Children With Sickle Cell Disease and Silent Cerebral Infarct, Regular Blood Transfusions Might Decrease Risk of Overt Stroke or Silent Infarct Recurrence

EBM Focus - Volume 9, Issue 35

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Reference: N Engl J Med 2014 Aug 21;371(8):699 (level 2 [mid-level] evidence)

Silent cerebral infarction is the most common neurologic injury in children with sickle cell anemia, with a cumulative risk of about 37% by age 14 (Blood 2011 Jan 27;117(4):1130 full-text). Children with sickle cell disease and silent cerebral infarction have an increased risk of other adverse neurologic outcomes, including stroke (Blood 2002 Apr 15;99(8):3014) and reduced cognitive function (Neurology 2001 Apr 24;56(8):1109). The STOP trial previously demonstrated that regular blood transfusions reduced the risk of stroke in children with sickle cell disease and abnormal transcranial Doppler ultrasound findings (N Engl J Med 1998 Jul 2;339(1):5 full-text). Based on these findings, the current guidelines from the American Heart Association/American Stroke Association recommend blood transfusion therapy for these patients (Stroke 2011 Feb;42(2):517 full-text). However, the optimal management of children with sickle cell disease who have other risk factors for stroke is currently unclear. A recent randomized trial compared regular blood transfusions with usual care in 196 children aged 5-15 years with sickle cell disease who had 1 or more silent cerebral infarctions demonstrated on MRI but no history of overt stroke.

The regular blood transfusion intervention targeted a hemoglobin level > 9 g/dL and a hemoglobin S level ≤ 30% of the total hemoglobin, and was given about once monthly for a median of 3 years. It also included additional chelation therapy if the ferritin level was > 1,500 ng/mL for at least 2 months. The primary outcome was a composite of overt stroke, new silent cerebral infarct, or enlargement of an existing infarct (as assessed by neuroimaging). Transfusion therapy was associated with a significant improvement in the primary outcome compared to usual care during follow-up (2 vs. 4.8 per 100 patient years, incidence rate ratio 0.41, 95% CI 0.12-0.99, NNT 36 per year). Overt stroke occurred in 1% with regular blood transfusion vs. 7% with usual care (no p value reported). Compared to usual care, regular blood transfusion was associated with significantly decreased rates of vaso-occlusive pain, acute chest syndrome, and symptomatic avascular necrosis of the hip. There were no significant between-group differences in IQ or function scores, and no deaths occurred.

The results of this trial support the use of regular blood transfusions in children with sickle cell anemia with evidence of a silent cerebral infarct on MRI. These results, combined with the results of the STOP trial, suggest that regular transfusion therapy may improve neurologic outcomes for a significant proportion of children with sickle cell disease. However, children receiving hydroxyurea were excluded from the current trial, which limits the generalizability of these new findings. In addition, a previous Cochrane review of 3 randomized trials evaluating blood transfusion for children with sickle cell disease (including the STOP trial) found that transfusions were associated with several complications, including iron overload, alloimmunization, and transfusion reactions (Cochrane Database Syst Rev 2013 Nov 14;(11):CD003146). Importantly, the current trial did not demonstrate any between-group differences in IQ or other neurocognitive outcomes, and the long-term effects on cognitive function are currently unknown.

For more information see the Transfusion therapy in sickle cell disease topic in DynaMed.