Long Term Outcome of Patients Enrolled Into STOP and STOP II Trials: A Single Center Experience

Abstract ³²¹⁹

The landmark STOP trial established chronic transfusion as an effective therapeutic modality for primary stroke prevention in children with sickle cell disease (SCD) who are at risk for ischemic stroke as determined by elevated transcranial Doppler (TCD) velocities (>200 cm/sec) in major intracranial arteries. The ensuing STOP II trial sought to optimize the duration of chronic transfusion therapy for primary stroke prevention; however, the study was stopped early when 14/41 patients who discontinued transfusions after normalization of TCD reverted to high TCD velocities and 2 subjects had overt stroke. Since it is well known that not all subjects with high TCD velocities proceed to have overt stroke, it is important to refine the stroke risk among patients with high TCD velocities thereby limiting chronic transfusion to those at the highest risk, while minimizing complications of chronic transfusion (iron overload, alloimmunization, disease transmission). While additional analytic approaches such as the incorporation of MRI/MRA and genetic and genomic analyses have been applied to refine the risk of CVA and have yielded interesting results, these are far from definitive and conclusive. Therefore, to date, TCD velocity remains the gold standard for determining stroke risk in young SCD patients.

We performed a longitudinal follow up analysis of patients enrolled in STOP and STOP II studies from GHSU and report our results here. Twenty six patients (12 male, 14 female) were enrolled in these two trials from the GHSU Pediatric Sickle Cell Program; all had the Hb SS genotype. Of these, 23 patients participated in STOP, and 9 in STOP II, with six patients participating in both studies. The mean age at entry to STOP was 7.7 years and to STOP II was 10.6 years. Thirteen of the 26 patients (50%) are currently followed at GHSU Adult Sickle Cell Clinic. Two patients are deceased (cause of death unknown) and 11 are lost to follow up. The mean age of active patients is 23.8 years; median duration of follow-up is 16.2 years. Of the 13 active patients, 7 had normalized their TCD, 4 had conditional readings, and 2 continued to be abnormal (see table). Overall, 14 of the 26 patients enrolled in STOP and STOP II had normalized their TCD at the time of their last available study. Ten of these 14 patients were on transfusion for variable periods of time. A total of two patients had overt, symptomatic stroke during the observation period; one subject was randomized to transfusion, and the other to standard care while in STOP; one subject's last TCD was abnormal, the other was normal; neither of these patients were on HU at the time of stroke. The subject in the transfusion arm remained on transfusion for 3 years and had a stroke 2 months after discontinuing transfusion. Both strokes occurred in the territory of the vessel that had abnormal TCD reading. Of the 13 patients actively followed at GHSU Adult Sickle Cell Clinic, 12 are on Hydroxyurea therapy and are doing well.

Our observational study on long term follow up of pediatric SCD patients at risk for stroke determined by high TCD velocities in intracranial vessels suggests that few (2/13; 15.4%) develop overt stroke on long term follow up, following a variable period of primary stroke prophylaxis per STOP protocol with > 50% of patients normalizing their TCD over time. While it is encouraging that long-term HU therapy appears to be effective in preventing strokes in the majority of the patients, the numbers are too small for a definitive conclusion. The long term risks of CVA associated with high TCD velocities in childhood and its modifications by therapeutic interventions such as transfusions and HU therapy can be answered by similar longitudinal follow up studies of the entire STOP/STOP II cohort (such as the ongoing post-STOP study) and prospective studies such as TWiTCH.