Discontinuing prophylactic transfusions increases the risk of silent brain infarction in children with sickle cell disease: data from STOP II

Abstract

In the STOP II trial, discontinuation of prophylactic transfusions in high risk children with sickle cell disease (SCD) resulted in a high rate of reversion to abnormal blood-flow velocities on transcranial Doppler (TCD) ultrasonography and strokes. We analyzed data from STOP II to determine the effect of discontinuing transfusions on the development or progression of silent brain infarcts on magnetic resonance imaging (MRI). At study entry, 21 of 79 (27%) patients had evidence of silent infarcts. There were no statistically significant differences in baseline characteristics between patients with normal brain MRI or silent infarcts at study entry. At study end, 3 of 37 (8.1%) patients in the continued-transfusion group developed new brain MRI lesions compared with 11 of 40 (27.5%) in the transfusion-halted group (P ‫؍‬ .03). The total number of lesions remained essentially unchanged decreasing from 25 to 24 in the continuedtransfusion group while increasing from 27 to 45 in transfusion-halted patients. Thus, discontinuation of transfusions in children with SCD and abnormal TCD who revert to low-risk increases the risk of silent brain infarction. Together with data from STOP, these findings demonstrate that transfusions prevent the development of silent infarcts in patients with SCD and abnormal TCD but normal MRA. (Blood. 2011;118(4):894-898) IntroductionEstimates of the prevalence of silent brain infarcts, in children with sickle cell disease (SCD) range from 17% to 35%. [1][2][3][4] Despite the terminology, 'silent infarcts' are clinically significant given their association with subsequent overt stroke and neurocognitive deficits in school-aged children. 2,[5][6][7][8][9] Better understanding of the associated risk factors and efforts to optimize prevention remain essential. Reported risk factors for silent infarction are raised white blood-cell count, anemia, severe vasculopathy, and the SEN ␤-globin haplotype. 4,[10][11] Transfusions have been successfully used to prevent initial or recurrent strokes in SCD. [12][13][14][15][16] To prevent first strokes, the Stroke Prevention Trial in Sickle Cell Anemia (STOP) used prophylactic red-cell transfusions in children who were identified by transcranial Doppler (TCD) ultrasonography as being at high risk for stroke. This strategy reduced the incidence of stroke among such children from 10% per year to Ͻ 1% per year. 15 The STOP study led to recommendations for TCD screening and prophylactic transfusion for children with abnormal velocities on ultrasonography. 17 Among patients with MRI evidence of silent infarction and raised velocities by TCD enrolled in STOP, transfusion also diminished the risk of new silent infarcts. 18 Despite the reduced risk of stroke, the potentially indefinite duration of transfusion aroused concern about adverse effects, especially iron overload. In the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP II) Trial, discontinuation of transfusions in patients whose TCD velocities had normalized (normal TCD) resulted in a hig...

Chronic and acute anemia and extracranial internal carotid stenosis are risk factors for silent cerebral infarcts in sickle cell anemia

“…This is in accordance with the STOP II trial, which randomly assigned patients who had no evidence of stenosis and a history of abnormal intracranial velocities that had normalized on transfusion program to pursuing vs halting transfusions. 31 In the pursuing transfusion group, the number of SCI remained the same (n 5 25 vs 24), whereas the number of SCI increased from 27 to 45 in the transfusion-halted group. 31 Thus, current data suggest that transfusion program may be beneficial in preventing SCI occurrence in patients with a history of abnormal TCD.…”

“…31 In the pursuing transfusion group, the number of SCI remained the same (n 5 25 vs 24), whereas the number of SCI increased from 27 to 45 in the transfusion-halted group. 31 Thus, current data suggest that transfusion program may be beneficial in preventing SCI occurrence in patients with a history of abnormal TCD. For patients with no abnormal intracranial velocities, the SIT Trial, which randomly assigned patients with SCI to transfusions vs simple observation, recently reported that transfusion program significantly reduced the incidence of SCI recurrence.…”

Stroke in patients with sickle cell disease

“…Among children with both abnormal TCD and silent infarcts, those who received transfusion therapy were significantly less likely to develop new silent infarcts [42]. A subset of those patients later had transfusions discontinued and demonstrated an increased frequency of progression of silent infarcts compared with those who continued transfusion therapy [112]. However, a recent study looking at transfusion in patients with overt stroke found progression of silent infarcts in 25% of subjects despite being optimally transfused [46].…”

Transfusion therapy for sickle cell disease: a balancing act

“…14 Discontinuing transfusions on the STOP 2 trial was also associated with a higher occurrence of silent cerebral infarcts, documented in 3 of 37 patients (8.1%) in the continued-transfusion group compared with 11 of 40 (27.5%) in the transfusion-halted group. 15 Two ongoing randomized interventional trials aim to address current dilemmas regarding the use of chronic RBC transfusions to prevent neurologic complications in children with SCD. Comparison of hydroxyurea and transfusion therapy for children with abnormally elevated TCD velocities but no primary stroke is currently ongoing in the TCD with Transfusions Changing to Hydroxyurea (TWiTCH) trial (www.ClinicalTrials.gov identifier NCT01425307).…”