The TWiTCH Trial

In children with sickle cell disease, one of the most devastating long-term sequelae is a stroke. Prior to 1998, approximately 11 percent of the children with sickle cell disease would have strokes. Unfortunately for the majority of children, the only option of secondary stroke prevention was the burdensome responsibility of monthly blood transfusion therapy followed by the eventual requirement of iron chelation therapy. Without regular blood transfusion therapy, approximately 50 percent of the children would have a stroke recurrence within two years of the initial stroke, and a significant proportion would go on to have a third stroke or additional strokes. In 1998, the landmark STOP trial demonstrated that among children with sickle cell disease and elevated transcranial Doppler (TCD) measurements, regular blood transfusion therapy (experimental arm) resulted in a 92 percent relative risk reduction in strokes when compared with observation (standard arm). The impact of implementing TCD screening coupled with blood transfusion therapy has resulted in up to a log-fold decrease in the rate of strokes in children with sickle cell disease. However, the impact of decreasing the rate of strokes is not without its consequences, and the most significant of these is the commitment to lifelong blood transfusion therapy and chelation therapy for the majority of children treated with elevated TCD velocities.

With this background, Dr. Russell Ware and colleagues completed a randomized, open-label, noninferiority trial referred to as the TWiTCH (TCD With Transfusions Changing to Hydroxyurea) trial. The team tested the hypothesis that children with elevated TCD measurements (> 200 cm/sec nonimaging technique) who had been placed on blood transfusion therapy for primary stroke prevention could be safely switched to hydroxyurea therapy. The two arms of the trial were regular blood transfusion therapy with iron chelation (standard arm) versus hydroxyurea therapy and phlebotomy (experimental arm). The primary endpoint was the 24-month TCD velocity with a non-inferiority margin set at 15 cm/sec. A minimum of 12 months of blood transfusion therapy for elevated TCD measurements were required for inclusion and individuals with severe magnetic resonance angiogram-defined vasculopathy were excluded from the trial. The DSMB stopped the trial early because of the convincing evidence that the experimental arm was noninferior to the standard arm. Significantly, no strokes occurred in either arm, as would be expected because the stroke event rate in children with elevated TCD measurements treated with blood transfusion therapy is very low (0.06 to 0.9 events per 100 patient years), and the trial had a short follow-up with only 121 total participants. For children who met the inclusion and exclusion criteria, the main conclusion of the trial is that for children with sickle cell disease and high TCD velocities, maximum tolerated dose of hydroxyurea therapy is noninferior to blood transfusion.