TY - JOUR
T1 - Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs)
T2 - a multicentre, open-label, randomised, crossover trial
AU - Kopczak, Anna
AU - Stringer, Michael S.
AU - van den Brink, Hilde
AU - Kerkhofs, Danielle
AU - Blair, Gordon W.
AU - van Dinther, Maud
AU - Reyes, Carmen Arteaga
AU - Garcia, Daniela Jaime
AU - Onkenhout, Laurien
AU - Wartolowska, Karolina A.
AU - Thrippleton, Michael J.
AU - Kampaite, Agniete
AU - Duering, Marco
AU - Staals, Julie
AU - Lesnik-Oberstein, Saskia
AU - Muir, Keith W.
AU - Middeke, Martin
AU - Norrving, Bo
AU - Bousser, Marie Germaine
AU - Mansmann, Ulrich
AU - Rothwell, Peter M.
AU - Doubal, Fergus N.
AU - van Oostenbrugge, Robert
AU - Biessels, Geert Jan
AU - Webb, Alastair J.S.
AU - Wardlaw, Joanna M.
AU - Dichgans, Martin
AU - Muir, Keith
AU - Wardlaw, Joanna
AU - André, Elisabeth
AU - Kääb, Stefan
AU - Anders, Hans Joachim
AU - Hack, Remco
AU - Kaffe, Maria
AU - Dewenter, Anna
AU - Malik, Rainer
AU - TREAT-SVDs collaborators
N1 - Funding Information:
This study was funded by the EU's Horizon 2020 research and innovation programme under grant agreement number 666881. MD has received grants from the Vascular Dementia Research Foundation and the German Research Foundation (DFG) as part of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and DI 722/16-1 (ID 428668490/405358801), and for the procurement of the MRI scanner in Munich (DFG, INST 409/193-1 FUGG). JMW received funding from the UK Dementia Research Institute (which receives its funding from the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK), Fondation Leducq, UK Stroke Association and Garfield Weston Foundation, the Wellcome Trust and Dunhill Trust (which funded the MRI scanner in Edinburgh), and from the NIHR Biomedical Research Centre, Oxford, UK. AK was supported by the DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198). CAR is funded by the UK Dementia Research Institute, which receives funding from the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK, the Mexican National Council of Science and Technology, and the Anne Rowling Regenerative Neurology Clinic. KAW was supported by an Alzheimer's Society grant (450-AS-PG-18-018). MJT acknowledges financial support from the NHS Lothian Research and Development Office. We thank our serious adverse event assessors, the team at the Münchner Studienzentrum, all TREAT-SVDs collaborators, as detailed in the appendix (pp 5–7) , and the patients and their families for their participation.
Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/11/1
Y1 - 2023/11/1
N2 - Background: 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. Methods: 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. Findings: 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 × 10–4%/mm Hg [SE 20·1; 95% CI –37·6 to 41·2] for amlodipine; 16·7 × 10–4%/mm Hg [20·0; –22·3 to 55·8] for losartan; –7·1 × 10–4%/mm Hg [19·6; –45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10–4%/mm Hg [SE 27·5; 95% CI –38·3 to 69·7] for amlodipine; 19·4 × 10–4%/mm Hg [27·9; –35·3 to 74·2] for losartan; –23·9 × 10–4%/mm Hg [27·5; –77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (–39·6 × 10–4%/mm Hg [95% CI –72·5 to –6·6; p=0·019) and with losartan compared with atenolol (–43·3 × 10–4%/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. Interpretation: 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. Funding: EU Horizon 2020 programme.
AB - Background: 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. Methods: 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. Findings: 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 × 10–4%/mm Hg [SE 20·1; 95% CI –37·6 to 41·2] for amlodipine; 16·7 × 10–4%/mm Hg [20·0; –22·3 to 55·8] for losartan; –7·1 × 10–4%/mm Hg [19·6; –45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10–4%/mm Hg [SE 27·5; 95% CI –38·3 to 69·7] for amlodipine; 19·4 × 10–4%/mm Hg [27·9; –35·3 to 74·2] for losartan; –23·9 × 10–4%/mm Hg [27·5; –77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (–39·6 × 10–4%/mm Hg [95% CI –72·5 to –6·6; p=0·019) and with losartan compared with atenolol (–43·3 × 10–4%/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. Interpretation: 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. Funding: EU Horizon 2020 programme.
U2 - 10.1016/S1474-4422(23)00293-4
DO - 10.1016/S1474-4422(23)00293-4
M3 - Article
SN - 1474-4422
VL - 22
SP - 991
EP - 1004
JO - Lancet Neurology
JF - Lancet Neurology
IS - 11
ER -