effects of amlodipine and other blood pressure lowering agents on microvascular function

Conditions: Cerebral Small Vessel Diseases

Summary: multicentre, multinational, prospective randomised, open-label, 3 sequence crossover phase iii b clinical trial with blinded endpoint assessment (probe-design) * in 75 patients with sporadic small vessel diseases (svds) and * in 30 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil)

treat-svds will be carried out as a multicentre open label trial at five trial sites across 3 european countries: germany, the netherlands, and the united kingdom. patients meeting eligibility criteria will be randomly allocated to one of three sequences of antihypertensive treatment which are given as open-label oral medications in standard dose in the following order arm a: amlodipine \> losartan \> atenolol arm b: atenolol \> amlodipine \> losartan arm c: losartan \> atenolol \> amlodipine. the study starts with a two week run-in phase. during these first two weeks, patients are not allowed to take antihypertensive drugs except for the rescue medication. after the run-in period,every patient will take subsequently three different antihypertensive drugs (each drug from a separate drug class) according to the randomly assigned arm. each study drug will be administered for four weeks. patients will be monitored telemetrically with a dedicated bp device during the whole trial period of 14 weeks.

Eligibility criteria:
inclusion criteria: patients may be enrolled in the trial if all of the following criteria have been met: * symptomatic svd defined as * history of clinical lacunar stroke in the last 5 years with a corresponding small subcortical infarct visible on mri scan or ct scan\* compatible with the clinical syndrome. \*on mri, recent infarct is defined as a diffusion-weighted imaging (dwi) lesion on the acute mri scan. on ct, recent infarct is defined as a novel infarct on ct within 3 weeks after the event that was not visible on the admission ct. patients admitted to the hospital with an obvious lacunar syndrome and an admission ct/ct perfusion compatible with a lacunar infarct but without an mri in the (sub)acute stage and no repeat ct performed in the context of clinical care can be recruited for treat-svds. after providing informed consent they will be invited for the screening visit including a 3t mri. the 3t mri will be used to verify the presence of a new lesion, relative to the admission ct, compatible with a lacunar infarct and compatible with the lacunar syndrome. if such a lesion is present the patient will undergo the further treat-svds workup. if no such lesion is observed the patient will be excluded from the study and considered as a screening failure. * or cognitive impairment defined as visiting a memory clinic with cognitive complaints, objective cognitive impairment\*, and capacity to consent, and with confluent deep white matter hyperintensities (wmh) on mri (defined on the fazekas scale as deep wmh score ≥ 2) \*concluded by the treating physician based on a validated cognitive measurement tool (for example but not limited to moca or camcog) * or a diagnosis of cadasil established by molecular genetic testing of the notch3 gene (presence of an archetypical, cysteine-affecting mutation) or the presence of granular osmiophilic material in ultrastructural, electron microscopy analysis of skin biopsy * indication for antihypertensive treatment (as defined by meeting one of the following): * hypertension defined as sbp ≥ 140 mmhg or diastolic bp (dbp) ≥ 90 mmhg without antihypertensive treatment or use of an antihypertensive drug for previously diagnosed hypertension * prior history of stroke or transient ischaemic attack (tia) * age 18 years or older * written informed consent exclusion criteria: patients will be excluded from the trial for any of the following reasons: * inclusion criteria are not met * unwillingness or inability to give written consent * pregnant or breastfeeding women, women of childbearing age not taking contraception. acceptable contraception in women of childbearing age is a "highly effective" contraceptive measure as defined by the clinical trials facilitation group and includes combined (oestrogen and progesterone containing) or progesterone-only contraception associated with inhibition of ovulation, or intrauterine device, or bilateral tubal occlusion. * contraindications to mri (pacemaker, aneurysm clip, cochlear implant etc.) * other major neurological or psychiatric conditions affecting the brain and interfering with the trial design (e.g. multiple sclerosis) * in case of clinical lacunar stroke syndrome other causes of stroke such as * ≥ 50% luminal stenosis (nascet) in large arteries supplying the area of ischaemia * major-risk cardioembolic source of embolism (permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumours, mitral stenosis, recent (\< 4 weeks) myocardial infarction, left ventricular ejection fraction less than 30%, valvular vegetations, or infective endocarditis) * other specific causes of stroke identified (e.g. arteritis, dissection, migraine/vasospasm, drug misuse) * other stroke risk factor requiring immediate intervention that would preclude involvement in the trial * renal impairment (egfr \< 35ml/min) * life expectancy \< 2 years * use of \> 2 antihypertensive drugs at maximum dose or equivalent (one drug at the maximum dose and two drugs at half of the maximum dose) for an appropriate bp control * contraindications to the applied antihypertensive drugs as known * severe aortic stenosis * bilateral renal artery stenosis * severe arterial circulatory disorders * atrioventricular block ii° or iii° or sick sinus syndrome * heart failure (nyha iii or iv) * bradycardia, resting heart rate \< 50/min * bronchospastic diseases such as severe bronchial asthma * severe hepatic dysfunction such as liver cirrhosis * use of monoamine oxidase (mao)-a-blockers * use of simvastatin \> 20mg/d * metabolic acidosis * disturbed electrolyte homeostasis such as hypercalcaemia, hypokalaemia, and hyponatraemia * symptomatic hyperuricaemia (gout)

Keywords: hypertension cerebrovascular reactivity blood pressure variability