Objectives: Cerebral small vessel disease (SVD) is a common disease in patients with ischemic stroke and the most common cause of vascular dementia. Blood pressure (BP)-lowering is generally considered neuroprotective. Nevertheless, in patients with severe SVD burden, the optimal BP target is uncertain.

Hypothesis: BP-lowering to a systolic BP of 120-129mmHg in ischemic stroke patients with severe SVD is not associated with impaired cerebral perfusion, nor does it associate with worsening of structural connectivity and cognitive function.

Design and subjects: One-year trial where patients aged ≥50 with a history of ischaemic stroke and severe cerebral SVD will be randomised (1:1) to a systolic BP target of 120-129mmHg versus 130-140mmHg.

Study instruments: At baseline and one-year, all subjects will receive a brain magnetic resonance imaging (MRI) to evaluate their cerebral blood flow (CBF) and white matter integrity. They will also receive neuropsychological batteries to evaluate cognitive functioning. In addition, subjects will receive home BP monitoring with periodic medication changes prescribed by medical doctor to ensure the target BP is achieved.

Main outcome measures: Primary end-point is the change in CBF. Secondary end-points include changes in structural connectivity and cognitive performance.

Cerebral small vessel disease (SVD) is a common disease in patients with ischemic stroke and the most common cause of vascular dementia. The global burden of cerebral SVD is high and strategies to better prevent and manage cerebral SVD is urgently needed. Whilst blood pressure (BP) lowering is considered neuroprotective in patients with cerebral SVD, the optimal BP target in ischaemic stroke patients with severe SVD remains uncertain. Therefore, this randomised clinical trial aims to investigate whether two selected systolic blood pressure targets [systolic BP (SBP) 120-129mmHg versus 130-140mmHg] have different effects on cerebral blood flow and white matter integrity (structural connectivity) detected by magnetic resonance imaging (MRI) of the brain, as well as on cognition, over a one-year intervention period.

Chinese patients aged ≥50 with a prior history of TIA/ischaemic stroke fitting the inclusion and exclusion criteria will be recruited. At baseline, recruited subjects will undergo clinical and cognitive assessments. Blood pressure will be measured at clinic with an automated BP measurement system. A baseline non-contrast MRI of the brain will be arranged. The non-contrast MRI and cognitive assessments will be repeated at approximately 1 year after recruitment into the study.

To ensure consistency, our trial's antihypertensive strategy and titration shall align with those recommended by international guidelines. Blood tests for renal function will be arranged after modifying the prescription of specific anti-hypertensive agents (e.g. ACEis, ARBs, thiazide diuretics and spironolactone).

Inclusion Criteria:

1. Aged ≥50
2. Chinese ethnicity
3. History of TIA/ischaemic stroke
4. Underlying severe cerebral SVD as evidenced by brain MRI with total SVD score ≥3
5. Underlying hypertension (defined as either SBP >140mmHg and taking no more than two anti-hypertensive agents, or SBP between 130-140mmHg and on at least one and not more than three anti-hypertensive agents)
6. Able to provide written informed consent
7. Able to perform study cognitive assessments
8. Modified Rankin Scale (mRS) ≤3
9. Expected life expectancy >2 years

Exclusion Criteria:

1. Unable to, or unwilling to consent
2. TIA/ischaemic stroke within three months (to avoid confounding effects of recovery on cognition from recent stroke)
3. Brain MR angiogram showing significant symptomatic or asymptomatic carotid, vertebral or intracranial large artery stenosis ≥50% as measured using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria
4. Cortical infarction >2cm in diameter
5. Paroxysmal or permanent atrial fibrillation
6. Known single gene disorder causing cerebral SVD, e.g. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
7. Symptomatic postural hypotension
8. Moderate- and severe-stage dementia with Montreal Cognitive Assessment (MOCA)-HK score <10
9. Moderate and severe depressive symptoms with Patient Health Questionnaire-9 score ≥10
10. Known secondary hypertension, e.g. hypertension is due to established obstructive sleep apnoea, renal parenchymal disease, renal artery stenosis, primary aldosteronism etc.
11. Unable to complete cognitive assessments
12. mRS >3
13. Life expectancy of less than 2 years

To avoid bias in outcome assessment, evaluation of the primary and secondary outcome measures will be performed by a group who is independent from the clinical investigators and who will be blinded from all clinical, cognitive and radiological assessments.