SIT
(2014)Objective
To test whether regular blood transfusion therapy reduces the incidence of recurrence of cerebral infarct (stroke or new/enlarged silent cerebral infarct) in children with sickle cell anemia and silent cerebral infarcts
Study Summary
• Incidence: 2.0 vs 4.8 events per 100 person-years (transfusion vs observation)
• NNT of 13 for 3 years to prevent one infarct recurrence
Intervention
Regular blood transfusion therapy (target hemoglobin S ≤30%) vs standard care (observation)
Inclusion Criteria
Children 5-15 years with sickle cell anemia (HbSS or HbS-β0 thalassemia), ≥1 silent cerebral infarct on MRI, normal neurologic examination, no history of stroke
Study Design
Arms: Transfusion therapy vs Observation (standard care)
Patients per Arm: 99 transfusion, 97 observation
Outcome
• Stroke: 1 vs 7 patients
• New/enlarged SCI: 5 vs 7 patients
• Absolute risk reduction 8%, relative risk reduction 58%
Bottom Line
Regular blood transfusion therapy significantly reduced the incidence of infarct recurrence by 58% (from 14% to 6%) in children with sickle cell anemia and silent cerebral infarcts, with a number needed to treat of 13 for 3 years to prevent one recurrence. Transfusion also reduced rates of vaso-occlusive pain, acute chest syndrome, priapism, and avascular necrosis.
Major Points
- Primary endpoint (infarct recurrence) occurred in 6% of transfusion group vs 14% of observation group
- Incidence rate ratio 0.41 (95% CI 0.12-0.99, P=0.04), representing 58% relative risk reduction
- NNT for 3 years to prevent one infarct recurrence: 13
- Strokes occurred in 1 transfusion patient vs 7 observation patients
- New or enlarged silent cerebral infarcts: 5 transfusion vs 7 observation
- TIAs occurred only in observation group (3 patients)
- Significant reductions in vaso-occlusive pain (IRR 0.41), acute chest syndrome (IRR 0.13), priapism (IRR 0.13), and avascular necrosis (IRR 0.22)
- No deaths occurred during the trial
- Alloimmunization rate was 0.278 per 100 units with antigen-matched transfusions
- Younger age, recurring headaches, and higher reticulocyte count were associated with infarct recurrence
Study Design
- Study Type
- Multicenter, randomized, single-blind clinical trial
- Randomization
- Yes
- Blinding
- Single-blind. Neuroradiology and neurology committees adjudicating MRI findings and neurologic events were unaware of study-group assignments. Participants and treating physicians were not blinded.
- Sample Size
- 196
- Follow-up
- Median 3 years
- Centers
- 29
- Countries
- United States, Canada, France, United Kingdom
Primary Outcome
Definition: Recurrence of infarct or hemorrhage as determined by neuroimaging, clinical evidence of permanent neurologic injury, or both. Includes stroke, new silent cerebral infarct (≥3 mm, visible in two planes), or enlarged silent cerebral infarct (increased by ≥3 mm in any dimension).
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 14% (14/97); 4.8 events per 100 person-years at risk | 6% (6/99); 2.0 events per 100 person-years at risk | - (0.12-0.99) | 0.04 |
Limitations & Criticisms
- 15% crossover rate from transfusion to observation (9 declined immediately, 6 crossed over later)
- 32% of observation group received episodic transfusions; 6 crossed over to regular transfusions
- Open-label to participants and treating physicians
- Not powered to detect changes in IQ or cognitive outcomes
- Duration of blood transfusion therapy for secondary prevention unknown; minimum 3 years suggested
- Excluded children on hydroxyurea, with elevated TCD, or receiving transfusions for primary stroke prevention
- Results not directly applicable to all children with sickle cell anemia due to exclusion criteria
- Iron overload requiring chelation is a significant burden of transfusion therapy
- Two participants with TCD above eligibility threshold were inadvertently randomized due to programming error
Citation
N Engl J Med 2014;371:699-710