Initiating adjunct low-dose hydroxyurea therapy for stroke prevention in children with SCA during the COVID-19 pandemic.
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ABSTRACT:
SUBMITTER: DeBaun MR
PROVIDER: S-EPMC7256359 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionStroke is a severe complication of sickle cell anemia (SCA), with devastating sequelae. Transcranial Doppler (TCD) ultrasonography predicts stroke risk, but implementing TCD screening with suitable treatment for primary stroke prevention in low-resource environments remains challenging. SPHERE (NCT03948867) is a prospective phase 2 open-label hydroxyurea trial for SCA in Tanzania.MethodsAfter formal training and certification, local personnel screened children 2-16 years old; those with conditional (170-199 cm/s) or abnormal (≥200 cm/s) time-averaged mean velocities (TAMVs) received hydroxyurea at 20 mg/kg/day with dose escalation to maximum tolerated dose (MTD). The primary study endpoint is change in TAMV after 12 months of hydroxyurea; secondary endpoints include SCA-related clinical events, splenic volume and function, renal function, infections, hydroxyurea pharmacokinetics, and genetic modifiers.ResultsBetween April 2019 and April 2020, 202 children (average 6.8 ± 3.5 years, 53% female) enrolled and underwent TCD screening; 196 were deemed eligible by DNA testing. Most had numerous previous hospitalizations and transfusions, with low baseline hemoglobin (7.7 ± 1.1 g/dL) and %HbF (9.3 ± 5.4%). Palpable splenomegaly was present at enrollment in 49 (25%); average sonographic splenic volume was 103 mL (range 8-1,045 mL). TCD screening identified 22% conditional and 2% abnormal velocities, with hydroxyurea treatment initiated in 96% (45/47) eligible children.ConclusionSPHERE has built local capacity with high-quality research infrastructure and TCD screening for SCA in Tanzania. Fully enrolled participants have a high prevalence of elevated baseline TCD velocities and splenomegaly. SPHERE will prospectively determine the benefits of hydroxyurea at MTD for primary stroke prevention, anticipating expanded access to hydroxyurea treatment across Tanzania.
| S-EPMC10100573 | biostudies-literature
Project description:This study investigated the effects of hydroxyurea (HU) on hematological, biochemical and inflammatory parameters in children with sickle cell anemia (SCA) in association with βS haplotype and α-thalassemia. We included 22 children with SCA who were followed for an average of 14.5 months. Laboratory parameters were assessed by electronic methods, and molecular analysis was investigated by PCR-RFLP and allele-specific PCR. Results showed significant increases in hemoglobin, HbF, hematocrit, MCV, MCH, glucose, HDL-C and albumin levels, as well as significant decreases in MCHC and AST levels, WBC, neutrophils, eosinophils, lymphocytes and reticulocytes, in children during HU therapy. HbF levels were positively correlated with hemoglobin, hematocrit, MCV and total protein, yet negatively correlated with MCHC, RDW, AAT and AST during HU therapy (p<0.05). Children who carried the Central African Republic haplotype, in response to HU therapy, presented significant increases in hemoglobin, hematocrit, triglycerides and uric acid levels, as well as significant decreases in MCHC, AST and direct bilirubin levels, WBC, neutrophils, eosinophils, lymphocytes and reticulocytes. Those with the Benin haplotype presented increases in HbF and albumin levels, and a reduction in platelet counts (p<0.05). Children with α-thalassemia presented decreased ALT during HU use, while those without this deletion presented increases in hemoglobin, hematocrit, MCV, MCH, HDL-C and albumin, as well as decreases in MCHC, neutrophils, lymphocytes, reticulocytes and AST (p<0.05). Hence, regardless of its use in association with βS haplotypes or α-thalassemia, HU seems to be linked to alterations in hemolytic, inflammatory, hepatic, lipid and glycemic profiles.
| S-EPMC6629070 | biostudies-literature
Project description: Not available
| S-EPMC8697367 | biostudies-literature
Project description:BackgroundIn high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. In Africa, where regular blood transfusion is not feasible for most children, we tested the hypothesis that initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities.MethodsSPRING is a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5-12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, we used a permuted block allocation scheme with block sizes of four, stratified by sex and site. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 1:1 ratio to low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea taken once daily with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. The secondary outcome was all-cause hospitalisation. We used the intention-to-treat population for data analysis. The trial was stopped early for futility after a planned minimum follow-up of 3·0 years to follow-up for participants. This trial was registered with ClinicalTrials.gov, number NCT02560935.FindingsBetween Aug 2, 2016, and June 14, 2018, 220 participants (median age 7·2 years [IQR 5·5-8·9]; 114 [52%] female) were randomly allocated and followed for a median of 2·4 years (IQR 2·0-2·8). All participants were Nigerian and were from the following ethnic groups: 179 (82%) people were Hausa, 25 (11%) were Fulani, and 16 (7%) identified as another ethnicity. In the low-dose hydroxyurea group, three (3%) of 109 participants had strokes, with an incidence rate of 1·19 per 100 person-years and in the moderate-dose hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1·92 per 100 person-years (incidence rate ratio 0·62 [95% CI 0·10-3·20], p=0·77). The incidence rate ratio of hospitalisation for any reason was 1·71 (95% CI 1·15-2·57, p=0·0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27·43 vs 16·08). No participant had hydroxyurea treatment stopped for myelosuppression.InterpretationCompared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke.FundingNational Institute of Neurological Disorders and Stroke.
| S-EPMC10072240 | biostudies-literature
Project description:BackgroundTranscranial Doppler screening with chronic transfusions reduces stroke risk in children with sickle cell anaemia but is not feasible in low-resource settings. Hydroxyurea is an alternative treatment to decrease stroke risk. We aimed to estimate stroke risk in children with sickle cell anaemia in Tanzania and to determine the efficacy of hydroxyurea to decrease and prevent stroke.MethodsWe did an open-label, phase 2 trial (SPHERE) at Bugando Medical Centre, Mwanza, Tanzania. Children aged 2-16 years with a diagnosis of sickle cell anaemia confirmed by haemoglobin electrophoresis were eligible for enrolment. Participants had transcranial Doppler ultrasound screening by a local examiner. Participants with elevated Doppler velocities, either conditional (170-199 cm/s) or abnormal (≥200 cm/s), received oral hydroxyurea starting at 20 mg/kg once daily and escalated every 8 weeks by 5 mg/kg per day to the maximum tolerated dose. Participants with normal Doppler velocities (<170 cm/s) received usual care from the sickle cell anaemia clinic and were rescreened after 12 months to determine whether they qualified for treatment on trial. The primary endpoint was change in transcranial Doppler velocity from the baseline visit to after 12 months of hydroxyurea treatment, analysed in all patients who had paired baseline and follow-up measurements collected after 12 months of treatment. Safety was analysed in the per-protocol population (all participants who received study treatment). This study is registered with ClinicalTrials.gov, NCT03948867.FindingsBetween April 24, 2019, and April 9, 2020, 202 children were enrolled and had transcranial Doppler screening. Sickle cell anaemia was confirmed by DNA-based testing in 196 participants (mean age 6·8 years [SD 3·5], 103 [53%] were female, and 93 [47%] were male). At the baseline screening, 47 (24%) of 196 participants had elevated transcranial Doppler velocities (43 [22%] conditional, four [2%] abnormal); 45 initiated hydroxyurea at a mean dose of 20·2 mg/kg per day (SD 1·4) with escalation to a mean dose of 27·4 mg/kg per day (5·1) after 12 months. Treatment response was analysed after 12 months (± 1 month; median 11 months, IQR 11-12) and 24 months (±3 months; median 22 months, 22-22). Transcranial Doppler velocities decreased to a mean of 149 cm/s (SD 27) compared with 182 cm/s (12) at baseline, which was significantly lower than baseline (p<0·0001), with an average decline of 35 cm/s (SD 23) after 12 months of treatment in 42 participants with paired results available at baseline and 12 months. No clinical strokes occurred, and 35 (83%) of 42 participants reverted to normal transcranial Doppler velocities. Clinical adverse events were mild, and dose-limiting toxicities were uncommon. The most common grade 3 adverse events were malaria (12 [29%] episodes in 45 patients) and sepsis (13 [32%] episodes). There were three serious adverse events, none of which were treatment-related, and no treatment-related deaths occurred.InterpretationChildren with sickle cell anaemia in Tanzania have a high baseline stroke risk. Hydroxyurea at the maximum tolerated dose significantly lowers transcranial Doppler velocities and reduces primary stroke risk. Transcranial Doppler screening plus hydroxyurea at the maximum tolerated dose is an effective stroke prevention strategy, supporting wider hydroxyurea access for patients with sickle cell anaemia across sub-Saharan Africa.FundingAmerican Society of Hematology, National Institutes of Health, Cincinnati Children's Research Foundation.
| S-EPMC10132280 | biostudies-literature
Project description: Not available
| S-EPMC7520898 | biostudies-literature
Project description: Not available
| S-EPMC7316219 | biostudies-literature
Project description:Approximately 5% to 10% of children with Down syndrome (DS) are diagnosed with transient myeloproliferative disorder (TMD). Approximately 20% of these patients die within 6 months (early death), and another 20% to 30% progress to myeloid leukemia (ML-DS) within their first 4 years of life. The aim of the multicenter, nonrandomized, historically controlled TMD Prevention 2007 trial was to evaluate the impact of low-dose cytarabine treatment on survival and prevention of ML-DS in patients with TMD. Patients received cytarabine (1.5 mg/kg for 7 days) in case of TMD-related symptoms at diagnosis (high white blood cell count, ascites, liver dysfunction, hydrops fetalis) or detection of minimal residual disease (MRD) 8 weeks after diagnosis. The 5-year probability of event-free and overall survival of 102 enrolled TMD patients was 72 ± 5% and 91 ± 3%, respectively. In patients eligible for treatment because of symptoms (n = 43), we observed a significantly lower cumulative incidence (CI) of early death as compared with symptomatic patients in the historical control (n = 45) (12 ± 5% vs 33 ± 7%, PGray = .02). None of the asymptomatic patients in the current study suffered early death. However, the treatment of symptomatic or MRD-positive patients did not result in a significantly lower CI of ML-DS (25 ± 7% [treated] vs 14 ± 7% [untreated], PGray = .34 [per protocol analysis]; historical control: 22 ± 4%, PGray = .55). Thus, low-dose cytarabine treatment helped to reduce TMD-related mortality when compared with the historical control but was insufficient to prevent progression to ML-DS. This trial was registered at EudraCT as #2006-002962-20.
| S-EPMC6039662 | biostudies-literature
Project description:Hydroxyurea is widely used in high-income countries for the management of sickle cell disease (SCD) in children. In Kenyan clinical guidelines, hydroxyurea is only recommended for adults with SCD. Yet many deaths from SCD occur in early childhood, deaths that might be prevented by an effective, disease modifying intervention. The aim of this review was to summarise the available evidence on the efficacy, effectiveness and safety of hydroxyurea in the management of SCD in children below 5 years of age to support guideline development in Kenya. We undertook a systematic review and used the Grading of Recommendations Assessment, Development and Evaluation system to appraise the quality of identified evidence. Overall, available evidence from 1 systematic review (n=26 studies), 2 randomised controlled trials (n=354 children), 14 observational studies and 2 National Institute of Health reports suggest that hydroxyurea may be associated with improved fetal haemoglobin levels, reduced rates of hospitalisation, reduced episodes of acute chest syndrome and decreased frequency of pain events in children with SCD. However, it is associated with adverse events (eg, neutropenia) when high to maximum tolerated doses are used. Evidence is lacking on whether hydroxyurea improves survival if given to young children. Majority of the included studies were of low quality and mainly from high-income countries. Overall, available limited evidence suggests that hydroxyurea may improve morbidity and haematological outcomes in SCD in children aged below 5 years and appears safe in settings able to provide consistent haematological monitoring.
| S-EPMC3812872 | biostudies-other
Project description:Low-dose aspirin is recommended to reduce the risk of cardiovascular disease. However, the questions with regard to primary prevention have been raised among patients with diabetes. We evaluated low-dose aspirin use for preventing ischemic stroke in patients with diabetes using a national health insurance database.Using data from the Korean Health Insurance Review and Assessment Service database from January 1, 2005, through December 31, 2009, a population-based retrospective cohort study was conducted with incident patients with diabetes aged 40 to 99 years old with the initial use of low-dose aspirin during the index period from January 1, 2006 to December 31, 2007. We matched each low-dose aspirin user to one non-user using a propensity score. The Cox proportional hazards model was used to compare the risk of hospitalization for ischemic stroke in users and nonusers of low-dose aspirin until December 31, 2009.Out of 261,065 incident patients with diabetes, 15,849 (6.2%) were low-dose aspirin users. Compared to non-users, the adjusted hazard ratio (95% confidence interval) of low-dose aspirin users for hospitalization due to ischemic stroke was 1.73 (95% CI; 1.41-2.12). In a sensitivity analysis of study subjects with more than 1 year follow-up periods, slightly higher adjusted hazard ratio (1.97, 95% CI; 1.51-2.62) was observed. In the subgroup analyses, there were no significant changes in the risk of hospitalization for ischemic stroke irrespective of gender, age, or comorbidity.In this study of patients with diabetes, the use of low-dose aspirin showed an increased risk of hospitalization for ischemic stroke. These results suggest that low-dose aspirin use for the primary prevention of ischemic stroke should be reconsidered in patients with diabetes.
| S-EPMC4346109 | biostudies-other