Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany.
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
Lancet Neurol. 2023 Nov;22(11):991-1004. doi: 10.1016/S1474-4422(23)00293-4.
Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease.
We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated.
Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10%/mm Hg [19·6; -45·5 to 31·1] for atenolol; p=0·39) but did differ in patients with CADASIL (15·7 × 10%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10%/mm Hg [27·5; -77·7 to 30·0] for atenolol; p=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake.
4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research.
EU Horizon 2020 programme.
高血压是导致小血管疾病的主要风险因素。我们旨在确定降压药物类别是否会对小血管疾病患者的微血管功能产生不同影响。
我们在欧洲的五个专业中心进行了一项多中心、开放标签、随机交叉试验，使用盲法终点评估。我们纳入了年龄在 18 岁及以上的、有症状的散发性小血管疾病或伴有皮质下梗死和白质脑病的脑常染色体显性动脉病（CADASIL）且需要降压治疗的患者。参与者按照 1:1:1 的比例随机分配（1:1:1）至三种降压治疗方案之一，使用计算机生成的多块随机化，按研究地点和患者群体分层。在洗脱期后，进行为期 4 周的单药治疗，分别使用氨氯地平、氯沙坦或阿替洛尔，剂量为批准剂量。主要终点是通过血氧水平依赖性 MRI 对正常外观白质的高碳酸血症反应来确定脑血管反应性（CVR）的变化，从洗脱结束到每个治疗期结束。在至少有一个主要终点的有效评估的所有随机分配参与者中，根据意向治疗原则进行疗效分析，分别对散发性小血管疾病和 CADASIL 患者进行分析。该试验在 ClinicalTrials.gov、NCT03082014 和 EudraCT 注册，注册号分别为 2016-002920-10，现已终止。
2018 年 2 月 22 日至 2022 年 4 月 28 日，75 名散发性小血管疾病患者（平均年龄 64.9 岁[9.9]）和 26 名 CADASIL 患者（53.1 岁[7.0]）入组并随机分配至治疗组。79 名参与者（62 名散发性小血管疾病患者和 17 名 CADASIL 患者）进入主要疗效分析。在散发性小血管疾病患者中，研究药物之间的 CVR 变化没有差异（氨氯地平组 CVR 变化为 1.8×10%/mmHg[SE 20.1；95%CI-37.6 至 41.2]；氯沙坦组 16.7×10%/mmHg[20.0；-22.3 至 55.8]；阿替洛尔组-7.1×10%/mmHg[19.6；-45.5 至 31.1]；p=0.39），但在 CADASIL 患者中存在差异（氨氯地平组 15.7×10%/mmHg[SE 27.5；95%CI-38.3 至 69.7]；氯沙坦组 19.4×10%/mmHg[27.9；-35.3 至 74.2]；阿替洛尔组-23.9×10%/mmHg[27.5；-77.7 至 30.0]；p=0.019）。在 CADASIL 患者中，两两比较显示与阿替洛尔相比，氨氯地平（-39.6×10%/mmHg[95%CI-72.5 至-6.6；p=0.019）和氯沙坦（-43.3×10%/mmHg[-74.3 至-12.3]；p=0.0061）可以改善 CVR。没有死亡发生。记录了两例严重不良事件，一例在服用氨氯地平期间（腹泻伴脱水），一例在服用阿替洛尔期间（跌倒伴骨折），均与研究药物摄入无关。
4 周的氨氯地平、氯沙坦或阿替洛尔治疗对散发性小血管疾病患者的脑血管反应性没有差异，但在 CADASIL 患者中产生了不同的治疗效果。降压药物类别是否会对小血管疾病患者的临床结局产生不同影响，还需要进一步研究。
欧盟地平线 2020 计划。
