Sickle cell disease is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. Sickle cell disease can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Stroke affects around 10% of children with sickle cell anaemia (HbSS). Chronic blood transfusions may reduce the risk of vaso-occlusion and stroke by diluting the proportion of sickled cells in the circulation.
This is an update of a Cochrane Review first published in 2002, and last updated in 2013.
To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease for primary and secondary stroke prevention (excluding silent cerebral infarcts).
We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 04 April 2016.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 25 April 2016.
Randomised controlled trials comparing red blood cell transfusions as prophylaxis for stroke in people with sickle cell disease to alternative or standard treatment. There were no restrictions by outcomes examined, language or publication status.
Data collection and analysis
Two authors independently assessed trial eligibility and the risk of bias and extracted data.
We included five trials (660 participants) published between 1998 and 2016. Four of these trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of sickle cell disease.
Three trials compared regular red cell transfusions to standard care in primary prevention of stroke: two in children with no previous long-term transfusions; and one in children and adolescents on long-term transfusion.
Two trials compared the drug hydroxyurea (hydroxycarbamide) and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children); and one in secondary prevention (children and adolescents).
The quality of the evidence was very low to moderate across different outcomes according to GRADE methodology. This was due to the trials being at a high risk of bias due to lack of blinding, indirectness and imprecise outcome estimates.
Red cell transfusions versus standard care
Children with no previous long-term transfusions
Long-term transfusions probably reduce the incidence of clinical stroke in children with a higher risk of stroke (abnormal transcranial doppler velocities or previous history of silent cerebral infarct), risk ratio 0.12 (95% confidence interval 0.03 to 0.49) (two trials, 326 participants), moderate quality evidence.
Long-term transfusions may: reduce the incidence of other sickle cell disease-related complications (acute chest syndrome, risk ratio 0.24 (95% confidence interval 0.12 to 0.48)) (two trials, 326 participants); increase quality of life (difference estimate -0.54, 95% confidence interval -0.92 to -0.17) (one trial, 166 participants); but make little or no difference to IQ scores (least square mean: 1.7, standard error 95% confidence interval -1.1 to 4.4) (one trial, 166 participants), low quality evidence.
We are very uncertain whether long-term transfusions: reduce the risk of transient ischaemic attacks, Peto odds ratio 0.13 (95% confidence interval 0.01 to 2.11) (two trials, 323 participants); have any effect on all-cause mortality, no deaths reported (two trials, 326 participants); or increase the risk of alloimmunisation, risk ratio 3.16 (95% confidence interval 0.18 to 57.17) (one trial, 121 participants), very low quality evidence.
Children and adolescents with previous long-term transfusions (one trial, 79 participants)
We are very uncertain whether continuing long-term transfusions reduces the incidence of: stroke, risk ratio 0.22 (95% confidence interval 0.01 to 4.35); or all-cause mortality, Peto odds ratio 8.00 (95% confidence interval 0.16 to 404.12), very low quality evidence.
Several review outcomes were only reported in one trial arm (sickle cell disease-related complications, alloimmunisation, transient ischaemic attacks).
The trial did not report neurological impairment, or quality of life.
Hydroxyurea and phlebotomy versus red cell transfusions and chelation
Neither trial reported on neurological impairment, alloimmunisation, or quality of life.
Primary prevention, children (one trial, 121 participants)
Switching to hydroxyurea and phlebotomy may have little or no effect on liver iron concentrations, mean difference -1.80 mg Fe/g dry-weight liver (95% confidence interval -5.16 to 1.56), low quality evidence.
We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: risk of stroke (no strokes); all-cause mortality (no deaths); transient ischaemic attacks, risk ratio 1.02 (95% confidence interval 0.21 to 4.84); or other sickle cell disease-related complications (acute chest syndrome, risk ratio 2.03 (95% confidence interval 0.39 to 10.69)), very low quality evidence.
Secondary prevention, children and adolescents (one trial, 133 participants)
Switching to hydroxyurea and phlebotomy may: increase the risk of sickle cell disease-related serious adverse events, risk ratio 3.10 (95% confidence interval 1.42 to 6.75); but have little or no effect on median liver iron concentrations (hydroxyurea, 17.3 mg Fe/g dry-weight liver (interquartile range 10.0 to 30.6)); transfusion 17.3 mg Fe/g dry-weight liver (interquartile range 8.8 to 30.7), low quality evidence.
We are very uncertain whether switching to hydroxyurea and phlebotomy: increases the risk of stroke, risk ratio 14.78 (95% confidence interval 0.86 to 253.66); or has any effect on all-cause mortality, Peto odds ratio 0.98 (95% confidence interval 0.06 to 15.92); or transient ischaemic attacks, risk ratio 0.66 (95% confidence interval 0.25 to 1.74), very low quality evidence.
There is no evidence for managing adults, or children who do not have HbSS sickle cell disease.
In children who are at higher risk of stroke and have not had previous long-term transfusions, there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke, and low quality evidence they also reduce the risk of other sickle cell disease-related complications.
In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration.
In secondary prevention of stroke there is low-quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events.
All other evidence in this review is of very low quality.
Plain language summary
Long-term blood transfusions to prevent a stroke in people with sickle cell disease
We wanted to determine if long-term blood transfusions given to people with sickle cell disease who are at a higher risk of stroke (primary prevention) or have had a previous stroke (secondary prevention) decreases their risk of a subsequent stroke without causing severe side effects. We compared long-term blood transfusions to standard treatment or other ways of preventing a stroke. This is an update of a previously published Cochrane Review.
Interventions for silent stroke are addressed in a separate Cochrane Review.
Sickle cell disease is a serious inherited blood disorder where the red blood cells, which carry oxygen around the body, develop abnormally.
Normal red blood cells are flexible and disc-shaped, but in sickle cell disease they can become rigid, crescent shaped and also stickier. This can lead to blockage of blood vessels, resulting in tissue and organ damage and episodes of severe pain. The abnormal blood cells are more fragile and break apart, which leads to a decreased number of red blood cells, known as anaemia.
Sickled red blood cells can block flow in blood vessels in the brain, leading to strokes.
Strokes occur in up to 10% of children with sickle cell anaemia (HbSS) and can cause limb weakness, slurred speech, seizures, and cognitive impairment.
Two tests have been used in trials to identify children at higher risk of having a first stroke. One (transcranial Doppler ultrasonography) measures the speed of blood flowing through arteries in the brain, and those children with high blood flow are at increased risk of a stroke. The other (magnetic resonance imaging) takes images of the brain to see if there are any small areas of damage (silent strokes), those children with evidence of damage are at increased risk of stroke.
Blood transfusions may help prevent a stroke by reducing the level of anaemia, diluting the sickled red blood cells, and increasing the level of oxygen in the blood.
Blood transfusions can be linked to adverse events, e.g. the development of antibodies to proteins on donor red blood cells (alloimmunisation), accumulation of too much iron in the body from repeated transfusions, increased risk of infection, and extended length of stay in hospital.
We searched the medical literature to 25 April 2016. We found five randomised controlled trials which enrolled a total of 660 participants. Three trials compared blood transfusions to no blood transfusions and two trials compared blood transfusion to the drug hydroxyurea. Trials were published between 1998 and 2016 and included children and sometimes adolescents; the majority had one form of sickle cell disease (HbSS).
All trials received government funding.
In children who are at a higher risk of having a stroke who have not had previous blood transfusions, a long-term blood transfusion regime probably reduces clinical strokes, and may also reduce other sickle cell disease-related complications.
We are very uncertain if stopping blood transfusions in children and adolescents receiving transfusions for a long time (greater than 12 months) increases the risk of stroke.
We are very uncertain whether switching from long-term transfusions with iron chelation to hydroxyurea with phlebotomy has any effect on stroke, mortality, or sickle cell disease-related complications in children who have not had a stroke. Hydroxyurea may have little or no effect on iron levels in the liver.
We are very uncertain if switching from long-term transfusions with iron chelation to hydroxyurea with phlebotomy increases the risk of stroke or mortality in children and adolescents who have had a stroke and were previously receiving regular transfusions. Switching from long-term transfusions to hydroxyurea may increase some sickle cell disease-related serious adverse events such as painful crises.
Quality of the evidence
In children at higher risk of stroke who have not had previous long-term transfusions, there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke. The quality of evidence was rated as low to very low for the rest of the outcomes due to trials being at high risk of bias and because there were a small number of trials and a small number of participants included in the trials.