The MTD then usually remains relatively stable unless there is substantial weight gain, development of splenomegaly, or change in renal function. Periodic increases in absolute daily dose due to weight gain are appropriate. When a stable MTD is reached, it may be appropriate to decrease the frequency of clinic visits to bimonthly, depending on patient response and family reliability.
Extension to quarterly visits usually is associated, however, with a decline in adherence, likely because of lack of frequent reminders from medical providers. Hematologic toxicity is by far the most common reason to modify the hydroxyurea dose, usually before reaching the MTD. Practical toxicity definitions and thresholds for erythrocytes, reticulocytes, neutrophils, and platelets are listed in Table 3.
An increase in alanine aminotransferase or creatinine should never be assumed to be drug related, and additional investigations with ultrasonography or other tests should be strongly considered. When a hematologic toxicity occurs on hydroxyurea therapy, the medication should be discontinued to allow the counts to recover.
Almost all hematologic toxicities are transient, reversible, and dose dependent and recover within 1 week of drug interruption, although severe toxicities may feature pancytopenia and take 2 to 3 weeks until recovery. If the counts recover in 1 week, then the dose can either be resumed at the previous amount or decreased modestly eg, reduced by 2.
Conversely, if laboratory values suggest that a dose increase would be tolerated after 2 months at a stable dose, the MTD dose can be increased by a small amount such as 2. Before increasing a hydroxyurea dose beyond a previously established stable MTD, however, the likelihood of diminished medication adherence should be strongly considered.
Children and their family members are much more likely to be adherent to hydroxyurea therapy and the frequent clinic visits if they believe that treatment will be beneficial. At each clinic visit, the importance of daily medication should be emphasized; specific questions should be asked regarding who gives the dose, what time it is administered, how many doses are missed per week, and so forth.
Visualization of the peripheral blood smear is an effective way to illustrate the benefits of hydroxyurea therapy. The de-identified peripheral blood smears of several patients, which were obtained pre- and post-treatment MTD, can be shown to children and family members.
The authors use a multiheaded microscope before initiating hydroxyurea therapy to demonstrate the obvious changes that occur with good adherence and a good treatment response Fig. This viewing and explanation should be performed by an experienced medical provider who can emphasize that adherence also can be monitored by review of the blood counts and the peripheral blood smear.
Changes in complete blood cell count parameters and erythrocyte morphology in association with hydroxyurea therapy, from dose initiation through escalation to MTD. The initial panel shows blood counts and the peripheral blood smear at dose initiation, with hemolytic anemia and leukocytosis evident along with sickled forms. When explanations of risks and benefits of hydroxyurea therapy are given to patients and family members, it is emphasized that a parent must be in charge of ensuring that the medication actually is swallowed each day.
It is imperative to anticipate that occasionally children miss a dose of hydroxyurea without any ill effect, and therefore be tempted to miss several days, wondering if they somehow have been cured. Explaining that blood cells are produced every day, hence the medication must be taken every day, is logical even for young patients. Parents must be reminded at each interval visit that they must be sure to give the medication; teenagers are especially notorious for embellishing adherence.
In some instances, patients can be remarkably adherent and even remind parents about dosing. Serial listing of monthly blood counts according to various blood count parameters can be used to show beneficial changes, such as increased hemoglobin concentration, mean corpuscular volume MCV , and HbF; concomitant decreases in WBC and ANC also easily can be seen.
Whatever the mnemonic devices used, among the best strategies for successful treatment are a thorough understanding of the rationale for treatment, a limited number of health care providers for continuity to patients and family, and regular clinic visits on a 1 to 2 month basis, to engender trust and loyalty with emphasis on the beneficial treatment effects and the need for daily adherence.
Hydroxyurea is a powerful therapeutic agent with proved laboratory and clinical efficacy for children with SCD. Although there are important questions regarding its long-term efficacy and safety, hydroxyurea has the potential to ameliorate many of the signs and symptoms of the disease.
Ongoing clinical trials will help answer questions about the proper clinical indications for its use and, in particular, its ability to prevent organ damage and preserve organ function and long-term safety. The authors thank Nicole A. We appreciate their insights and advice regarding the optimal use of hydroxyurea in this patient population.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
National Center for Biotechnology Information , U. Hematol Oncol Clin North Am. Author manuscript; available in PMC Feb Matthew M. Ware , MD, PhD c. Russell E. Ware c Department of Hematology, St.
Author information Copyright and License information Disclaimer. Copyright notice. See other articles in PMC that cite the published article. An ideal drug for sickle cell disease? Clinical experience Preclinical studies in anemic cynomolgus monkeys showed that hydroxyurea increased HbF levels [ 33 ]. Table 1 Children with homozygous sickle cell anemia have similar laboratory efficacy using hydroxyurea at maximum tolerated dose as adults.
Open in a separate window. Practical considerations Hydroxyurea therapy cannot be prescribed, monitored, and adjusted properly according to exact and specific written guidelines.
Beginning hydroxyurea therapy The decision to initiate hydroxyurea therapy in a child who has SCD should be made deliberately and thoughtfully. Table 2 Potential indications for hydroxyurea therapy in children with homozygous sickle cell anemia.
Explaining the rationale The recommendation to begin hydroxyurea therapy and a description of the potential risks and benefits of taking the drug should be communicated to patients and family members in a straightforward and honest way, using age-appropriate and culturally sensitive language and vocabulary. Describing risks and benefits The potential benefits of hydroxyurea therapy are best discussed with patients and families not only in terms of preventing acute clinical complications, such as pain and ACS, but also as helping avoid hospitalizations and transfusions, enhancing growth, and possibly preventing chronic organ damage.
Dose initiation Before initiating hydroxyurea therapy, baseline laboratory studies should be obtained Fig. Dose escalation to maximum tolerated dose Beneficial effects of hydroxyurea can begin in the first few weeks after commencing therapy [ 71 ], which can lead to some reluctance by medical providers to increase the dose beyond that needed for subjective clinical improvement.
Dose modification Hematologic toxicity is by far the most common reason to modify the hydroxyurea dose, usually before reaching the MTD. Table 3 Hematologic toxicity thresholds requiring hydroxyurea dose modifications.
Summary Hydroxyurea is a powerful therapeutic agent with proved laboratory and clinical efficacy for children with SCD. Acknowledgments The authors thank Nicole A. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.
References 1. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. Effects of thalassemia and microcytosis on the hematologic and vasoocclusive severity of sickle cell anemia. The painful crisis of homozygous sickle cell disease. A study of the risk factors. Arch Intern Med. Relationship of clinical severity to packed cell rheology in sickle cell anemia. Powars DR. Sickle cell anemia: beta s-gene-cluster haplotypes as prognostic indicators of vital organ failure. Semin Hematol.
Mortality in sickle cell disease. Life expectancy and risk factors for early death. Charache S. Fetal hemoglobin, sickling, and sickle cell disease. Adv Pediatr. Wood WG. Increased HbF in adult life. Baillieres Clin Haematol. Serjeant GR. Fetal haemoglobin in homozygous sickle cell disease. Clin Haematol. F-cells in the adult: normal values and levels in individuals with hereditary and acquired elevations of Hb F.
Significance of paucity of sickle cells in newborn negro infants. Am J Med Sci. Steinberg MH. Compound heterozygous and other hemoglobinopathies. Disorders of hemoglobin: genetics, pathophysiology, and clinical management. The relationship between fetal hemoglobin and disease severity in children with sickle cell anemia. Am JMed Genet. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. There are no randomised studies comparing the effect of using a standard dose versus dose escalation to the MTD.
Clearly, with careful laboratory monitoring and appropriate patient education, cytopenia should rarely represent a major issue as demonstrated. In addition, in the MSH study there was no increase in the incidence of leg ulcers and avascular necrosis in those treated with hydroxyurea. This is important as they have both been associated with hydroxyurea use in observational reports and leg ulcers are associated with hydroxyurea use in people with myeloproliferative disease.
Furthermore, observational data looking at 15 years of hydroxyurea use from infancy has not shown any concerns about safety Hankins , although as with the mortality data this is not based on randomised data and should be treated with caution. There are still questions about the impact of hydroxyurea on the chronic organ damage associated with SCD. These results suggest that hydroxyurea may have some beneficial effect on renal function, but these results do not automatically translate into clinical benefit BABY HUG There has been no evidence of malignancy in those with SCD treated with hydroxyurea in large observational studies Steinberg ; Voskaridou Small numbers of case reports have reported myelodysplasia or acute leukaemia in people with SCD treated with hydroxyurea and two of these have been associated with 17p deletions.
This is of interest as 17p deletions have also been associated with the development of myelodysplasia or acute leukaemia in people with myeloproliferative disease treated with hydroxyurea Aumont ; Baz In vitro work has not shown increased chromosome breakages or decreased repair in people with SCD on hydroxyurea McGann Concerns have been raised about whether hydroxyurea is associated with abnormal spermatogenesis and teratogenic effects but there are few data to confirm or refute that.
There is a theoretical risk of hydroxyurea affecting sperm development and abnormal spermatogenesis has been shown in animals treated with hydroxyurea. Sperm abnormalities, including oligospermia and azoospermia, have been shown in males with SCD taking hydroxyurea, but it is not clear if these are due to the hydroxyurea as similar abnormalities have been described in males with SCD not taking hydroxyurea. One small study compared semen analysis before, during and after hydroxyurea treatment and showed semen parameters were affected whilst on hydroxyurea and did not seem to recover quickly Berthaut This included only small numbers of individuals and needs further investigation.
Evidence of adverse outcomes and teratogenic effects in humans exposed to hydroxyurea in utero is limited. An expert panel report evaluating the toxicity of hydroxyurea has led to recommendations that hydroxyurea is stopped in men and women who are trying to conceive and in breastfeeding women National Toxicology Program The risks of stopping hydroxyurea whilst attempting conception should be carefully discussed with the individual.
It was not powered to measure efficacy and terminated early due to low enrolment so it is not possible to make conclusions about the efficacy of hydroxyurea in prevention of pain episodes in people with HbSC.
We judged the quality of the evidence for the comparison 'Hydroxyurea compared to placebo' to be moderate for most outcomes and low for quality of life and adverse events, where data were more limited and imprecise Table 1. Furthermore, for the two most recently completed studies, results for secondary outcomes such as neuropsychological status, growth and development, functional evaluations and neurocognitive evaluations have not yet been reported.
Any results relevant to this review from further publications will be included in this review. For the other two comparisons in the review 'Hydroxyurea compared to observation for participants with SCD and risk of stroke' and 'Hydroxyurea compared to no hydroxyurea for participants with SCD,' evidence was limited and of very low quality Table 3 ; Table 4. Furthermore, due to the factorial design of one of the studies CHAMPS , a direct comparison between hydroxyurea and a control treatment was not possible so all results for this comparison must be interpreted as indirect.
A rigorous methodological approach was applied to the review and a comprehensive search strategy was employed as outlined in Electronic searches , therefore, we do not believe that our methodological approach has introduced any bias into the review.
Given the designs of some of the studies included in this review e. We encourage particular caution when interpreting results of the outcome 'adverse events or toxicity', as it is difficult to distinguish between adverse reactions i. For completeness, we have reported all "adverse events" or "adverse effects" as they are reported in the study publications, regardless of any noted relationship to treatment.
As described earlier in this section, there have been several studies supporting the findings of this review. In addition to these, numerous reviews and other studies discussing the role of hydroxyurea in SCD are available but this is the only Cochrane Review of the topic. To ensure proper use of hydroxyurea and maximize benefits and safety, use an established prescribing and monitoring protocol. In adults with sickle cell anaemia who have a history of severe or recurrent ACS or both , treat with hydroxyurea.
In adults with sickle cell anaemia who have severe symptomatic chronic anaemia that interferes with daily activities or quality of life, treat with hydroxyurea.
This led to recommendations that hydroxyurea should be offered to this group of individuals. The evidence of similar efficacy in a group of infants not selected for severity BABY HUG is suggestive that all infants with sickle cell anaemia may benefit from hydroxyurea.
This has led to recommendations that it should be offered to all children with sickle cell anaemia regardless of clinical severity NIH and has led to an increased use of hydroxyurea, particularly in children. Hydroxyurea is the only licensed drug for the treatment of SCD and its efficacy in reducing the acute complications of the disease and potential risks of use should be discussed with all individuals with SCD and the families of children with SCD, allowing them to take an informed decision about its use.
There is insufficient evidence to recommend its routine use in those individuals with genotypes other than sickle cell anaemia, but its potential benefits and risks of use should be discussed with those with a severe disease phenotype. Randomised comparisons of hydroxyurea and transfusion showed that hydroxyurea seems to be as effective as transfusion in preventing stroke in children with sickle cell anaemia and abnormal TCD velocities who have received at least one year of transfusion therapy and have no evidence of vasculopathy on MRA.
Hydroxyurea does not seem to be as effective as transfusion therapy in preventing stroke in children with sickle cell anaemia who have already experienced a stroke. There is insufficient evidence on whether to prescribe a standard dose or dose escalation to the MTD. Many questions remain unanswered relating to the role of hydroxyurea in SCD as discussed below. All of these questions need to be addressed by appropriately structured randomised controlled studies.
Particular issues for future studies include:. Protocol first published: Issue 3, Review first published: Issue 2, We note the previous contribution of Adebayo Olujohungbe AO to previous versions of the review. The protocol stated that odds ratios would be used as the measure of treatment effect for dichotomous data, however on reflection, we felt it more appropriate to present risk ratios in preference to odds ratios OR , as odds ratios give an inflated impression of the size of effect where event rates are high, as is the case of these studies.
SD drafted review. Ashley Jones AJ became lead author in September and assisted in drafting the update and now acted as guarantor of the review. AJ acts as guarantor of the review. SJN became lead author in and led the current update on screening, data extraction, risk of bias assessment, analysis, summary of findings table and drafting results and discussion. JH provided clinical interpretation of the review, drafted text of the discussion and commented on all sections of the review. AJ extracted and data and drafted text as well as commenting on later draft versions.
Sarah Nevitt: none known. Ashley Jones: none known. Jo Howard: no declarations in relation to the use of hydroxyurea.
National Center for Biotechnology Information , U. Cochrane Database Syst Rev. Published online Apr Sarah J Nevitt, Email: ku. Author information Copyright and License information Disclaimer. Corresponding author. This article is an update of " Hydroxyurea for sickle cell disease. This article has been cited by other articles in PMC. Objectives To assess the effects of hydroxyurea therapy in people with SCD all genotypes , 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: 16 January Data collection and analysis Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias. Background SCD is an inherited genetic disorder that creates problems with haemoglobin the substance in red blood cells that carries oxygen around the body. Search date The evidence is current to 16 January Key results and quality of the evidence In four studies, adults and children with SCD were randomly selected to receive hydroxyurea or placebo.
Conclusions The evidence shows that hydroxyurea is likely to be effective in the short term at decreasing the frequency of painful episodes and raising fetal haemoglobin levels in the blood in people with SCD.
Summary of findings. Background Description of the condition Haemoglobinopathies, including sickle cell disease SCD , are among the most common inherited disorders in the world. How the intervention might work It has long been recognised that raised HbF levels can ameliorate the clinical effects of SCD Perrine ; Platt Why it is important to do this review It is important to examine as a whole, the body of work relating to the use of hydroxyurea in SCD, to evaluate the drug's effectiveness and tolerability in adults and children, and in the different types of SCD, the dosage regimens and whether the setting appears to influence the outcome, i.
Objectives The aims of this review are to determine whether the use of hydroxyurea in people with SCD: alters the pattern of acute events, including pain; prevents, delays or reverses organ dysfunction; alters mortality and quality of life; is associated with adverse effects. Types of participants This review is limited to studies of hydroxyurea in SCD only.
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. Secondary outcomes Measures of fetal haemoglobin HbF or F cells and neutrophil counts Other surrogate markers of response e. Karnofsky Measures of organ damage e.
Search methods for identification of studies We searched for all relevant published and unpublished trials without restrictions on language, year or publication status. We also searched the following trials registries on 20 March Searching other resources The bibliographic references of all retrieved studies and reviews were assessed for additional reports of studies.
Data collection and analysis Selection of studies For the initial review, two authors SCD and AO independently applied inclusion criteria. 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 using the Cochrane Risk of Bias tool Higgins 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.
Assessment of heterogeneity We assessed clinical heterogeneity by reviewing the differences across trials in the characteristics of recruited participants and treatment protocols. Summary of findings and quality of the evidence GRADE In a post hoc change from the protocol, we have presented four summary of findings tables, one for each comparison of the review Table 1 ; Table 2 ; Table 3 ; Table 4. No significant differences in terms of stroke, hepatic or splenic sequestration two studies.
No significant differences between groups in terms of all other events. The basis for the assumed risk is the event rate in the control group unless otherwise stated in the comments and footnotes.
GRADE Working Group grades of evidence High quality : further research is very unlikely to change our confidence in the estimate of effect. Moderate quality : further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality : further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality : we are very uncertain about the estimate. Open in a separate window. High quality : further research is very unlikely to change our confidence in the estimate of effect. Risk of bias in included studies See Figure 2 and Characteristics of included studies for more information.
Primary outcomes 1. Pain alteration Hydroxyurea compared to placebo for participants with SCD The MSH study defined pain crisis as a visit to a medical facility, lasting four or more hours, requiring opiate analgesia MSH Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 1 Pain crises. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 2 Proportion experiencing pain. Analysis Comparison 2 Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 1 Proportion experiencing pain.
Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 3 Proportion experiencing life threatening events during study. Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and an increased risk of stroke The primary aim of the TWiTCH study was to prevent primary stroke; 29 neurologic events occurred during the study, 17 in the hydroxyurea group and 12 in the standard treatment group; but none were deemed to be stroke or cerebral infarcts TWiTCH Hydroxyurea compared to observation for participants with SCD and an increased risk of stroke The primary aim of the SCATE study was to prevent stroke and no strokes or transient ischaemic attacks occurred during the study.
Death during the study Hydroxyurea compared to placebo for participants with SCD The MSH study reported death and causes of death MSH ; no deaths were reported to be related to hydroxyurea treatment. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 5 Deaths during the study. Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and an increased risk of stroke In the SWiTCH study, there was one death in the standard treatment arm pulmonary embolism and one death in the hydroxyurea treatment arm fatal haemorrhagic stroke SWiTCH Analysis Comparison 2 Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 3 Deaths during the study.
Secondary outcomes 1. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 11 Change from baseline in m corpuscular volume fL. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 18 Mean corpuscular volume fL.
Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 20 Reticulocytes. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 21 Platelet count. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 22 Packed cell volume. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 23 F reticulocytes. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 24 F cells.
Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 25 Red blood count. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 26 White blood cells. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 27 Dense cells. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 28 Leucocytes.
Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 29 Creatinine. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 30 Aspartate aminotransferase. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 31 Alkaline phosphatase.
Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 32 Change from baseline in growth. Analysis 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.
Analysis 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. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 33 Quality of life: general health perception. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 34 Quality of life: pain recall.
Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 35 Quality of life: social function. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 36 Changes in 'Ladder of Life'.
Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and an increased risk of stroke Quality of life was measured in the TWiTCH study, but results have not yet been published; if results are published at a later date, they will be included in an update of this review TWiTCH Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 37 Proportion of participants with signs of organ damage.
Hydroxyurea compared to observation for participants with SCD and an increased risk of stroke The aim of the SCATE study was to prevent conversion from conditional to abnormal time averaged mean velocity TAMV and subsequent stroke; one participant in the hydroxyurea group and five participants in the observation group converted, this difference between groups was not statistically significant Analysis 3.
Adverse effects or toxicity As it is difficult to distinguish between adverse reactions i. Analysis Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 52 Proportion of participants experiencing adverse events and toxicity. Analysis Comparison 3 Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 4 Adverse events and toxicity.
Quality of the evidence We judged the quality of the evidence for the comparison 'Hydroxyurea compared to placebo' to be moderate for most outcomes and low for quality of life and adverse events, where data were more limited and imprecise Table 1. Potential biases in the review process A rigorous methodological approach was applied to the review and a comprehensive search strategy was employed as outlined in Electronic searches , therefore, we do not believe that our methodological approach has introduced any bias into the review.
Agreements and disagreements with other studies or reviews As described earlier in this section, there have been several studies supporting the findings of this review.
Authors' conclusions Implications for practice. Implications for research. Summary of findings tables are now included in the review. These include participants with different genotypes, different disease severities and participants at risk of primary and secondary stroke. The inclusion of these new trials has impacted upon the conclusions of the review.
History Protocol first published: Issue 3, Review first published: Issue 2, Date Event Description 10 November New search has been performed A search of the Group's Haemoglobinopathies Trials Register identified 25 new references potentially eligible for inclusion in this review. Eight references were to the already included MSH trial and provide no further data or information not already included within the review MSH The remaining two references each published in abstract form have been added to ' Studies awaiting classification ', and we await publication of the full papers in order to accurately assess eligibility Jain ; CHAMPS a.
One was an additional reference to the already included MSH study Ballas , however, this did not include any new data that can be added to the review. A further reference was to the already excluded De Montalembert study De Montalembert In addition, the Plain Language Summary has been updated in line with latest guidance from The Cochrane Collaboration. Two of the new references were additional references to the already included MSH study; however, no further data have been included in the review.
Seven of the references were to one study, which is listed in 'Studies awaiting assessment' Baby Hug The remaining three new references have been excluded De Montalembert ; Voskaridou ; Ware This reference provided no additional data. Ashley Jones became lead author in September and acts as guarantor of the review.
Blood ;88 10 Suppl 1 a. Following on from the inclusion of this reference, a further outcome has been added to the review: cost effectiveness of hydroxyurea. Acknowledgements We note the previous contribution of Adebayo Olujohungbe AO to previous versions of the review.
Notes New search for studies and content updated conclusions changed. Data and analyses Comparison 1 Hydroxyurea versus placebo for participants with sickle cell disease. Outcome or subgroup title No. Comparison 2 Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke. Comparison 3 Hydroxyurea compared to observation for participants with SCD and risk of stroke. Methods Randomised, double blind participant, investigator , placebo control, parallel assignment, efficacy study conducted at 13 centres in the USA.
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. Mean SD age: hydroxyurea group : Allocation concealment selection bias Low risk Centralised telephone randomisation was used. Incomplete outcome data attrition bias All outcomes 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 All outcomes Low risk Participants, caregivers and medical coordinating centre staff were masked to treatment allocation via packaging and treatment of the same appearance. Blinding of outcome assessment detection bias All outcomes Low risk An unmasked "primary endpoint person" monitored laboratory values and assisted clinical management.
Other outcome assessors e. Belgian Study Treatment period was for 6 months. Outcomes Number of hospitalisations. Number of inpatient days. Notes Data are not presented in a way that results can be included in the review so 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 are 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 are not clear from this statement. There was no discussion of whether or not an ITT analysis was used so the risk is unclear. Blinding of participants and personnel performance bias All outcomes 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 results. Blinding of outcome assessment detection bias All outcomes Unclear risk No information provided. Mean age: Interventions Participants randomised to 1 of 4 arms in a factorial design: 1.
Outcomes Primary outcome: proportion of hyperdense red blood cells at 8 weeks. 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.
Due to factorial design, no data can be entered into analysis and 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. Allocation concealment selection bias Unclear risk No information provided. Incomplete outcome data attrition bias All outcomes High risk 36 out of 44 participants completed 8 weeks and 22 out of 44 completed 44 weeks.
This is not an ITT approach. Selective reporting reporting bias Low risk Outcome defined in the methods section well described in the results section. Study was not designed to measure efficacy. Other bias Low risk Study terminated early after only 44 of planned sample size of 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. Jain 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. 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. Selective reporting reporting bias Low risk No protocol available, outcomes defined in the methods reported well in the results.
Blinding of participants and personnel performance bias All outcomes Low risk Participants were blinded with placebo tablets of identical appearance.
The clinician who assessed participants were not aware of treatment arm. Blinding of outcome assessment detection bias All outcomes Low risk The laboratory technician and the clinician who assessed participants were not aware of treatment arm.
MSH Conducted in the USA and Canada across 21 sites. MTD compared to placebo for 2 years. Risk of bias Bias Authors' judgement Support for judgement Random sequence generation selection bias Low risk Treatment assignments were made centrally using a computer programme to generate separate, randomised block assignment schedules for each clinic.
Allocation concealment selection bias Unclear risk There was no clear discussion on allocation concealment. Incomplete outcome data attrition bias All outcomes 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.
Blinding of outcome assessment detection bias All outcomes Unclear risk There was no clear discussion on blinding of outcome assessors. SCATE Mean age SD : hydroxyurea group: 6. Secondary outcomes: changes in serial TCD velocities. Indicence of acute events including stroke. 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 All outcomes Low risk Numbers screened, randomised and number receiving randomised treatment reported. Analysis conducted using an ITT approach. Other bias High risk Study terminated early after only 22 of planned sample size of were recruited therefore study is likely to be statistically underpowered.
Blinding of participants and personnel performance bias All outcomes 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 All outcomes Low risk All TCD site examiners, central reviewers were masked and site clinicians were masked to participants TCD results. SWiTCH 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. Mean SD age at study enrolment in years: hydroxyurea group 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. 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 All outcomes 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.
Blinding of participants and personnel performance bias All outcomes 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 All outcomes 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. TWiTCH Exclusion criteria were documented clinical stroke, TIA or severe vasculopathy. Mean SD age at study enrolment in years: hydroxyurea group 9. Outcomes Primary outcome: maximum TCD time averaged mean velocity on the index side i.
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 All outcomes Low risk Numbers discontinuing the interventions stated, all participants included in analysis 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.
Forty-four children were in the low-dose group and 98 were in the high-dose group. In addition, there was an observed clinical improvement regarding the acute chest syndrome ACS. Both groups had comparable significant improvements in their laboratory markers [e. All patients tolerated the treatment well.
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