Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient.

To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD.

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 19 September 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 06 October 2016.

Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status.

We used standard Cochrane methodological procedures.

We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention.

Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion.

Two trials compared the drug hydroxyurea 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 moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates.

Long-term red blood cell transfusions versus standard care

Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts)

Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence).

No deaths were reported in either trial.

Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence).

Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence).

Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial)

Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence).

We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence).

The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function.

Hydroxyurea and phlebotomy versus transfusions and chelation

Primary prevention, children (121 participants; one trial)

We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence).

Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial)

We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95%CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence).

Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence).

Neither trial reported on quality of life or cognitive function.

We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD.

Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises).

In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions.

Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention.

All other evidence in this review is of very low-quality.

Review question

We wanted to determine if there were any safe and effective interventions that prevent silent strokes (also known as silent cerebral infarcts) in people with sickle cell disease (SCD).

Background

SCD 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 and crescent shaped. Sickled cells are not only less flexible than healthy red blood cells, they are also stickier. This can lead to the 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 fewer red blood cells, known as anaemia. Sickled red blood cells can block blood flow in vessels in the brain, leading to a silent stroke.

Silent strokes are common, occurring in up to 39% of people with SCD by 18 years of age. Two tests have been used to identify children at higher risk of having a first stroke. Transcranial doppler ultrasonography (TCD) measures the speed of blood flowing through arteries in the brain. Children with a high blood flow have an increased risk of stroke. Whereas magnetic resonance imaging (MRI) takes images of the brain to see if there are any small areas of damage called silent strokes. Children with silent strokes have an increased risk of clinical stroke.

Treatments that have been considered for preventing silent strokes include long-term red blood cell transfusions, the drug hydroxyurea and stem cell transplantation.

Trial characteristics

Evidence is current to 19 September 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 hydroxyurea. Trials were published between 1998 and 2016 and included children and sometimes adolescents; the majority had one form of SCD (HbSS). No trials included stem cell transplantation.

All trials received government funding.

Key Results

In children with abnormal TCD velocities, red blood cell transfusions may decrease the risk of silent strokes, but have little or no effect in children with normal TCD velocities.

In children at higher risk of stroke (abnormal TCD velocities or previous silent stroke), red blood cell transfusions probably reduce the risk of clinical stroke; may reduce the risk of acute chest syndrome and painful crisis; but we are very uncertain whether they have any effect on the risk of death.

In children with normal TCD velocities and previous silent stroke, red blood cell transfusions may improve quality of life, but make little or no difference to IQ.

In children and adolescents who have had at least 12 months of regular red blood cell transfusions to prevent a stroke, continuing red blood cell transfusions may reduce the risk of silent stroke, but we are very uncertain whether they have any effect on the risk of death or clinical stroke.

For children on long-term red blood cell transfusions with iron chelation (treatment to remove excess iron) who have not had a stroke, we are very uncertain whether switching to hydroxyurea with phlebotomy (withdrawing blood to reduce excess iron) has any effect on the risk of a silent stroke, clinical stroke, death, or SCD-related complications.

For children and adolescents on long-term red blood cell transfusions and iron chelation who have had a clinical stroke, we are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on the risk of silent stroke or death. Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications.

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 blood cell transfusions reduce the risk of stroke. The quality of evidence was rated as low to very-low for the rest of the outcomes including risk of silent cerebral infarcts 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.