care therefore, should be taken when it is prescribed for people with milder disease of different genotypes or for indications other than pain. All individuals should be counselled prior to commencing therapy relating to the known and potential risks of hydroxyurea in SCD, as well as the need to avoid pregnancy and continue in long-term follow up. Implications for research There remain many unanswered questions related to the role of hydroxyurea in SCD as discussed below. All of these questions need to be addressed by appropriately structured randomised controlled trials. However, there is a need for international agreement on a baseline common data set which should be collected in such trials so that they can be analysed later using meta-analysis techniques, as well as the need for standardised and validated measures for sickle painful crisis and quality of life in people with SCD. The continued long-term follow up of the participants of the MSH study, with regular reporting of outcomes, is welcomed. Particular issues for future trials include: 1. the impact of hydroxyurea in children with SCD; 2. the role of hydroxyurea in the management of specific hard to treat complications of SCD of all ages; 3. study of the long-term toxicity profile of hydroxyurea in SCD; 4. the impact of low (15 mg/kg/day) or medium dose (20 mg/ kg/day) hydroxyurea dosage in SCD; 5. role of hydroxyurea in developing countries; 6. the impact of hydroxyurea in other groups of people with SCD. 9

12 R E F E R E N C E S References to studies included in this review Belgian study 1996 {published data only} Ferster A, Vermylen C, Cornu G, Buyse M, Corazza F, Devalck C, et al.hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial. Blood 1996;88(6): MSH 1995 {published data only} Armstrong FD, Steinberg MH, Ballas SK, Ataga KI, Waclawiw MA, Kutlar A, et al.development outcomes of offspring of adults treated with hydroxyurea in the multicenter study of hydroxyurea [abstract]. Blood 2009, issue 22:Abstract no: Ballas SK, Barton F, Castro O, Bellevue R, Investigators of the multicenter study of hydroxyurea in sickle cell anemia. Narcotic analgesia use among adult patients with sickle cell anemia [abstract]. Blood 1995;86(10 Suppl 1):642a. Ballas SK, Barton F, Castro O, Koshy M, Bellevue R. Pattern of narcotic analgesic consumption among adult patients with sickle cell anemia [abstract]. Proceedings of the National Sickle Cell Disease Program 21st Annual Meeting; 1996 March. 1996:63. Ballas SK, Barton FB, Waclawiw MA, Swerdlow P, Eckman JR, Pegelow CH, et al.hydroxyurea and sickle cell anemia: effect on quality of life. Health and Quality of Life Outcomes 2006;4:59. Ballas SK, Bauserman RL, McCarthy WF, Castro OL, Smith WR, Waclawiw MA. Utilization of analgesics in the multicenter study of hydroxyurea in sickle cell anemia: Effect of sex,age, and geographical location. American Journal of Hematology 2010;85(8): Ballas SK, Bauserman RL, McCarthy WF, Waclawiw MA, Barton BA. Impact of hydroxyurea on employment among patients with sickle cell anemia [abstract]. Blood 2009; Vol. 114, issue 22:Abstract no: Ballas SK, Marcolina MJ, Dover GJ, Barton FB. Erythropoietic activity in patients with sickle cell anaemia before and after treatment with hydroxyurea. British Journal of Haematology 1999;105(2): Ballas SK, Marcolina MJ, Investigators of the multicenter study of hydroxyurea in sickle cell anemia. In vivo RBC survival and ferrokinetic data in patients with sickle cell anemia before and after treatment with hydroxyurea [abstract]. Blood 1995;86(10 Suppl 1):140a. Ballas SK, McCarthy WF, Bauseman RI, Castro OL, Swerdlow PS, Smith W, et al.patterns of analgesic utilization in the multicenter study of hydroxyurea (MSH) [abstract]. Blood 2009; Vol. 114, issue 22:Abstract no: Ballas SK, McCarthy WF, Bauserman RL, Castro OL, Waclawiw MA, Barton BA. Sickle cell genetic markers: geographic distribution and relation to pain outcomes in multicenter study of hydroxyurea in sickle cell anemia [abstract]. Blood 2009; Vol. 114, issue 22:Abstract no: Ballas SK, McCarthy WF, Bauserman RL, Valafar F, Waclawiw M, Barton BA, Kutlar A. Definition of the responder to hydroxyurea therapy: revisited [abstract]. Blood 2009;114(22):Abstract no: Ballas SK, McCarthy WF, Guo N, Brugnara C, Kling G, Bauserman R, et al.early detection of responders to hydroxyurea therapy [abstract]. 4th Annual Sickle Cell Disease Research and Educational Symposium & Grant Writing Institute AND Annual Sickle Cell Disease Scientific Meeting; 2010 Feb 14-19; Hollywood, Florida. 2010; Vol. 26:Abstract no: 030. Barton F, Terrin M, Moore R, McMahon RP, Charache S. Ascertainment of the primary end point in the Multicenter Study of Hydroxyrea in Sickle Cell Anemia (MSH). The MSH Investigators [abstract]. Controlled Clinical Trials 1996;17(2 Suppl):67S. Brandon AE, McCarthy WF, Barton FB, Terrin ML. Vital status determination of patients lost to follow-up in the multicenter study of hydroxyurea in sickle cell anemia (MSH) patients follow-up study [abstract]. Clinical Trials 2004;2:209. Charache S. Effects of hydroxyurea therapy in patients with sickle cell anemia [abstract]. Australian and New Zealand Journal of Medicine 1996;26:326. Charache S. Experimental therapy of sickle cell disease. Use of hydroxyurea. American Journal of Pediatric Hematology/ Oncology 1994;16(1):62 6. Charache S. Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults [review]. Seminars in Hematology 1997;34(3 Suppl 3): Charache S. Preventing Pain in Sickle Cell Anemia (HB SS): Baseline Data from Patients in a Hydroxyurea Trial [abstract]. Blood 1993;82(10 Suppl):356a. Charache S, Barton FB, Moore RD, Terrin ML, Steinberg MH, Dover GJ, et al.hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive switching agent. Medicine 1996;75(6): Charache S, Terrin M, Moore RD, Dover GJ, Barton FB, Eckert SV, et al.effect of hydroxyurea on the frequency of painful crisis in sickle cell anemia. New England Journal of Medicine 1995;332(20): Charache S, Terrin ML, Moore RD, Dover GJ, McMahon RP, Barton FB, et al.design of the multicenter study of hydroxyurea in sickle cell anemia. Controlled Clinical Trials 1995;16(6): Hackney AC, Heizer W, Hoffman E, Jones S, Strayhorn D, Orringer EP. Effect of hydroxyurea (HU) administration on the body weight, body composition and exercise performance of patients with sickle cell anemia [abstract]. Blood 1995;86(10 Suppl 1):141a. Hackney AC, Hezier W, Gulledge TP, Jones S, Strayhorn D, Busby M, et al.effects of hydroxyurea administration on the body weight, body composition and exercise performance of patients with sickle-cell anaemia. Clinical Science 1997; 92(5): Handy C, Barton F, Moore R, McMahon R, Eckert S, Terrin M. Dose titration in the Multicentre Study of Hydroxyurea 10

13 in Sickle Cell Anemia (MSH) [abstract]. Controlled Clinical Trials 1996;17(Suppl 2):92S. Heizer WD, Hackney AC, Busby M, Gulledge T, Jones S, Strayhorn G, et al.the composition and etiology of weight gain in sickle cell patients receiving hydroxyurea (HU): An ancillary study to the multicentre study of hydroxyurea (MSH) [abstract]. Proceedings of the National Sickle Cell Disease Program 18th Annual Meeting; 1993 May. 1993: 117a. Kutlar A, Barton F, Terrin M, Steinberg MH. Effect of hydroxyurea on hematologic and biochemical laboratory values in sickle cell disease: The MSH at 7-8 years follow-up [abstract]. Proceedings of the National Sickle Cell Disease Program 25th Annual Meeting; 2001 April. 2001:Abst # 126. McCarthy WF, Bauserman RL, Barton BA, Guo N, Ballas SK, Smith W. Time series analysis of the pain diary data obtained during the multicenter study for hydroxyurea (MSH) clinical trial [abstract]. Blood 2006, (11):Abst McMahon RP, Waclawiw MA, Geller NL, Barton FB, Terrin ML, Bonds DR. An extension of stochastic curtailment for incompletely reported events: The multicenter study of hydroxyurea in sickle cell anemia (MSH). Controlled Clinical Trials 1997;18(5): Moore RD, Charache S, Terrin M, Barton FB, Ballas SK. Cost-effectiveness of hydroxyurea in sickle cell anemia [abstract]. Proceedings of the National Sickle Cell Didease Program 23rd Meeting; 1999 March. 1999:210. Moore RD, Charache S, Terrin ML, Barton FB, Ballas SK, and the investigators of the MSH study of hydroxyurea in sickle cell anemia. Cost-effectiveness of hydroxyurea in sickle cell anemia. American Journal of Hematology 2000;64 (1): Orringer EP, Jones S, Strayhorn D, Hoffman E, Parker J, Greenberg C. The effect of hydroxyurea (HU) administration on circulating D-dimer levels in patients with sickle cell anemia (HbSS) [abstract]. Proceedings of the National Sickle Cell Disease Program 21st Meeting; 1996 March. 1996:131. Orringer EP, Jones S, Strayhorn D, Hoffman E, Parker J, Greenberg CS. The effect of hydroxyurea (HU) administration on circulating d-dimer levels in patients with sickle cell anemia [abstract]. Blood 1996;88(10 Suppl 1): 496a. Smith WR, Bauseman RL, McCarthy WF, Barton BA, Ballas SK. Effect of geography and climate on pain frequency in patients enrolled in the multicenter study of hydroxyurea in sickle cell anemia [abstract]. 3rd Annual Sickle Cell Disease Research and Educational Symposium and Annual Sickle Cell Disease Scientific Meeting; 2009 Feb :Abstract no: 253. Steinberg MH. Determinants of fetal hemoglobin response to hydroxyurea. Seminars in Hematology 1997;3(Suppl 3): Steinberg MH. Mortality at 3-5 years: The multicenter study of hydroxyurea in sickle cell anemia (MSH) [abstract]. Proceedings of the National Sickle Cell Disease Program Annual Meeting; 1997 Sept. 1997:68. Steinberg MH, Ballas S, Barton F, Terrin M, the MSH. Mortality at 4-5 years: results from the multicenter study of hydroxyurea in sickle cell anemia (MSH) [abstract]. Blood 1997;90(10 Suppl 1 Pt 1):444a. Steinberg MH, Barton F, Castro O, Koshy M, Eckman J, Terrin M. Risks and benefits of hydroxyurea (HU) in adult sickle cell anaemia. Effects at 6- to 7- years [abstract]. Blood 1999;94(10 Suppl 1 Pt 1):644a 5a. Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, et al.effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment.. JAMA 2003;289(13): Steinberg MH, Barton F, Castro O, Ramirez G, Bellevue R, Terrin M, et al.hydroxyurea (HU) is associated with reduced mortality in adults with sickle cell anemia [abstract]. Blood 2000;96(11 Pt 1):485a. Steinberg MH, Castro O, Ballas SK, Barton F, Terrin M. The multicenter study of hydroxyurea in sickle cell anemia (MSH): mortality at 5-6 years [abstract]. Blood 1998;92(10 Suppl 1 Pt 1):496a. Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ. Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Blood 1997;89 (3): Steinberg MH, Lu ZH, Barton M, Terrin S, Charache S, Dover G, MSH study group. Fetal hemoglobin (Hb F) in sickle cell anemia (HbSS): Determinents of response to hydroxyurea (HU) [abstract]. Blood 1995;86(10 Suppl 1): 418a. Terrin ML, Barton FB, Bonds D, Ballas SK, Swerdlow P, Pegelow CH, et al.effect of hydroxyurea on quality of life: 2-year results from the multicenter study of hydroxyurea in sickle cell anemia [abstract]. Proceedings of the National Sickle Cell Disease Program 23rd Annual Meeting; 1999 March. 1999:161. References to studies excluded from this review De Montalembert 2006 {published data only} de Montalembert M, Bachir D, Hulin A, Gimeno L, Mogenet A, Bresson JL, et al.pharmacokinetics of hydroxyurea 1,000 mg coated breakable tablets and 500 mg capsules in pediatric and adult patients with sickle cell disease. Haematologica 2006;91(12): De Montalembert M, Bachir D, Hulin A, Gimeno L, Mogenet A, Bresson JL, et al.a phase 1 pharmacokinetics (PK) study of hydroxyurea (HU) 1,000 mg coated breakable tablets and 500mg capsules in pediatric and adult patients with sickle cell disease [abstract]. Blood 2005;106(11):Abst Silva-Pinto 2007 {published data only} Silva-Pinto AC, Carrara RC, Oliveira VC, Palma PV, Campos AD, Zago MA, et al.hydroxyurea treatment of sickle cell diseases causes megaloblastic transformation of the bone marrow that is responsible for the increase of the mean corpuscular volume [abstract]. Haematologica 2007; Suppl 1:

14 Voskaridou 2005 {published data only} Voskaridou E, Terpos E, Margeli A, Hantzi E, Meletis J, Papassotiriou I, et al.renal dysfunction and osteodystrophy in patients with sickle cell thalassaemia under long-term treatment with hydroxyurea [abstract]. 10th Congress of the European Hematology Association; 2005 June 2-5; Stockholm International Fairs, Sweden. 2005:Abst Ware 2006 {published data only} Ware RE, McMurray MA, Schultz WH, Alvarez OA, Aygun B, Cavalier ME, et al.academic community standards for chronic transfusion therapy in children with sickle cell anemia and stroke [abstract]. Blood 2006;108(11):Abst References to studies awaiting assessment Jain 2010 {published data only} Jain D. Low dose hydroxyurea in children severely affected with sickle cell disease: hospital based randomized controlled study [abstract]. 4th Annual Sickle Cell Disease Research and Educational Symposium & Grant Writing Institute AND Annual Sickle Cell Disease Scientific Meeting ; 2010 Feb 14-19; Hollywood, Florida 2010; Vol. 52:Abstract no: 076. Wang 2009 {published data only} Wang WC, Snyder C, Brugnara C, Telen MJ, Steinberg MH, Wynn LW, et al.effects of hydroxyurea (HU) and magnesium pidolate (Mg) in hemoglobin SC disease (HbSC): the CHAMPS trial [abstract]. Blood 2009; Vol. 22:Abstract no: 819. References to ongoing studies Baby Hug 2007 {published data only} Adams RJ, Barredo J, Bonds DR, Brown C, Casella J, Daner L, et al.tcd in infants: A report from the BABY HUG trial [abstract]. Blood 2005;106(11):Abst 952. Adams RJ, Luden J, Miller S, Wang W, Rees R, Li D, et al.tcd in infants: a report from the Baby Hug study [abstract]. 28th Annual Meeting of the National Sickle Cell Disease Program; 2005 April 9-13; Cincinnati, Ohio. 2005:105. Armstrong FD, Elkin TD, Brown RC, Glass P, Rees RC, Wang WC, et al.neurodevelopment in infants with sickle cell anemia: baseline data from the Baby HUG trial [abstract]. Blood 2008;112(11):713. Armstrong FD, Rees RC, Li D, Bonner M, Elkin D, Strouse JJ, et al.baseline developmental function by age for children in the pediatric hydroxyurea phase 3 clinical trial (Baby Hug) [abstract]. 28th Annual Meeting of the National Sickle Cell Disease Program; 2005 April 9-13; Cincinnati, Ohio. 2005:137. McCarville MB//Rees RC//Rogers ZR//Kalpatthi R//Miller ST//Wang WC//the Baby Hug Investigators. Adbominal ultrasound findings in infants with sickle cell anemia; baseline data from the BABY HUG Trial [abstract]. 3rd Annual Sickle Cell Disease Research and Educational Symposium AND Annual Sickle Cell Disease Scientific Meeting; 2009 Feb :Abstract no: 212. Miller ST, Barredo J, Brown C, Bonds DR, Casella JF, Li D, et al.renal concentrating ability in infants with sickle cell anemia; baseline data from Baby Hug, a multicenter trial [abstract]. 29th Annual Meeting of the National Sickle Cell Disease Program; 2006 April 8-12; Memphis, USA. 2006: Abst 141. Miller ST, Wang WC, Iyer RV, Rana SR, Lane PA, Ware RE, et al.urine concentrating ability in infants with sickle cell anemia: baseline data from the Baby HUG trial [abstract]. Blood 2008;112(11):1413. Miller ST, Ware RE, Kutlar A, Alvarez OA, Iyer RV, Sarnaik SA, et al.serum cystatin-c levels in infants with sickle cell anemia: baseline data from the BABY HUG trial [abstract]. Blood 2008;112(11):4791. Miller ST//Wang WC//Iyer R//Rana S//Lane P//Ware RE//Li D//Rees RC. Urine concentrating ability in infants with sickle cell disease: baseline data from the phase III trial of hydroxyurea (BABY HUG). Pediatric Blood & Cancer 2010, issue 2: Pavlakis SG//Rees RC//Huang X//Brown RC//Casella JF//Iyer RV//Kalpatthi R//Luden J//Miller ST//Rogers ZR//Thornburg CD//Wang WC//Adams RJ. Transcranial doppler ultrasonography (TCD) in infants with sickle cell anemia: baseline data from the BABY HUG trial. Pediatric Blood & Cancer 2010, issue 2: Rogers ZR, Capparelli EV, Thompson B, Ware RE, Wang WC, Iyer RV, et al.pharmacokinetics of hydroxyurea in young children with sickle cell anemia: a report from the Baby Hug trial [abstract]. 29th Annual Meeting of the National Sickle Cell Disease Program; 2006 April 8-12; Memphis, USA. 2006:157. Rogers ZR, Rees RC, Files B, Iyer RV, Shulkin BL, Shalaby- Rana E, et al.spleen function in infants with sickle cell anemia : baseline data from the BABY HUG trial [abstract]. Blood 2008;112(11):1416. Rogers ZR, Rees RR, Wang WC, Li D, Iyer RV, Rana S, et al.evaluation of splenic function in infants with sickle cell anemia in the Baby Hug trial [abstract]. 28th Annual Meeting of the National Sickle Cell Disease Program; 2005 April 9-13; Cincinnati, Ohio. 2005:106. Rogers ZR, Thompson B, Ware RE, Wang WC, Iyer RV, Miller ST, et al.pharmacokinetics of hydroxyurea in young children with sickle cell anemia: a report from the BABY HUG trial [abstract]. Blood. 2005, issue 11:Abst Rogers ZR//Rees RC//Files B//Iyer RV//Shulkin BL// Shalaby-Rana E//Miller JH//Dertinger SD//Lane PA// Wang WC//Ware RE//The Baby Hug Investigators. Spleen function in infants with sickle cell anemia: baseline data from the Baby Hug trial [abstract]. 3rd Annual Sickle Cell Disease Research and Educational Symposium AND Annual Sickle Cell Disease Scientific Meeting; 2009 Feb :Abstract no: 199. Thompson BW//Miller ST//Rogers ZR//Rees RC//Ware RE//Waclawiw MA//Iyer RV//Casella JF//Luchtman- Jones L//Rana S//Thornburg CD//Kalpatthi RV//Barredo 12

15 JC//Brown RC//Sarnaik S//Howard TH//Luck L//Wang WC. The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design. Pediatric Blood & Cancer 2010, issue 2: Thornburg CD, Rogers ZR, Wang W, Jeng M, Rana SR, Iyer RV, et al.study drug and visit adherence: data from the Baby HUG trial [abstract]. Blood 2008;112(11):1275. Thornburg CD//Rogers ZR//Jeng MR//Rana SR//Iyer RV//Faughnan L//Hassen L//Marshall J//McDonald RP//Wang WC//Huang X//Rees RC. Adherence to study medication and visits: data from the BABY HUG trial. Pediatric Blood & Cancer 2010, issue 2: Wang W, Rees RC, Miller ST, Brown RC, Casella JF, Iyer RV, et al.transcranial doppler (TCD) ultrasonography in infants with sickle cell anemia: baseline data from the BABY HUG trial [abstract]. Blood 2008;112(11):1436. Ware RE, Rees RC, Sarnaik SA, Iyer RV, Alvarez OA, Casella JF, et al.renal function in infants with sickle cell anemia: baseline data from the BABY HUG trial [abstract]. Blood 2008;112(11):1414. Ware RE//Rees RC//Sarnaik SA//Iyer RV//Alvarez OA//Casella JF//Shulkin BL//Shalaby-Rana E//Strife CF//Miller JH//Lane PA//Wang WC//Miller ST. Renal function in infants with sickle cell anemia: baseline data from the BABY HUG trial. Journal of Pediatrics 2010, issue 1: Wynn L, Debenham E, Faughnan L, Martin B, Kelly T, Reed C, et al.recruitment in the Baby Hug pediatric hydroxyurea phase 3 clinical trial [abstract]. Proceedings of 35th Anniversary Convention of the National Sickle Cell Disease Program; 2007 Sep 17-22; Washington DC, USA. 2007:245. Wynn LW, Faughnan L, Li D, Wang W, Martin B, Kelly T, et al.recruitment of infants with sickle cell anemia to a phase III trials: data from the BABY HUG study [abstract]. Blood 2008;112(11):1429. Additional references Ballas 1996 Ballas SK, Barton F, Castro O, Koshy M, Bellevue R. Pattern of narcotic analgesic consumption among adult patients with sickle cell anemia [abstract]. Proceedings of the National Sickle Cell Disease Program 21st Annual Meeting; 1996 March. 1996:63. Barton 1996 Barton F, Terrin M, Moore R, McMahon RP, Charache S. Ascertainment of the primary end point in the Multicenter Study of Hydroxyrea in Sickle Cell Anemia (MSH). The MSH Investigators [abstract]. Controlled Clinical Trials 1996;17:67S. Berk 1995 Berk PD, Wasserman LR, Fruchtman SM, Goldberg JD. Treatment of polycythemia vera: a summary of clinical trials conducted by the Polycythemia Vera Study Group. In: Wasserman LR BP, Berlin NI editor(s). Polycythemia vera and the myeloproliferation disorders. Philadelphia: W B Saunders, 1995: Brozovic 1987 Brozovic M, Davies SC. Management of sickle cell disease. Postgraduate Medical Journal 1987;63: Charache 1991 Charache S. Hydroxyurea as treatment for sickle cell anemia. [Review]. Hematology - Oncology Clinics of North America 1991;5(3): Charache 1992 Charache S, Dover GJ, Moore RD, Eckert S, Ballas SK, Koshy M, et al.hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia [see comments]. Blood 1992;79(10): Charache 1995 Charache S, Terrin TL, Moore RD, Dover GJ, Barton FB, Eckert SV, et al.effect of hydroxyurea on the frequency of painful crises in sickle cell anaemia. New England Journal of Medicine 1995;332: Davies 1997a Davies SC, Roberts-Harewood M. Blood transfusion in sickle cell disease. Blood Reviews 1997;11: Davies 1997b Davies SC, Oni L. The management of patients with sickle cell disease. British Medical Journal 1997;315: El Alfy 2000 El Alfy MS. Hydroxyurea in children with sickle cell anaemia, should it be a life long treatment? [abstract]. Blood 2000;96(11):16b. El-Hazmi 2000 El-Hazmi MAF, Warsy AS. Long term experience of hydroxyurea treatment in sickle cell disease - Saudi experience [abstract]. Blood 2000;96(11):752a 753a. Elbourne 2002 Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta-analysis involving crossover trials: methodological issues.. International Journal of Epidemiology 2002;31: Fruchtman 1994 Fruchtman SM, Kaplan ME, Peterson P, Mack K, Berk PD, Wasserman LR. Acute leukemia (AL), hydroxyurea (HU), and polycythemia vera (PV): an analysis of risk from the Polycythemia Vera Study Group [abstract]. Blood 1994;84 (Suppl 1):518a. Fuggle 1996 Fuggle P, Shand PAX, Gill LJ, Davies SC. Pain, quality of life, and coping in sickle cell disease. Archives of Disease in Childhood 1996;75: Gray 1991 Gray A, Anionwu EN, Davies SC, Brozovic M. Mortality in sickle cell disease: the experience of a British centre. Journal of Clinical Pathology 1991;44: Handy 1996 Handy C, Barton F, Moore R, McMahon R, Eckert S, Terrin M. Dose titration in the Multicentre Study of Hydroxyurea 13

16 in Sickle Cell Anemia (MSH) [abstract]. Controlled Clinical Trials 1996;17(Suppl 2):92S. Higgins 2003 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. British Medical Journal 2003;327: Kutlar 2000 Kutlar A, Woods KF, Clair B, Daitch L, Milner PF, Samuels BJ, et al.long term use of hydroxyurea in adults with sickle cell disease: a large single centre experience [abstract]. Blood 2000;96(11):10a. Leikin 1989 Leikin SL, Gallagher D, Kinney TR, Sloane D, Klug P, Rida W. Mortality in children and adolescents with sickle cell disease. Cooperative Study of Sickle Cell Disease. Pediatrics 1989;84(3): Lima 1997 Lima CS, Arruda VR, Costa FF, Saad ST. Minimal doses of hydroxyurea for sickle cell disease. Brazilian Journal of Medical & Biological Research 1997;30(8): Moore 1999 Moore RD, Charache S, Terrin M, Barton FB, Ballas SK. Cost-effectiveness of hydroxyurea in sickle cell anemia [abstract]. Proceedings of the National Sickle Cell Disease Program 23rd Meeting; 1999 March. 1999:210. Moore 2000 Moore R, Charache S, Terrin M, Barton FB, Ballas SK. Cost-effectiveness of hydroxyurea in sickle cell anemia [abstract]. American Journal of Hematology 2000;64(1): Najean 1997 Najean Y, Rain JD. Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood 1997;90(9): Perrine 1978 Perrine RP, Pembrey ME, John P, Perrine S, Shoup F. Natural history of sickle cell anaemia in Saudi Arabs: a study of 270 subjects. Annals of Internal Medicine 1978;88:1 6. Platt 1991 Platt OS, Thorington DB, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, et al.pain in sickle cell disease: rates and risk factors [comment in: New England Journal of Medicine 1991; 325(24): ]. New England Journal of Medicine 1991;325(1):11 6. Platt 1994 Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al.mortality in sickle cell disease - life expectancy and risk factors for early death. New England Journal of Medicine 1994;330: Powars 1983 Powars D, Overturf G, Turner E. Is there an increased risk of Haemophilus influenzae septicemia in sickle cell anaemia?. Pediatrics 1983;71: Rodgers 1990 Rodgers GP, Dover GJ, Noguchi CT, Schechter AN, Nienhuis AW. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea. New England Journal of Medicine 1990;322(15): Rogers 1978 Rogers DW, Clarke JM, Cupidore L, Ramlal A, Sparke BR, Serjeant GR. Early deaths in Jamaican children with sickle cell disease. British Medical Journal 1978;1: Steinberg 1997 (SC) Steinberg MH, Nagel R, Brugnara C. Cellular effects of hydroxyurea in Hb SC disease. British Journal of Hematology 1997;98: Steinberg 1999 Steinberg MH. The Management of Sickle Cell Disease. New England Journal of Medicine 1999;340: Steinberg 2000 Steinberg MH, Barton F, Castro O, Ramirez G, Bellvue R, Terrin M. Hydroxyurea is associated with reduced mortality in adults with sickle cell anaemia. Blood 2000;96(11):485a. Sterkers 1998 Sterkers Y, Preudhomme C, Lai JL, Demory JL, Caulier MT, Wattel E, et al.acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion [see comments]. Blood 1998;91(2): Terrin 1999 Terrin ML, Barton FB, Bonds D, Ballas SK, Swerdlow P, Pegelow CH, et al.effect of hydroxyurea on quality of life: 2-year results from the multicenter study of hydroxyurea in sickle cell anemia [abstract]. Proceedings of the National Sickle Cell Disease Program 23rd Annual Meeting; 1999 March. 1999:161. Triadou 1994 Triadou P, Maier-Redelsperger M, Krishnamoorty R, Deschamps A, Casadevall N, Dunda O, et al.fetal haemoglobin variations following hydroxyurea treatment in patients with cyanotic congenital heart disease. Nouvelle Revue Francaise d Hematologie 1994;36(5): Veith 1985 Veith R, Galanello R, Papayannopoulou T, Stamatoyannopoulos G. Stimulation of F-cell production in patients with sickle cell anaemia treated with cytarabine or hydroxyurea. New England Journal of Medicine 1985;313: Vichinsky 1994 Vichinsky EP, Lubin BH. A cautionary note regarding hydroxyurea in sickle cell disease. Blood 1994;83(4): Voskaridou 1995 Voskaridou E, Kalotychou V, Loukopoulos D. Clinical and laboratory effects of long-term administration of hydroxyurea to patients with sickle-cell/b thalassaemia. British Journal of Haematology 1995;89(3):

17 Ware 1999 Ware RE, Zimmerman SA, Schultz WH. Hydroxyurea as an alternative to blood transfusions in the prevention of recurrent stroke in children with sickle cell disease. Blood 1999;94(9): Indicates the major publication for the study 15

18 C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] Belgian study 1996 Methods Participants Randomised cross-over study. HU versus placebo control. Belgium, single centre. SS, 25 children, age 2-22 years (median 9 years). > 3 vaso-occlusive events reported in preceding 12 months and/or history of CVA off transfusion (severe alloimmunisation or compliance), ACS, ASS Interventions HU 20 mg/kg/day rising to 25 (unless toxic cytopenia) versus placebo. Treatment period was for 6 months Outcomes Notes Number of hospitalisations. Number of inpatient days. FBC. HbF%. Only first 6-month period eligible for analysis. Data only published for HU versus control as a 12-month study, so details requested from author Risk of bias Item Authors judgement Description Adequate sequence generation? Unclear Described as drawing sealed envelopes, patients were randomly allocated to one of the following treatment sequences, therefore the generation of the treatment sequence are not clear from this statement Allocation concealment? Unclear Described as drawing sealed envelopes, patients were randomly allocated to one of the following treatment sequences, therefore the allocation of the treatment sequence are not clear from this statement Blinding? Participant Blinding? Physician Yes No The hospital pharmacy provided the treatment and placebo for each participant and both were described as indistinguishable The physician was aware of the treatment schedule because of the difficulty of blinding the attending physician to the treatment received 16

19 MSH 1995 Methods Participants Interventions Outcomes Notes Randomised parallel study. Double-blind placebo-controlled study. USA, multicentre. SS, over 18 years of age 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 HU therapy 152 randomised to HU and 147 given placebo HU 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. maximum tolerated dose) for 2 years Pain events - attending hospital >4 hours & parenteral opiate treatment. Crises including ACS, CVA, priapism etc. Pain charts daily. Time to first and second crisis. FBC. F cells & Hb F%. Dense cells. 93% follow up at 2 years, treatment stopped in 14 HU and 6 placebo participants. Hb F% and pain diaries not reported. Risk of bias Item Authors judgement Description Adequate sequence generation? Yes Treatment assignments were made centrally using a computer programme to generate separate, randomised block assignment schedules for each clinic Allocation concealment? Unclear There was no clear discussion on allocation concealment. Blinding? Participant Blinding? Physician Yes Yes Stated as double-blind (physician and participant), where treatment was assigned in combinations of identically appearing capsules. Stated as double-blind (physician and participant), where treatment was assigned in combinations of identically appearing capsules ACS: acute chest syndrome ASS: acute splenic sequestration CVA: cerebro-vascular accident Cytopenia: refers to either neutropenia or thrombocytopenia, anaemia is also a risk but was not reported 17

20 FBC: full blood count HbF: fetal haemoglobin HU: hydroxyurea Characteristics of excluded studies [ordered by study ID] Study De Montalembert 2006 Silva-Pinto 2007 Voskaridou 2005 Ware 2006 Reason for exclusion This study does not fulfil the inclusion criteria. The length of treatment was eight days, the inclusion criteria state that treatment should be at least one month This is not a randomised trial. This is not a randomised trial. The group of participants who received hydroxyurea also received phlebotomy Characteristics of studies awaiting assessment [ordered by study ID] Jain 2010 Methods Participants Interventions Outcomes Randomised double-blind multicentre phase II trial. 180 children (5-18 years) with SS hemoglobin electrophoresis pattern who had experienced 5 or more crises or admitted to hospital in the year prior to study entry Split into two equal groups. HU versus placebo. HU was administered in a single fixed daily dose of 10 mg/kg for 24 months and the patients were assessed monthly for signs of toxicity Hb levels, fetal Hb levels, reticulocyte counts, serum bilirubin, SGPT levels, number of crises, number of crises requiring hospitalisation, mean period of hospitalisation, number of transfused blood units required Notes Wang 2009 Methods Randomised placebo-controlled trial. Participants Eligible participants had HbSC and at least 1 vaso-occlusive event in the previous 12 months (but none in the 4 weeks prior to study entry). Aged 5 years Interventions Participants randomised to 1 of 4 arms: (1) HU (20 mg/kg/d PO) and Mg (0.6 meq/kg/d PO in 2 doses); (2) HU and placebo for Mg; (3) HU placebo and Mg; or (4) placebos for both 18

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