Therapy Preference and Outcomes of Hydroxyurea for Pediatric Patients with Silent Cerebral Infarcts

Introduction: The Silent Infarct Transfusion (SIT) Trial demonstrated that transfusion therapy over three years, as compared to no sickle cell disease (SCD) modifying therapy, reduces the risk of new CNS events, defined as an overt stroke or new or enlarged silent cerebral infarct (SCI), in patients with SCI on screening MRI. Despite the significant reduction in CNS events with transfusion therapy, patients/caregivers may choose to decline chronic transfusion therapy for secondary CNS events. Hydroxyurea is known to decrease complications of SCD, and while its impact on new CNS events in patients with a SCI has not been tested in a randomized trial, it was offered as an alternative for patients who declined transfusion therapy. We evaluated therapy preference for prevention of new CNS events among patients with SCI on screening MRI and three year outcomes of patients with SCI that elected treatment with hydroxyurea at our institution.

Methods: We performed a 15-year IRB approved retrospective chart review for all patients with the diagnosis of SCI at Children's of Alabama based on their original MRI report. Ninety-two patients were identified and subsequently confirmed by an additional pediatric radiologist to have suffered a SCI and had no history of a prior overt stroke while 39 patients were excluded because of their history of overt stroke prior to the detection of a SCI. We recorded the patient/caregiver initial preference for therapy and evaluated differences in therapy selection prior to, during, and post SIT Trial. We recommend annual or biennial follow-up MRI exams to evaluate for SCI progression and recorded and reviewed all subsequent MRIs and SCD therapies for overt stroke or new or enlarged SCI. To compare outcomes of hydroxyurea for secondary CNS events to the SIT Trial, we evaluated the 27 patients with SCI that were treated with hydroxyurea (HU) for their SCI and had a subsequent MRI/MRA at least three years after their initial diagnosis of SCI. Descriptive statistics and Fisher's exact test were performed using JMP10. Sample size was calculated for a superiority trial design using a power of 85% and alpha of 5% with PASS version 14.

Results: We evaluated patient/caregiver therapy preference for secondary SCI prevention among 54 patients that were not receiving a SCD modifying therapy at the time of their index SCI. We identified a significantly higher number of patients/caregivers who, after discussion with their primary SCD provider about therapeutic options, elected to initiate transfusion or enroll in the SIT Trial prior to and during SIT Trial enrollment but a higher percentage of patients/families that elected to initiate hydroxyurea after enrollment (p=0.04). Three of 36 patients (8%) elected hydroxyurea prior to and during SIT Trial enrollment as compared to 6 of 18 patients (33%) post enrollment. Among 27 participants on HU at the time of their incident SCI finding on MRI, 25 (93%) participants elected to remain on HU while only two (11%) participants elected to change to chronic transfusion therapy. The two patients that switched to transfusion also had MRA abnormalities identified at the time of their incident SCI finding. To evaluate outcomes of HU for secondary SCI prevention, 27 participants were prescribed HU for at least three years and underwent serial MRI evaluations. Three of these 27 participants developed a new SCI. Four participants had an abnormal MRA at the time of their index MRI and five patients developed an abnormal MRA on subsequent studies. The three participants that had an additional SCI had normal MRA examinations. In comparison to the SIT Trial, which identified 2.0 and 4.8 new CNS events per 100 patient years at risk for transfusion and no therapy respectively, we identified 3.7 new CNS events per 100 patient years among patients prescribed hydroxyurea. Combining our results with that of SIT Trial, a sample size of 1100 participants would be required to conduct a trial to show the superiority of transfusion over HU for secondary SCI.

Conclusion: While the SIT Trial showed chronic transfusion to be superior to no therapy in preventing new CNS events in patients with SCI, patients and caregivers at our institution prefer hydroxyurea to transfusion for initial therapy to prevent secondary CNS events. A randomized trial to show superiority of transfusion over hydroxyurea for secondary stroke prevention would require a sample size too large to be practical.