ALBERT

Description: Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established routine transcranial Doppler ultrasound (TCD) screening with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. To identify children at high-risk of stroke, annual TCD screening is recommended from ages 2 to 16 years, with more frequent monitoring if the result is not normal. A reduction in stroke incidence in children with SCD has been reported in several clinical series and analyses utilizing large hospital databases when comparing rates before and after the publication of the STOP study in 1998. We sought to determine the rate of first ischemic stroke in a multicenter cohort of children who had previously participated in the STOP and/or STOP 2 trials and to determine whether these strokes were screening or treatment failures. Subjects and Methods: Between 1995 and 2005, STOP and STOP 2 (STOP/2) were conducted at 26 sites in the US and Canada. These studies included 3,835 children, ages 2 to 16 y with SCD type SS or S-beta-0-thalassemia. Participation in STOP/2 ranged from a single screening TCD to randomization. STOP 2 also had an observational arm for children on CRCT for abnormal TCD whose TCD had not reverted to normal. The Post-STOP study was designed to follow-up the outcomes of children who participated in one or both trials. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3,539 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 (depending on site) including follow-up TCD and brain imaging results, clinical information, and laboratory results. Two vascular neurologists, blinded to STOP/2 status and prior TCD and neuroimaging results, reviewed source records to confirm all ischemic strokes, defined as a symptomatic cerebral infarction; discordant opinions were resolved through discussion. For the first Post-STOP ischemic stroke, prior TCD result and treatment history subsequently were analyzed. Results: Of the 3,539 subjects, follow-up data were available for 2,850 (81%). Twelve children who had a stroke during STOP or STOP2 were excluded from these analyses resulting in data on 2,838 subjects. The mean age at the start of Post-STOP was 10.5 y and mean duration of follow-up after exiting STOP/2 was 9.1 y. A total of 69 first ischemic strokes occurred in the Post-STOP observation period (incidence 0.27 per 100 pt years). The mean age at time of stroke was 14.4±6.2 (median 13.8, range 3.5-28.9) y. Twenty-five of the 69 patients (36%) had documented abnormal TCD (STOP/2 or Post-STOP) prior to the stroke; 15 (60%) were receiving CRCT and 9 (36%) were not (treatment data not available for 1 subject). Among the 44 subjects without documented abnormal TCD, 29 (66%) had not had TCD re-screen in the Post-STOP period prior to the event; 7 of these 29 (24%) were 16 y or older at the start of Post-STOP, which is beyond the recommended screening age. Four of the 44 (9%) patients had inadequate TCD in Post-STOP (1 to 10.7 y prior to event). Six (14%) had normal TCD more than a year before the event (1.2 - 4 y); all but one of these children were younger than 16 y at the time of that TCD. Only 5 (11%) had a documented normal TCD less than 1 year prior to the event. Conclusions: In the Post-STOP era, the rate of first ischemic stroke was substantially lower than that reported in the Cooperative Study of Sickle Cell Disease, prior to implementation of TCD screening. Many (39%) of the Post-STOP ischemic strokes were associated with a failure to re-screen according to current guidelines, while only 11% occurred in children who had had recent low-risk TCD. Among those known to be at high risk prior to stroke, treatment refusal or inadequate treatment may have contributed. While TCD screening and treatment are effective at reducing ischemic stroke in clinical practice, significant gaps in screening and treatment, even at sites experienced in the STOP protocol, remain to be addressed. Closing these gaps should provide yet further reduction of ischemic stroke in SCD. Disclosures No relevant conflicts of interest to declare.

Description: Background: Factors influencing participation in clinical trials have been reported, but few studies analyze the combination of issues which affect overall patient accrual. When designing clinical trials, investigators are aware that some potential subjects may not be candidates for research participation and other subjects will decline. Total sample size is further affected by protocol-defined eligibility. BABY HUG (NCT00006400) is a randomized, double-blind, placebo-controlled Phase III clinical trial of hydroxyurea (HU), which had an enrollment goal of 200 infants, age 9–17 mo, with Hb SS or Sβ0-thalassemia. A number of screening tests (spleen scan, 99mTc-DTPA renal clearance, abdominal sonogram, transcranial Doppler ultrasound, neuropsychological testing, blood analyses) were required prior to study entry and at exit, with at least monthly follow-up visits during the 2-year study period. To enhance recruitment, an anonymized registry of potential subjects was created to identify factors affecting enrollment. Methods: BABY HUG study coordinators considered all infants with an FS/SS diagnosis on newborn screening who were less than age 17 mo. The coordinators developed an IRB-approved spreadsheet to record the number of potentially eligible subjects; whether parents were approached and, if not, why not; and reasons of those approached for participating or declining. Most of these reasons could be categorized into one of several common themes. Results: Of 1107 potential participants (23–132/center) identified between October 2003 and June 2007, 239 (22%) entered the screening process and 193 (17%) were randomized. More than 25% were not approached for various reasons, including poor adherence to standard clinical care or failing to meet eligibility criteria. Factors influencing enrollment decisions are shown in the figure. The willingness to contribute to medical knowledge, the hope of being randomized to receive the investigational drug (HU), and the desire for closer clinical care were the most common reasons for participating in BABY HUG. Conversely, fear of research, transportation problems, parental work schedules and the demanding nature of the study (with frequent blood samples and clinic visits) were the primary reasons for parents declining. Disease severity had less impact on decision-making, perhaps reflecting the often asymptomatic history of potential subjects. Conclusion: The time and effort required by multiple screening tests and frequent visits impact the willingness of eligible subjects to participate in a study. Similar trials may require a larger pool of potential participants than expected to meet accrual goals. Factors that influence subject availability and the decision-making process of participating families must be considered for successful recruitment. Figure Figure

Description: Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) study established routine transcranial Doppler ultrasound (TCD) screening with indefinite transfusions for children with abnormal TCD as standard of care. Children with normal TCD studies have the lowest risk of stroke of ~0.5-1% per year (y). Annual TCD screening is usually recommended for these children to detect possible subsequent conversion to high risk. We sought to determine the frequency of TCD screening utilized in “real world” clinical practice and the TCD outcomes for children with prior normal TCD. Subjects and Methods: During STOP and STOP2 (STOP/2), 3,837 children, ages 2 to 16 y with sickle cell disease type SS or S-Beta-0-thalassemia underwent screening TCD. The Post-STOP study was designed to follow-up the outcomes of children who were screened for or participated in one or both of these randomized trials. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3,541 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 (depending on site) on follow-up TCD results and clinical information using standard data collection forms. The rates of TCD re-screening and the proportion of children who converted to abnormal TCD were calculated. Factors associated with conversion to abnormal TCD were assessed. Results: Of the 3,541 subjects, follow-up data were available for 2,838 (80%). The mean age at the last TCD study obtained in STOP/2 was 9.5 y and the mean age at last follow-up in Post-STOP was 19.6 y. The mean duration of follow-up after exiting STOP/2 was 9.2 y. Subjects were classified by their worst TCD in STOP/2: the TCD was normal in 1,814 (64%), conditional in 479 (17%), abnormal in 357 (13%) and inadequate 188 (7%). Among the 1,814 children with only normal studies in STOP/2, follow-up TCD screening was obtained in the Post-STOP era on 842 (46%) at a median rate of 0.28 TCD studies/y (range, 0.05-3.04/y). Among these children, 26 (3.1%) developed an abnormal TCD at a median of 11.5 y (2.2-18.2 y) from the last STOP/2 study, while 77.5% still had normal TCD at a median of 10.7 y (0.7-18.3 y) from last STOP/2 study. The worst follow-up TCD classification for this group with prior normal TCD was conditional in 9.7% and inadequate in 9.6%. Among those that converted from prior normal to abnormal TCD, 12 had an interval conditional study (at median 2.8 y, 0.98-9.2 y) while 14 children converted from normal to abnormal at a median of 4.2 y (1.4-12.7 y) without documented interval conditional study. Children who developed abnormal TCD were younger at STOP/2 study exit (4.9 vs. 7.8 y, p

Description: Background: Primary hemorrhagic stroke is a rare complication of sickle cell disease (SCD) that usually occurs in adults. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established routine transcranial Doppler ultrasound (TCD) screening with indefinite chronic red cell transfusions (CRCT) for patients with abnormal TCD as standard of care. Despite a notable improvement in the incidence of infarctive stroke in children with SCD after the introduction of TCD screening protocols, it is unclear how this protocol will affect the rate of hemorrhagic stroke. Presumably, early TCD screening and subsequent initiation of CRCT in high risk patients will prevent the progression of cerebral vasculopathy, which should decrease the risk of hemorrhagic stroke; however this has not been proven. Using the large multicenter cohort of children who participated in STOP and/or STOP 2 trials, we sought to assess whether the rate of hemorrhagic stroke was impacted by the use of TCD screening and/or CRCT. Subjects and Methods: Between 1995 and 2005, STOP and STOP 2 (STOP/2) were conducted at 26 sites in the US and Canada. These studies included 3835 children, ages 2 to 16 y with SCD type SS or S-beta-0-thalassemia. Participation in STOP/2 required at least a single screening TCD for randomization. Patients on STOP 2 also had an observational arm for children started on CRCT who had an abnormal TCD. The Post-STOP study was designed to follow-up the outcomes of children who participated in one or both of trials. For all participants the date of their last encounter in STOP/2 was defined as the start of their Post-STOP period. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3539 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 including follow-up TCD and brain imaging results, clinical information, and laboratory results. Two separate neurologists, blinded to STOP/2 status and prior TCD and neuroimaging results adjudicated all suspected strokes. Results: Follow-up data were available for 2850 of the 3539 subjects (81%). Twelve children who had a stroke during the STOP study period were further excluded from this analysis resulting 2838 subjects. The mean age at the start of Post-STOP was 10.5 years and mean duration of follow-up after exiting STOP/2 until time of last medical encounter was 9.1 years. A total of 31 patients had a primary hemorrhagic stroke during the Post-STOP observation period (incidence 0.12 per 100 pt years). The mean age at time of stroke was 16.2+5.6 (median 15.3 range (4.8-30.2) years of age. Of those 31 patients, only 52% had a TCD during Post-STOP prior to the event. Seven of those children who underwent screening had documentation of an abnormal TCD prior to the event (5 during STOP era and/or 3 Post-STOP). However, only 1/7 patients (14%) were documented on CRCT at the time of the stroke (4 patients were receiving HU and 2 patients had unknown treatment). Discussion: Although less common than infarctive stroke, patients with SCD are at increased risk for hemorrhagic stroke. There is an increased risk of mortality for patients who suffer from hemorrhagic stroke (up to 26% in some reports in the 2 weeks after the event). It is unclear if TCD screening and subsequent initiation of CRCT will impact the rate of hemorrhagic stroke in the long term. In our results, a similar incidence of primary hemorrhagic stroke was noted although the patients were overall younger than previously reported (16.5+/- 5.5 years versus 20-29 years in Cooperative Study of Sickle Cell Disease). Many patients who had a hemorrhagic stroke (48%) had not undergone TCD screening during the Post-Stop period. Additionally, although a safe stopping point for CRCT has not been established in patients who have had an abnormal TCD, only 1 patient was documented on CRCT at the time of the event (14%). Thus, it is unclear at this time whether TCD screening and subsequent, lifelong continuation of CRCT could have prevented these other events. Clearly, these results demonstrate that improved implementation of STOP protocol is needed as well as further evaluation of the impact of this protocol on the incidence of hemorrhagic stroke. Disclosures No relevant conflicts of interest to declare.