Hydroxyurea (also known as hydroxycarbamide) for people with sickle cell disease

Review question

What is the effect of hydroxyurea on clinical outcomes (changes in pain crises, life-threatening illnesses, survival, haemoglobin levels, quality of life and side effects) in people with sickle cell disease (SCD) of any genotype?

Background

SCD is an inherited genetic disorder that creates problems with haemoglobin (the substance in red blood cells that carries oxygen around the body). The disease can be inherited in different ways; people can inherit two sickle genes (HbSS genotype) or they can inherit the sickle gene from one parent and a different haemoglobin gene (such as haemoglobin C (HbSC genotype) or a beta thalassaemia gene (HbSβ+ or HbSβºthal genotype)) from the second parent.

In people with SCD the abnormal sickle haemoglobin forms long polymers (chains) within the red blood cells when they become de-oxygenated. This damages the red blood cells and makes them stickier, leading to blockages and reduced blood flow, causing pain and organ damage. Fetal haemoglobin stops these polymers forming in the sickle haemoglobin within the red blood cell. The drug hydroxyurea is used to raise fetal haemoglobin and can reduce the effects of the disease. This is an update of a previously published Cochrane Review.

Search date

The evidence is current to 16 January 2017.

Study characteristics

We included eight studies (899 adults and children with SCD (HbSS, HbSC or HbSβºthal genotypes)). Studies lasted from six to 30 months.

Key results and quality of the evidence

In four studies, 577 adults and children with SCD were randomly selected to receive hydroxyurea or placebo. In two studies, 254 children with SCD, who were also at an increased risk of having a first or second stroke, were randomly selected to receive hydroxyurea and phlebotomy (collection of blood) or blood transfusion and chelation (administration of agents to remove excess iron from the body). These six studies only recruited people with HbSS or HbSβºthal genotypes so results do not apply to people with the HbSC genotype.

There was moderate quality evidence from these six studies that those receiving hydroxyurea experienced significant reductions in the frequency of pain crises, increases in fetal haemoglobin and decreases in neutrophil (white blood cell) counts compared to the comparator treatment. There was no difference between people receiving hydroxyurea or other treatments in terms of quality of life, deaths during the studies and side effects (including serious and life-threatening side effects); however, there is less information about these outcomes in the studies, so the quality of this evidence is low.

Two further studies were included in the review. In one study, 22 children with SCD, who were also at an increased risk of having a stroke, were randomly selected to receive hydroxyurea or no treatment (observation only) and in one study 44 adults and children were randomly selected to receive treatments with or without adding hydroxyurea. Both studies showed an increase in fetal haemoglobin for people receiving hydroxyurea compared to the comparator treatment and there were no deaths during the studies. There was no difference between people receiving hydroxyurea or other treatments in terms of pain crises and side effects (including serious or life-threatening side effects) and these studies did not measure quality of life. The quality of the evidence from these studies is very low, given the studies were very small and only recruited around 20% of the intended number of people and results do not apply to all people with SCD (different genotypes).

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. Hydroxyurea is also likely to be effective in preventing first strokes for those at an increased risk of stroke and does not seem to be associated with an increase in any side effects (including serious and life-threatening side effects).

There is currently not much evidence on whether hydroxyurea is beneficial over a long period of time, what the best dose to take is, or whether treatment causes any long-term or serious side effects. More studies are needed to answer these questions.

Authors' conclusions: 

There is evidence to suggest that hydroxyurea is effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly in preventing chronic complications of SCD, recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with HbSC genotype. Future studies should be designed to address such uncertainties.

Read the full abstract...
Background: 

Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising fetal haemoglobin. This is an update of a previously published Cochrane Review.

Objectives: 

To assess the effects of hydroxyurea therapy in people with SCD (all genotypes), of any age, regardless of setting.

Search strategy: 

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. We also searched online trial registries.

Date of the most recent search: 16 January 2017.

Selection criteria: 

Randomised and quasi-randomised controlled trials, of one month or longer, comparing hydroxyurea with placebo, standard therapy or other interventions for people with SCD.

Data collection and analysis: 

Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias.

Main results: 

Seventeen studies were identified in the searches; eight randomised controlled trials were included, recruiting 899 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months.

Four studies (577 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; three recruited individuals with only severe disease and one recruited individuals with all disease severities. There were statistically significant improvements in terms of pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use), measures of fetal haemoglobin and neutrophil counts and fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. There were no consistent statistically significant differences in terms of quality of life and adverse events (including serious or life-threatening events). Seven deaths occurred during the studies, but the rates by treatment group were not statistically significantly different.

Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) compared hydroxyurea and phlebotomy to transfusion and chelation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts, but more occurrences of acute chest syndrome and infections in the hydroxyurea and phlebotomy group. There were no consistent statistically significant differences in terms of pain alteration and adverse events (including serious or life-threatening events). Two deaths occurred during the studies (one in a the hydroxyurea treatment arm and one in the control arm), but the rates by treatment group were not statistically significantly different. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early.

The quality of the evidence for the above two comparisons was judged as moderate to low as the studies contributing to these comparisons were mostly large and well designed (and at low risk of bias); however evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events and results are applicable only to individuals with HbSS and HbSβºthal genotypes.

Of the remaining two studies, one (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts but no statistically significant differences in terms of adverse events (including serious or life-threatening events).

The final study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea – there was statistically significant improvement in terms of measures of fetal haemoglobin, but no statistically significant differences in terms of adverse events (including serious or life-threatening events). No participants died in either of these studies and other outcomes relevant to the review were not reported.

The quality of the evidence for the above two comparisons was judged to be very low due to the limited number of participants, the lack of statistical power (as both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes.

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