New Treatment Approaches to Modify the Course of Cerebral Small Vessel Diseases

Eric E. Smith, MD, MPH; Hugh S. Markus, FMedSci

Stroke. 2020;51(1):38-46.

Abstract and Introduction

Introduction

Cerebral small vessel diseases (cSVDs) are a common cause of stroke and an important contributor to age-related cognitive decline and risk for dementia. Yet there is surprisingly little information on how to prevent their progression.

The common pathologies underlying cSVDs are arteriolosclerosis caused by aging, hypertension, and other conventional vascular risk factors and cerebral amyloid angiopathy (CAA) caused by vascular deposition of β-amyloid. These diseases lead to varied and overlapping types of vascular brain injury such as lacunes, white matter hyperintensities (WMHs) of presumed vascular origin, and microbleeds. These radiological manifestations of cSVD are common in aging populations. For example, >20% of elderly >80 years of age have ≥1 lacunes. Thus, cSVD is a major public health problem.

In this review, we discuss current treatment, identify gaps in our knowledge, review current trials addressing these gaps, and highlight methodological considerations that are important in planning future trials in cSVD.

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Table 1. Published Substudies of Cerebral Small Vessel Disease Progression Embedded Within Prevention Trials
Trial	Year	Population	Intervention	n	Duration	Outcome
PreDIVA¹⁹	2017	Community	Nurse-led vascular care	195	3 y	No difference in WMH progression or new infarcts
EVA²⁰	2010	AD with WMH	Aspirin, vascular care	65	2 y	Less progression of WMH by visual rating score; no difference in lacunes
FINGER²¹	2019	Older, at risk for cognitive decline	Multidomain: diet, exercise, cognitive training, vascular care	122	2 y	No difference in WMH progression
SPRINT¹⁷	2018	High blood pressure	Intensive BP control (systolic <120 mm Hg)	454	4.0 y	Less progression of WMH difference with intensive treatment; no difference in brain volume
SCOPE²²	2007	Older, hypertensive	Candesartan	133	2 y	Fewer patients with high WMH increase (fifth quintile) in candesartan vs placebo
PROGRESS²³	2004	Stroke	Perindopril plus indapamide	667	3.9 y	No difference in new infarcts
PROGRESS²⁴	2005	Stroke	Perindopril plus indapamide	192	3.0 y	Less WMH increase
PROFESS²⁵	2012	Ischemic stroke	Telmisartan	771	28 mo	No difference in WMH progression
VITATOPS²⁶	2012	Ischemic stroke/TIA	B vitamins	359	2 y	No difference in WMH progression or lacune incidence; less WMH increase if severe WMH at baseline
PROSPER²⁷	2005	Cardiovascular risk	Pravastatin, 40 mg daily	535	33 mo	No difference in WMH progression or change in infarct volume
ROCAS²⁸	2009	TIA	Simvastatin, 20 mg daily	208	2 y	No difference in WMH progression; less WMH increase if severe WMH at baseline
ACCORD²⁹	2011	Diabetes mellitus	Intensive glycemic control (HbA1c, <6.0%)	503	40 mo	Less decline in brain volume but higher increase in WMH volume

ACCORD indicates Action to Control Cardiovascular Risk in Diabetes; AD, Alzheimer disease; BP, blood pressure; EVA, Evaluation of Vascular Care in Alzheimer's Disease; FINGER, Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability; HbA1c, hemoglobin A1c; PreDIVA, Prevention of Dementia by Intensive Vascular Care; PROFESS, Prevention Regimen for Effectively Avoiding Second Strokes; PROGRESS, Perindopril Protection Against Recurrent Stroke Study; PROSPER, Prospective Study of Pravastatin in the Elderly at Risk; ROCAS, Regression of Cerebral Artery Stenosis; SCOPE, Study on Cognition and Prognosis in the Elderly; SPRINT, Systolic Blood Pressure Intervention Trial; TIA, transient ischemic attack; VITATOPS, Vitamins to Prevent Stroke; and WMH, white matter hyperintensity.

Table 2. Completed and Ongoing Early Phase Trials Targeting Lacunar Stroke
Intervention	Name/Registration	Population	Size	Key Outcomes	Duration	Results or Expected Completion Date
Lifestyle and behavior
High-intensity training	HITPALS/NCT02731235	History of lacunar stroke	84	WMH volume	1 y	Estimated completion: 2019
New drugs
Cilostazol³¹	ECLIPSE/NCT00741286	Lacunar stroke	130	WMH volume	90 d	No difference in WMH volume change
Cilostazol, 100 mg BID, and isosorbide mononitrate, 25 mg BID³²	LACI-1/NCT02481323	Lacunar stroke	57	MRI CO₂ reactivity	11 wk	Well tolerated and safe. MRI substudy in 28 showed higher proportion with WMH decrease in cilostazol arms
Cilostazol, 100 mg BID, and isosorbide mononitrate, 25 mg BID	LACI-2/NCT03451591	Lacunar stroke	400	Combined stroke, myocardial infarction, death, cognitive impairment, dependency	1 y	Estimated completion: November 2020
RIC
RIC	REM-PROTECT/NCT02169739	Lacunar stroke	60	WMH volume	1 y	Estimated completion: December 2019

Registration numbers are for https://www.clinicaltrials.gov. ECLIPSE indicates Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler; HITPALS, High Intensity Training in Patients With Lacunar Stroke; LACI, Lacunar Intervention; MRI, magnetic resonance imaging; REM-PROTECT, Remote Preconditioning Over Time to Empower Cerebral Tissue; RIC, remote ischemic conditioning; TCD, transcranial Doppler; and WMH, white matter hyperintensity.

Table 3. Completed and Ongoing Early Phase Trials Testing Interventions for Reducing Progression of Chronic Cerebral Small Vessel Disease
Intervention	Name/Registration	Population	Size	Key Outcomes	Duration	Results or Expected Completion Date
Lifestyle and behavior
Aerobic dance training	ADTSVD/NCT02730065	≥2 lacunes or early confluent or confluent WMH	110	30-min cognitive battery, TCD pulsatility index	6 mo	Estimated completion: 2019
Aerobic exercise^33,34	NCT01027858	WMH with neurological signs and cognitive impairment	70	ADAS-Cog, WMH volume	6 mo	Compared with placebo, better ADAS-Cog scores at 6 mo but the difference was not sustained at 6 mo; no change in WMH volume in substudy of 30
Aerobic exercise	RISE-2/NCT02068391	High WMH	39	CBF, gray matter density	6 mo	Final data, March 2018; not yet published
Moderate-intensity aerobic exercise³⁵	AIBL	Subjective memory complaints or MCI with ≥1 vascular risk factor	98	WMH volume	2 y	No difference in WMH volume at 24 mo
Resistance training twice weekly or once weekly³⁶	NCT00426881	Cognitively not impaired with WMH on MRI	54	WMH volume, Stroop test	1 y	End-study WMH volume lower in the twice-weekly group compared with stretching
Resistance training	Reshaping the Path of Vascular Cognitive Impairment/NCT02669394	Subcortical ischemic vascular cognitive impairment	88	ADAS-Cog subscale plus; WMH volume; MRI DTI	1 y	Estimated completion: December 2020
Optimizing vascular risk reduction
Telmisartan, 80 mg per day, and rosuvastatin, 10 mg per day³⁷	NA	Hypertensive	732	WMH volume; MMSE	5 y	Two-by-two factorial design with placebo. No effect of telmisartan; rosuvastatin treated had less increase in WMH but interpretation complicated by an interaction between the rosuvastatin and telmisartan arms
Target systolic <125 mm Hg^38,39	PRESERVE	Hypertensive, lacunar stroke with confluent WMH	111	DTI MRI; CBF by ASL MRI (n=62)	12 wk	No difference in DTI white matter damage between intensive and standard BP lowering; CBF preserved at lower target in substudy
Telemetric BP monitoring	PROHIBIT ICH/NCT03863665	Primary ICH with systolic >130 mm Hg	112	WMH volume	1 y	Estimated completion: December 2021
Amlodipine, losartan, and atenolol	TREAT-SVDS/NCT03082014	Lacunar stroke, cognitive impairment with WMH, or CADASIL	105	MRI-measured vascular reactivity to CO₂	4 wk of treatment with each (crossover design)	Estimated completion: March 2020
Pharmacological
Allopurinol, 300 mg BID	XILO-FIST/NCT02122718	Recent ischemic stroke or TIA	464	WMH volume	2 y	Estimated completion: September 2020
DL-3-n-butylphthalide, 200 mg TID⁴⁰	NA	Subcortical ischemic vascular cognitive impairment	281	ADAS-Cog, CIBIC-plus	6 mo	Change in ADAS-Cog and CIBIC-plus favored treatment arm
DL-3-n-butylphthalide, 200 mg TID⁴⁰	NCT03906123	Subcortical ischemic vascular dementia	64	WMH volume, CBF on ASL MRI, neuropsychological testing	48 wk	Estimated completion: December 2019
Tadalafil⁴¹	PASTIS/NCT02450253	Lacunar stroke or TIA with MRI lacunes or WMH	55	CBF by ASL MRI	Single dose	Completed but not yet published
RIC
RIC^42,43	NCT01658306	Lacunar infarction or generalized WMH	36	WMH volume, MoCA	1 y	Reduced WMH volume compared with sham-RIC; significantly better visuospatial and executive function sections of the MoCA

Registration numbers are for https://www.clinicaltrials.gov. ADAS-Cog indicates Alzheimer's Disease Assessment Scale-Cognitive; ADTSVD, Aerobic Dance Training in Small Vessel Disease; AIBL, Australian Imaging, Biomarkers and Lifestyle; ASL, arterial spin label; BP, blood pressure; CADASIL, Cerebral Autosomal Dominant Arteriopathy With Ischemic Leukoencephalopathy; CBF, cerebral blood flow; CIBIC-Plus, clinician's interview-based impression of change plus caregiver input; DTI, diffusion tensor imaging; ICH, intracerebral hemorrhage; MCI, mild cognitive impairment; MMSE, Folstein Minimental Status Exam; MoCA, Montreal Cognitive Assessment; MRI, magnetic resonance imaging; NA, not applicable; PASTIS, Perfusion by Arterial Spin Labelling Following Single Dose Tadalafil in Small Vessel Disease; PRESERVE, How Intensively Should We Treat Blood Pressure in Established Cerebral Small Vessel Disease?; PROHIBIT ICH, Prevention of Hypertensive Injury to the Brain by Intensive Treatment in Intracerebral Haemorrhage; RIC, remote ischemic conditioning; RISE-2, Recovery Improved in Covert Stroke With Exercise; TCD, transcranial Doppler ultrasound; TIA, transient ischemic attack; TREAT-SVDS, Effects of Amlodipine and Other Blood Pressure Lowering Agents on Microvascular Function in Small Vessel Diseases; WMH, white matter hyperintensity; and XILO-FIST, Xanthine Oxidase Inhibition for the Improvement of Long-Term Outcomes Following Ischaemic Stroke and Transient Ischaemic Attack.

Table 4. Completed and Ongoing Early Phase Trials Testing Interventions for Reducing Progression of CAA
Intervention	Name/Registration	Population	Size	Key Outcomes	Duration	Results or Expected Completion Date
Ponezumab⁴⁴	NCT01821118	CAA by Boston criteria	36	MRI visual BOLD activation, MRI microbleed count	90 d	No difference in MRI BOLD activation or microbleed count
Tramiprosate⁴⁵	NCT00056238	CAA by Boston criteria	24	MRI microbleed count	12 wk	No difference in microbleed count

Registration numbers are for https://www.clinicaltrials.gov. BOLD indicates blood oxygen level-dependent; CAA, cerebral amyloid angiopathy; and MRI, magnetic resonance imaging.

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