The EffecTs of Amlodipine and other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases (TREAT-SVDs) trial: Study protocol for a randomised crossover trial
Kopczak, Anna; S Stringer, Michael; van den Brink, Hilde; Kerkhofs, Danielle; W Blair, Gordon; van Dinther, Maud; Onkenhout, Laurien; A Wartolowska, Karolina; Thrippleton, Michael J.; Duering, Marco; Staals, Julie; Middeke, Martin; André, Elisabeth; Norrving, Bo; Bousser, Marie Germaine; Mansmann, Ulrich; Rothwell, Peter M.; N Doubal, Fergus; van Oostenbrugge, Robert; Jan Biessels, Geert; Webb, Alastair J.S.; Wardlaw, Joanna M.; Dichgans, Martin
(2023) European Stroke Journal, volume 8, issue 1, pp. 387 - 397
(Article)
Abstract
Background: Hypertension is the leading modifiable risk factor for cerebral small vessel diseases (SVDs). Yet, it is unknown whether antihypertensive drug classes differentially affect microvascular function in SVDs. Aims: To test whether amlodipine has a beneficial effect on microvascular function when compared to either losartan or atenolol, and whether losartan
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has a beneficial effect when compared to atenolol in patients with symptomatic SVDs. Design: TREAT-SVDs is an investigator-led, prospective, open-label, randomised crossover trial with blinded endpoint assessment (PROBE design) conducted at five study sites across Europe. Patients aged 18 years or older with symptomatic SVD who have an indication for antihypertensive treatment and are suffering from either sporadic SVD and a history of lacunar stroke or vascular cognitive impairment (group A) or CADASIL (group B) are randomly allocated 1:1:1 to one of three sequences of antihypertensive treatment. Patients stop their regular antihypertensive medication for a 2-week run-in period followed by 4-week periods of monotherapy with amlodipine, losartan and atenolol in random order as open-label medication in standard dose. Outcomes: The primary outcome measure is cerebrovascular reactivity (CVR) as determined by blood oxygen level dependent brain MRI signal response to hypercapnic challenge with change in CVR in normal appearing white matter as primary endpoint. Secondary outcome measures are mean systolic blood pressure (BP) and BP variability (BPv). Discussion: TREAT-SVDs will provide insights into the effects of different antihypertensive drugs on CVR, BP, and BPv in patients with symptomatic sporadic and hereditary SVDs. Funding: European Union’s Horizon 2020 programme. Trial registration: NCT03082014.
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Keywords: amlodipine, antihypertensive drug classes, blood pressure variability, CADASIL, cerebrovascular reactivity, lacunar stroke, magnetic resonance imaging, randomised clinical trial, Small vessel diseases, vascular cognitive impairment, Clinical Neurology, Cardiology and Cardiovascular Medicine
ISSN: 2396-9873
Publisher: SAGE Publications Inc.
Note: Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: TREAT-SVDs is part of the SVDs@target project which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 666881. Further support is provided by 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). The procurement of the MRI scanner in Munich was supported by the German Research Foundation (DFG) grant for major research instrumentation (DFG, INST 409/193-1 FUGG). Additional support is provided by 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, and the Wellcome Trust and Dunhill Trust which funded the MRI scanner in Edinburgh. Funding Information: We are grateful to the members of the Steering Committee (MDi, JMW, GJB, AJSW, RvO), the SMB (Prof. Bo Norrving, Prof. Marie-Germain Bousser), the 2nd SAE assessors (Germany and UK: Prof. Hans-Joachim Anders, Prof. Stefan Kääb; The Netherlands: Dr. Floris Vanmolkot, Dr. Inger de Ridder), the ethical advisory board (Prof. Marie-Germaine Bousser, Prof. Bo Norrving, Prof. Ale Algra), and the ethical advisor for the SVDs@target project (Prof. Steven Greenberg). We thank Silvia Egert-Schwender for assistance in planning of the study conduct, Lena Körber and Svetla Rangelova for the data management, Niels Brandt and Alfred Zollner for safety reviews, Adrian Balteanu for setting up the electronic case report form, ARTTIC innovation (Gabriele Wagner, Amrita Choudhary, Martin Dietz) for organisation of regular meetings, SAFE (Gary Randall, Jelena Misita) for distributing the information about the study, all study collaborators listed in the Supplemental Acknowledgement and most important, all patients for study participation. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: TREAT-SVDs is part of the SVDs@target project which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 666881. Further support is provided by 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). The procurement of the MRI scanner in Munich was supported by the German Research Foundation (DFG) grant for major research instrumentation (DFG, INST 409/193-1 FUGG). Additional support is provided by 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, and the Wellcome Trust and Dunhill Trust which funded the MRI scanner in Edinburgh. MDi conceptualised the trial. MDi, JMW, GJB, RvO, PMR obtained funding. MDi, JMW, GJB, RvO, PMR, AJSW, MM, UM, MDue and AK designed the study. UM designed the biometrical concept and performed the statistical analyses. MDi, AK, MDue, JMW, GWB, FND, MSS, MJT, AJSW, KAW, RvO, JS, DK, MvD, GJB, LO, TA and HvdB implemented the study at the respective study sites. MGB, BN, EA, MDi and AK setup the safety monitoring plan. AK and MDi drafted the manuscript. All authors read and approved the final manuscript. Publisher Copyright: © European Stroke Organisation 2022.
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