Mike: Hello, I'm Mike Clarke, podcast editor for the Cochrane Library. Several Cochrane Reviews evaluate treatments for sickle cell disease, which can cause a huge burden for patients and their families. The review on the effects of hydroxyurea was updated in September 2022 by Angela Rankine-Mullings from the Sickle Cell Unit, Caribbean Institute for Health Research at The University of the West Indies in Jamaica and Sarah Nevitt, from the Department of Health Data Science, University of Liverpool in UK. We asked Angela to outline the need for the review and its latest findings in this podcast.

Angela: Sickle cell disease is an inherited disorder that creates problems with haemoglobin, the substance in red blood cells that carries oxygen around the body. The illness results in the production of sickle haemoglobin known as HbS which forms long polymers (or chains) under certain conditions and damages the red cells, making them hard and sticky. They change shape from a biconcave disk to a sickle or crescent shape, which causes them to break easily. These changes make it more difficult for the cells to go through small blood vessels, contributing to blockages and reduced blood flow that in turn cause pain, strokes and organ damage. Other effects have also been noted among people with sickle cell disease, including depression, poor quality of life, coping issues and difficult family relationships. All these manifestations of the illness can require frequent visits to healthcare facilities.
Hydroxyurea is one of the drugs used to reduce sickle cell related complications and our review summarizes the findings of clinical trials of its effects on important outcomes such as pain, survival, life-threatening illness and quality of life, as well as side effects.
In this update, we included nine, eligible randomised trials, which involved just over a thousand people with sickle cell disease. The studies lasted between six and thirty months. Eight studies recruited children, with one of these also recruiting adults and there was one study in adults only. The studies compared hydroxyurea with placebo (an inactive substance) or with other active treatments and we found evidence of benefit.
Firstly, when hydroxyurea was compared to placebo, people receiving hydroxyurea experienced significantly fewer pain episodes than those on placebo. There were also significantly fewer events of hospitalization, dactylitis, sepsis and anaemia in children. Three studies reported fewer occurrences of acute chest syndrome and four studies reported fewer blood transfusions when hydroxyurea was given, rather than placebo. There's no evidence that hydroxyurea led to changes in survival, life-threatening illnesses, quality of life or that it caused any particular side effects, but this may be because the studies had limited information on these outcomes, and further research is likely to have an important impact on what we can say about this.
Secondly, when hydroxyurea was compared to placebo in children or with other treatments in people at increased risk for stroke, there was higher haemoglobin F concentration in the hydroxyurea group. This is a special haemoglobin found in high levels before birth that is considered protective in persons with sickle cell disease.
Thirdly, a study that we added to the review in this update found that among children and adults with haemoglobin SC, haemoglobin F was increased in the hydroxyurea group and reports of most common adverse events were evenly distributed across treatment groups.
In summary, randomised trials have shown that hydroxyurea used for the periods of time tested in the studies we included in our review is likely to be effective for decreasing the frequency of painful episodes in sickle cell disease and doesn't seem to be associated with an increase in side effects. Evidence as to whether the drug is beneficial when used for many years or whether it causes any long-term side effects is awaited. Answers to these important questions will require new studies, designed to run for longer than the trials that have been done up to now.

Mike: If you would like to read about the nine studies that are in this update of Angela and Sarah's review and watch for future updates if more evidence become available, you can find it at Cochrane Library dot com. Just visit the website and search 'hydroxyurea for SCD' to see it listed first.