Key result
Switching to hydroxyurea matches transfusions for maintaining transcranial Doppler velocities in pediatric sickle cell anemia.
Why the study?
The efficacy of hydroxyurea compared to chronic transfusions for maintaining transcranial Doppler flow velocities and preventing primary stroke in children with sickle cell anaemia was unknown.
Does hydroxyurea safely maintain transcranial Doppler velocities and prevent primary stroke compared to continued chronic blood transfusions in children with sickle cell anaemia?
RCT (n=121)
Open-label (with centrally masked outcome assessment)
1:1 blocked and stratified by site, using an adaptive randomization scheme
Yes
Does hydroxyurea safely maintain transcranial Doppler velocities and prevent primary stroke compared to continued chronic blood transfusions in children with sickle cell anaemia?
Hydroxyurea represents an effective, non-inferior alternative to lifelong chronic blood transfusions for managing stroke risk in high-risk children with sickle cell anemia lacking severe vasculopathy.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The primary question addressed by Russell Ware and colleagues was exactly that asked by every family when told that their child has a high TCD velocity needing blood transfusion therapy to prevent a first-time stroke: how long must my child be on blood transfusion therapy? Until now, the unsatisfactory answer has been, indefinitely.”
“The authors conclude non-inferiority of hydroxyurea to transfusions; however, this might have been observed because of the following study design factors. An intention-to-treat analysis was used that would predictably favour the hydroxyurea group (anti-conservative) when used with a non-inferiority model.”
“This is a landmark trial that will have a lasting impact on primary prevention of strokes in thousands of children in high-income countries. Due to the early cessation of the trial, the remaining question is the permanence of hydroxyurea therapy for primary stroke prevention in children with elevated TCD measurements. Hopefully the investigators can continue to formally follow TWiTCH participants for a longer span of time to determine the long-term benefits and risks, if any, of being treated for an indefinite period on hydroxyurea therapy.”
Supports hydroxyurea substitution to minimize transfusion burden and iron overload; extends randomized evidence for primary stroke prevention in sickle cell anaemia.
Background For children with sickle cell anaemia and elevated transcranial Doppler (TCD) flow velocities, regular blood transfusions effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxyurea in this setting is unknown. Methods TWiTCH was a multicentre Phase III randomised open label, non-inferiority trial comparing standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with abnormal TCD velocities but no severe vasculopathy. Iron overload was managed with chelation (Standard Arm) and serial phlebotomy (Alternative Arm). The primary study endpoint was the 24-month TCD velocity calculated from a general linear mixed model, with non-inferiority margin = 15 cm/sec. Findings Among 121 randomised participants (61 transfusions, 60 hydroxyurea), children on transfusions maintained <30% sickle haemoglobin, while those taking hydroxyurea (mean 27 mg/kg/day) averaged 25% fetal haemoglobin. The first scheduled interim analysis demonstrated non-inferiority, and the sponsor terminated the study. Final model-based TCD velocities (mean ± standard error) on Standard versus Alternative Arm were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively, with difference (95% CI) = 4.54 (0.10, 8.98), non-inferiority p=8.82 × 10−16 and post-hoc superiority p=0.023. Among 29 new neurological events adjudicated centrally by masked reviewers, no strokes occurred but there were 3 transient ischaemic attacks per arm. Exit brain MRI/MRA revealed no new cerebral infarcts in either arm, but worse vasculopathy in one participant (Standard Arm). Iron burden decreased more in the Alternative Arm, with ferritin difference −1047 ng/mL (−1524, −570), p<0.001 and liver iron difference −4.3 mg Fe/gm dry weight (−6.1, −2.5), p=0.001. Interpretation For high-risk children with sickle cell anaemia and abnormal TCD velocities, after four years of transfusions and without severe MRA vasculopathy, hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke.
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Ware et al. (2015) conducted an RCT in Sickle cell anaemia with abnormal transcranial Doppler velocities (n=121). Hydroxyurea vs. Standard chronic blood transfusions plus iron chelation was evaluated on 24-month transcranial Doppler time-averaged mean velocity on the index side (Mean difference 4.54 cm/sec, 95% CI 0.10-8.98, p=8.82 × 10−16 for non-inferiority). In children with sickle cell anaemia, switching to hydroxyurea was non-inferior to continued blood transfusions for maintaining transcranial Doppler velocities (difference 4.54 cm/sec, p=8.82 × 10−16).
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