PDF: STOP
(1998)Objective
Evaluate whether regular blood transfusion in children with sickle cell anemia and abnormal TCD velocities can reduce the risk of first-time stroke.
Study Summary
• In children with sickle cell disease (HbSS) and abnormal TCD velocities (≥200 cm/s), chronic transfusions reducing HbS to <30% significantly lowered the risk of first stroke by over 90% compared to standard care. The trial established TCD as a screening tool and transfusion as an effective prevention strategy.
Intervention
Randomized, multicenter trial. Children aged 2–16 years with HbSS or HbSβ0 thalassemia and abnormal TCD results were randomized to either chronic transfusion therapy (HbS <30%) or standard care. Follow-up continued for 30 months after randomization.
Study Design
Arms: Array
Outcome
• Primary endpoint (first clinical stroke): 11 strokes in standard care vs. 1 stroke in transfusion group
• Relative risk reduction: ~90% (P<0.001)
• Stroke incidence: 0.9 per 100 patient-years (transfusion) vs. 10.7 per 100 patient-years (standard care)
• No significant increase in severe transfusion complications
• MRI-defined silent infarcts and iron overload were monitored as secondary outcomes
• Relative risk reduction: ~90% (P<0.001)
• Stroke incidence: 0.9 per 100 patient-years (transfusion) vs. 10.7 per 100 patient-years (standard care)
• No significant increase in severe transfusion complications
• MRI-defined silent infarcts and iron overload were monitored as secondary outcomes
Bottom Line
Chronic blood transfusion therapy reduced stroke risk by 92% in high-risk children with sickle cell disease identified by TCD velocities ≥200 cm/s. The trial was stopped early due to overwhelming benefit and established TCD screening with prophylactic transfusion as standard of care.
Major Points
- STOP is the landmark trial establishing primary stroke prevention in sickle cell disease — the first demonstration that a screening test (TCD) could identify high-risk children and an intervention (transfusion) could prevent strokes before they occurred.
- 130 children (age 2–16) with HbSS or Sβ0-thalassemia and abnormal TCD (time-averaged mean velocity ≥200 cm/s in ICA or MCA) randomized at 14 US and Canadian centers.
- Stopped early by DSMB: 11 strokes in observation group vs 1 in transfusion group (92% risk reduction, p<0.001). The single stroke in the transfusion group occurred when transfusion was temporarily interrupted.
- TCD screening identified ~10% of screened children as high-risk (≥200 cm/s). Without transfusion, stroke rate was ~10%/year in this group — one of the highest stroke rates in any population.
- Transfusion target: reduce HbS to <30% with regular simple or exchange transfusions every 3–4 weeks. This became the standard protocol for primary stroke prevention in SCD worldwide.
- Established TCD as a standard screening tool — AHA/ASA guidelines now recommend annual TCD screening starting at age 2 for all children with HbSS or Sβ0-thalassemia (Class I, Level A evidence).
- Led directly to STOP II (2005), which showed that discontinuing transfusions after TCD normalization led to reversion to abnormal velocities in 39% and strokes — establishing that transfusion must be continued indefinitely.
- Raised critical questions about transfusion burden: iron overload requiring chelation therapy, alloimmunization risk, infection risk, and quality of life impact of lifelong transfusions.
- Hydroxyurea later emerged as an alternative in the TWiTCH trial (2016) for children with no MRA vasculopathy — but STOP transfusion remains standard for highest-risk patients.
- One of the most impactful pediatric neurology trials ever — transformed SCD stroke from a common devastating complication to a largely preventable disease when screening is implemented.
Study Design
- Study Type
- Prospective, randomized, controlled, multi-center treatment trial.
- Randomization
- Yes
- Blinding
- Blinded reading of TCDs and blinded adjudication of endpoints.
- Sample Size
- 130
- Follow-up
- Observation for stroke from entry through month 54.
- Centers
- Not specified
Primary Outcome
Definition: First cerebral infarction (ischemic or hemorrhagic stroke) confirmed by clinical presentation and CT/MRI.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 11 strokes in 67 patients (16.4%) | 1 stroke in 63 patients (1.6%) | - | <0.001 |
Limitations & Criticisms
- Small sample size (130 patients) — while the 92% risk reduction was overwhelming, the trial was underpowered for subgroup analyses and rare adverse events.
- Open-label design — families and clinicians knew treatment allocation, potentially affecting reporting of neurological symptoms and threshold for imaging.
- US/Canada only enrollment — generalizability to African, Caribbean, and other populations with high SCD burden but different healthcare infrastructure is uncertain.
- No blinding of TCD operators — knowledge of treatment allocation could theoretically bias velocity measurements and endpoint adjudication.
- Does not address the DURATION of transfusion — STOP established that transfusion prevents stroke but did not define when/if it could be stopped (STOP II later showed it cannot).
- Iron overload burden not fully characterized — the lifelong transfusion commitment creates substantial iron chelation requirements, quality-of-life impact, and healthcare costs not captured in the trial.
- Does not address hydroxyurea as an alternative — the trial predated widespread hydroxyurea use in SCD, leaving the question of whether a less burdensome therapy could achieve similar results (later addressed by TWiTCH).
- TCD screening requires trained operators and standardized protocols — implementation in resource-limited settings where SCD is most prevalent remains challenging.
- Selection of ≥200 cm/s threshold — while validated, some children below this threshold still develop strokes, suggesting the screening misses a proportion of at-risk patients. Conditional (170–199 cm/s) velocities have uncertain management.
Citation
Adams RJ, et al. N Engl J Med 1998;339:5-11.