Transcranial Doppler Ultrasound (TCD) Outcomes for Children with Prior Normal TCD: Post-STOP Study Results

Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) study established routine transcranial Doppler ultrasound (TCD) screening with indefinite transfusions for children with abnormal TCD as standard of care. Children with normal TCD studies have the lowest risk of stroke of ~0.5-1% per year (y). Annual TCD screening is usually recommended for these children to detect possible subsequent conversion to high risk. We sought to determine the frequency of TCD screening utilized in “real world” clinical practice and the TCD outcomes for children with prior normal TCD.

Subjects and Methods: During STOP and STOP2 (STOP/2), 3,837 children, ages 2 to 16 y with sickle cell disease type SS or S-Beta-0-thalassemia underwent screening TCD. The Post-STOP study was designed to follow-up the outcomes of children who were screened for or participated in one or both of these randomized trials. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3,541 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 (depending on site) on follow-up TCD results and clinical information using standard data collection forms. The rates of TCD re-screening and the proportion of children who converted to abnormal TCD were calculated. Factors associated with conversion to abnormal TCD were assessed.

Results: Of the 3,541 subjects, follow-up data were available for 2,838 (80%). The mean age at the last TCD study obtained in STOP/2 was 9.5 y and the mean age at last follow-up in Post-STOP was 19.6 y. The mean duration of follow-up after exiting STOP/2 was 9.2 y. Subjects were classified by their worst TCD in STOP/2: the TCD was normal in 1,814 (64%), conditional in 479 (17%), abnormal in 357 (13%) and inadequate 188 (7%). Among the 1,814 children with only normal studies in STOP/2, follow-up TCD screening was obtained in the Post-STOP era on 842 (46%) at a median rate of 0.28 TCD studies/y (range, 0.05-3.04/y). Among these children, 26 (3.1%) developed an abnormal TCD at a median of 11.5 y (2.2-18.2 y) from the last STOP/2 study, while 77.5% still had normal TCD at a median of 10.7 y (0.7-18.3 y) from last STOP/2 study. The worst follow-up TCD classification for this group with prior normal TCD was conditional in 9.7% and inadequate in 9.6%. Among those that converted from prior normal to abnormal TCD, 12 had an interval conditional study (at median 2.8 y, 0.98-9.2 y) while 14 children converted from normal to abnormal at a median of 4.2 y (1.4-12.7 y) without documented interval conditional study. Children who developed abnormal TCD were younger at STOP/2 study exit (4.9 vs. 7.8 y, p<0.001) and had higher TCD velocity at their last STOP/2 TCD study (154 vs. 136 cm/s, p<0.001) than children whose TCD remained normal. There was no significant difference between the time interval from the last STOP/2 TCD and the first Post-STOP TCD in these 2 groups.

Conclusions: In clinical practice, follow-up TCD for children with prior normal TCD was performed less frequently than the generally recommended annual basis. Among children re-screened, the risk of conversion to abnormal TCD was relatively low, but re-screening with TCD identified a subset of at-risk children who could benefit from transfusions to prevent a potentially devastating outcome. Predictors of conversion to abnormal TCD included younger age and prior TCD velocity in the high normal range.