Background
Phase III open-label RCT. 130 children aged 2–16 years with sickle cell disease (HbSS or HbSβ0-thalassemia) and elevated TCD velocity ≥200 cm/s on two measurements within 2 weeks, designating high risk for first stroke. No prior stroke or overt neurological event. Randomized 1:1. Trial stopped early by DSMB after median 14 months follow-up due to overwhelming efficacy in the transfusion arm.
Interventions and follow up
Arm A: Chronic transfusion therapy targeting HbS <30% (transfusions every 3–4 weeks)
Arm B: Standard care (observation; no prophylactic transfusions; hydroxyurea permitted at physician discretion)
Primary endpoint: First clinical stroke
mFollow up: 14 months (median; stopped early)
Arm B: Standard care (observation; no prophylactic transfusions; hydroxyurea permitted at physician discretion)
Primary endpoint: First clinical stroke
mFollow up: 14 months (median; stopped early)
Results
First stroke: 1 (1.6%) transfusion vs 11 (16.4%) standard care; RRR 91%, P<.001
TCD normalization: Not assessed as secondary endpoint
TCD normalization: Not assessed as secondary endpoint
Adverse events
Main adverse events: Transfusion arm: iron overload requiring chelation, alloimmunization (~19%). Standard care arm: 11 strokes (2 fatal or with permanent deficit). No increase in transfusion-related infection mortality. Transfusion reactions uncommon.
Conclusions
Chronic transfusion therapy reduced stroke risk by over 90% in children with SCD and TCD ≥200 cm/s, establishing TCD screening and prophylactic transfusion as the standard of care for primary stroke prevention in this population.
Key Limitations
Key Limitations: Open-label design; stopped early (median 14 months) may overestimate effect size. Limited to highest-risk TCD group (≥200 cm/s). Long-term risks of iron overload and alloimmunization were not addressed in this short trial. 61% of eligible patients declined enrollment, raising generalizability concerns. No hydroxyurea comparison arm.
Clinical Context
STOP changed practice globally and is reflected in ASH, NCCN, and BSH guidelines recommending annual TCD screening from age 2–16 and chronic transfusion for TCD ≥200 cm/s. STOP=.2 showed transfusions cannot safely be discontinued. TWiTCH (2016) subsequently established that hydroxyurea can replace chronic transfusion once TCD normalizes, providing a critical exit strategy from long-term transfusion therapy.
References
References: Adams RJ et al, NEJM 1998 (STOP primary)