Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial.
Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial.
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DOI：
10.1016/s2352-3026(21)00368-9
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发表时间：
2022-01
影响因子：
24.7
通讯作者：
DeBaun, Michael R.
中科院分区：
文献类型：
--
作者：
Abdullahi, Shehu U.;Jibir, Binta W.;Bello-Manga, Halima;Gambo, Safiya;Inuwa, Hauwa;Tijjani, Aliyu G.;Idris, Nura;Galadanci, Aisha;Hikima, Mustapha S.;Galadanci, Najibah;Borodo, Awwal;Tabari, Abdulkadir M.;Haliru, Lawal;Suleiman, Aisha;Ibrahim, Jamila;Greene, Brittany C.;Ghafuri, Djamila L.;Rodeghier, Mark;Slaughter, James C.;Kirkham, Fenelia J.;Neville, Kathleen;Kassim, Adetola;Trevathan, Edwin;Jordan, Lori C.;Aliyu, Mulctar H.;DeBaun, Michael R.
在高收入国家，对患有镰状细胞性贫血和经颅多普勒速度异常的儿童进行初级中风预防的标准护理可将中风相对风险降低 92%，但要求最初每月输血。在非洲，对大多数儿童来说定期输血是不可行的，我们测试了这样的假设：与低剂量羟基脲相比，初始中等剂量羟基脲可降低经颅多普勒速度异常儿童的中风发生率。 NCT02560935ClinicalTrials.gov 在 3 家教学医院对患有镰状细胞性贫血的 5-12 岁尼日利亚人进行了一项双盲、平行组随机对照试验。随机化采用块大小为 4 的排列块分配方案，按性别和地点分层。除了药剂师和统计学家之外，分配情况对所有人都保密。参与者按 1:1 的比例分配为低剂量（10 毫克/公斤/天）或中等剂量（20 毫克/公斤/天），每日一次口服羟基脲，每月进行临床评估和实验室监测。主要结局是初次卒中或短暂性脑缺血发作，由集中判定。次要结局包括全因住院治疗。使用意向治疗原则进行分析。该试验因参与者计划的最短随访时间为 3.0 年而实际中位随访时间为 2·4 年（IQR 2·0–2·8）后因徒劳而提前停止。 2016年8月2日至2018年6月14日期间，220名参与者（中位年龄7·2岁（IQR 5·5–8·9；114名，51·8％女性；）被随机分配并随访中位2·4年（IQR 2·0–2·8）。所有参与者均为尼日利亚人。种族包括豪萨族81％（n = 179）、富拉尼族11% (n=25)，其他 7% (n=16)。在低剂量（n=109）和中剂量（n=111）羟基脲组中，2·8%（3/109）和4·5%（5/111）发生卒中，发病率分别为每100人年1·19和1·92，发病率比为0·62（95%置信区间： 0·10–3·20，p=0·77）。因任何原因住院的发生率为1·71（95% CI，1·15–2·57；p=0·0071），其中低剂量组的发生率较高。没有参与者因骨髓抑制而停用羟基脲。与低剂量羟基脲治疗相比，中剂量羟基脲治疗 羟基脲对中风发生率没有差异。然而，中等剂量组的全因住院发生率较低。这些发现为有中风风险的镰状细胞性贫血儿童使用低剂量羟基脲治疗提供了循证指南。父母和医疗保健提供者之间的共同决策可能会导致羟基脲剂量增加至 20 毫克/公斤/天，如果事先 或随后住院率增加。国家神经疾病和中风研究所，ClinicalTrials.gov NCT02560935，招募已结束。
In 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 to low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities. A double-blind, parallel-group randomised controlled trial was conducted in Nigerians 5–12 years of age with sickle cell anaemia at 3 teaching hospitals NCT02560935ClinicalTrials.gov. Randomisation utilized a permuted block allocation scheme with block sizes of 4, 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/day) or moderate-dose (20 mg/kg/day) once daily oral hydroxyurea with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. Secondary outcomes included all-cause hospitalisation. Analyses were done using the intention-to-treat principle. The trial was stopped early for futility after a planned minimum follow-up of 3.0 years to an actual median of 2·4 years of follow-up (IQR 2·0–2·8) for participants. Between August 2, 2016, and June 14, 2018, 220 participants (median age 7·2 years (IQR 5·5–8·9; 114, 51·8% female;) were randomly allocated and followed for a median of 2·4 years (IQR 2·0–2·8). All participants were Nigerian. Ethnic groups included Hausa 81% (n=179), Fulani 11% (n=25), and other 7% (n=16). In the low- (n=109) and moderate-dose (n=111) hydroxyurea groups, 2·8% (3/109) and 4·5% (5/111) had strokes, with incidence rates 1·19 and 1·92 per 100 person-years respectively, incidence rate ratio 0·62 (95% confidence interval: 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 in the low-dose group. No participant had hydroxyurea stopped for myelosuppression. Compared to low-dose hydroxyurea therapy, moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, the moderate-dose group had lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of lower-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke. Shared decision-making between the parents and the health care provider may lead to an increase in hydroxyurea dose to 20mg/kg/day if prior or subsequent increased hospitalisation rate. National Institute of Neurological Disorders and Stroke, ClinicalTrials.gov NCT02560935, recruitment closed.