PDF: STOP II
(2005)Objective
Determine whether chronic transfusion therapy can be safely discontinued in children with sickle cell anemia and initially abnormal TCD velocities that normalize after transfusion.
Study Summary
• In children with sickle cell disease and previously abnormal TCD velocities that normalized after transfusion, discontinuing transfusion was associated with a high risk of reversion to abnormal velocities and recurrent stroke. Continued transfusion remained effective at preventing stroke.
Intervention
Randomized, multicenter trial of 79 children with sickle cell disease and abnormal baseline TCD who normalized after ≥30 months of transfusions. Randomized to continue transfusion vs. discontinue and observe. TCD monitoring and stroke surveillance were ongoing.
Study Design
Arms: Array
Outcome
• Stroke in 2 of 41 patients who discontinued transfusion vs. 0 of 38 who continued (P=0.10)
• 14 of 41 (34%) in discontinuation group reverted to abnormal TCD within a year
• 9 of 41 (22%) resumed transfusions due to TCD reversion
• Continued transfusion group had persistently low stroke risk
• Trial was stopped early due to increased stroke risk in discontinuation group
• 14 of 41 (34%) in discontinuation group reverted to abnormal TCD within a year
• 9 of 41 (22%) resumed transfusions due to TCD reversion
• Continued transfusion group had persistently low stroke risk
• Trial was stopped early due to increased stroke risk in discontinuation group
Bottom Line
Discontinuing prophylactic transfusions in children with sickle cell anemia, even after their TCD velocities have normalized, results in a high rate of reversion to abnormal high-risk velocities and stroke. The trial was stopped early for safety reasons, indicating that transfusion therapy should be continued indefinitely in this high-risk population.
Major Points
- STOP II definitively answered a critical clinical question: Can you STOP chronic transfusions after TCD normalizes in sickle cell disease? The answer is NO — 39% reverted to high-risk within a mean of only 4.5 months.
- Trial stopped prematurely after 79 of planned 100 patients — 16/41 (39%) in the transfusion-halted group had events (14 abnormal TCD, 2 strokes) vs 0/38 in continued transfusion (p<0.001).
- Companion to the original STOP trial (NEJM 1998), which showed TCD-guided prophylactic transfusion reduces stroke by 92% in sickle cell children. STOP II proves this benefit requires INDEFINITE transfusion.
- Events occurred rapidly — mean time to primary endpoint was only 4.5 months. This suggests ongoing vascular injury persists despite TCD normalization, and that TCD improvement reflects reduced blood velocity (lower HbS%) rather than structural vascular healing.
- The only baseline predictor of events was the pre-transfusion TCD velocity — patients with higher initial velocities were at greater risk of reversion, suggesting a dose-response relationship between vascular disease severity and treatment dependence.
- Established the clinical paradigm that chronic transfusion for stroke prevention in SCD is a LIFELONG commitment — raising major concerns about iron overload, alloimmunization, and transfusion access disparities.
- Led directly to investigation of alternatives to chronic transfusion: TWiTCH (NEJM 2016) showed hydroxyurea could replace transfusion in children with NORMAL MRA, and SCD-CURES-2 explored combination approaches.
- Iron overload was evident in both groups (ferritin >2,000 ng/mL) — highlighting the urgent need for chelation therapy and alternative stroke prevention strategies in SCD.
- All patients had received ≥30 months of prophylactic transfusions with HbS maintained <30% — the finding that this substantial treatment duration was insufficient for 'cure' was surprising and clinically important.
- Exclusion of patients with moderate-to-severe MRA lesions means STOP II applies to those with functional (hemodynamic) rather than structural vascular disease. Patients with fixed stenoses likely need even more aggressive management.
Study Design
- Study Type
- Randomized, controlled trial.
- Randomization
- Yes
- Blinding
- Blinded adjudication of TCD and imaging endpoints.
- Sample Size
- 79
- Follow-up
- Mean of 4.5 months to primary endpoint in the transfusion-halted group.
- Centers
- Multiple centers involved in the original STOP trial.
Primary Outcome
Definition: A composite of stroke (cerebral infarction or intracranial hemorrhage) or reversion to abnormal velocity on transcranial Doppler ultrasonography.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0% | 39% (16/41) | - | <0.001 |
Limitations & Criticisms
- Early termination (79 of 100 planned) — while ethically essential, limits precision of effect estimates and prevents assessment of longer-term outcomes in the continued-transfusion group.
- Small sample size limits power for subgroup analyses — cannot identify which patients (if any) might safely discontinue transfusion.
- Does not address alternatives to chronic transfusion — the question of whether hydroxyurea could substitute was unanswered until TWiTCH (2016). STOP II only compared continuing vs stopping transfusion.
- The primary endpoint combined TCD reversion with stroke — most events were TCD reversion (14/16), not stroke (2/16). TCD reversion is a surrogate that may overestimate clinical risk.
- No long-term follow-up beyond the short study period — cannot determine if continued transfusion patients eventually develop complications (iron overload, alloimmunization) that offset stroke prevention benefit.
- Iron overload was already severe at enrollment (ferritin >2,000 ng/mL) — the study did not systematically address chelation or assess organ damage from iron burden.
- Excluded patients with moderate-to-severe MRA lesions — these highest-risk patients may have different treatment dynamics. Results may not apply to children with structural vasculopathy.
- Generalizability limited to HbSS sickle cell anemia — does not address HbSC or sickle-beta thalassemia, which have different stroke risk profiles.
- The implication of indefinite transfusion raises equity concerns — chronic transfusion requires reliable blood supply, insurance coverage, and regular medical access, creating disparities in low-resource settings.
Citation
N Engl J Med 2005;353:2769-78.