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

Originally publishedhttps://doi.org/10.1161/STROKEAHA.119.024150Stroke. 2020;51:38–46

See related articles, p 9, p 12, p 21, p 29, p 47

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.

Where Are We Now? Current Treatment of cSVD

For patients with lacunar stroke, secondary prevention strategies are mostly inferred from studies of ischemic stroke in general, the majority of which did not specifically examine efficacy in lacunar stroke. The only large definitive phase 3 trial to focus exclusively on lacunar stroke patients, with magnetic resonance imaging (MRI) confirmation, is the SPS3 trial (Secondary Prevention of Small Subcortical Strokes) of 3020 patients. This trial showed that long-term dual antiplatelet therapy was not superior to aspirin alone1 and that more intensive blood pressure lowering (target systolic, <130 mm Hg) reduced recurrent strokes. This reduction did not reach statistical significance for total stroke (ie, ischemic and hemorrhagic combined; hazard ratio, 0.81 [95% CI, 0.64–1.03]) but did for hemorrhagic stroke alone (hazard ratio, 0.37 [95% CI, 0.15–0.95]).2 No trials similar to SPS3 have been performed to assess the effects of statins, smoking cessation, diabetes mellitus management, and lifestyle interventions on lacunar stroke.

Unfortunately, little reliable information on preventing lacunes is available from other clinical trials because unlike SPS3, they generally have not required MRI for stroke subtyping. Treatment approaches to lacunar stroke have recently been systematically reviewed.3 As many as half of patients with a lacunar syndrome do not have cSVD on more rigorous subtyping.4 A systematic review of only 2 prior studies reported single antiplatelet therapy is better than no therapy for preventing new stroke (ischemic and hemorrhagic combined; risk ratio, 0.77 [95% CI, 0.62–0.97]) or new ischemic stroke (risk ratio, 0.48 [95% CI, 0.30–0.78]) in patients with recent lacunar stroke, but cSVD subtyping within these studies was not optimal.5

For patients with diffuse WMHs with or without lacunes, there have been no large-scale, definitive trials. This includes no definitive trials in patients with covert signs of cSVD (such as confluent WMH) on neuroimaging,6 in patients with vascular cognitive impairment,7 or in patients with CAA.

Are New Treatments for cSVD Needed?

Given the success in preventing stroke in general, with important reductions in incidence and mortality, are new treatments to target cSVD progression even necessary? That they are is supported by the evidence that many patients with cSVD experience progression with cognitive and functional decline despite conventional stroke risk reduction.

In the SCANS study (St George’s Cognition and Neuroimaging in Stroke) of 99 patients with symptomatic lacunar stroke and confluent WMH receiving conventional medical therapy, 18% progressed to dementia over 5 years.8 Even though all patients were known to have stroke and receive routine stroke preventive care, significant radiological progression was detected for all cSVD-related markers except for enlarged perivascular spaces (specifically, changes in lacunar volume, WMH volume, mean diffusivity, and reduced fractional anisotropy on diffusion tensor imaging were seen).8–12 Only 3% had a symptomatic recurrent stroke, but 27% had new lacunes, with >3 new lacunes in 8%.8 Patients with new lacunes exhibited declines in executive function.8

Furthermore, the pathophysiology of cSVD is complex, involving multiple pathways (eg, blood-brain barrier permeability13) that are distinct from the thromboembolism, cholesterol dysmetabolism, and glucose dysregulation that are the primary targets for current ischemic stroke prevention. As an example, recent genetic studies have found genetic variants in thrombosis and hemostasis are associated with an increased the risk of both large artery and cardioembolic stroke but not with lacunar stroke.14,15 This raises the possibility that antiplatelet and anticoagulation therapy may have less effect in cSVD.

Insights From cSVD-Focused Substudies of Major Trials

An efficient approach to test the effect of vascular risk reduction on cSVD progression is to piggyback an MRI substudy onto large clinical trials. This provides access to large study populations but limits interventions to those being tested against cardiovascular disease in general (mostly caused by atherosclerosis or cardiac disease rather than small vessel disease) and that if lacunar stroke is used as an end point, then accurate subtyping of stroke end points is required.

To identify recent and ongoing cSVD trials, we systematically searched the PubMed and https://www.clinicaltrials.gov databases using keywords for cSVD, WMHs, and vascular cognitive impairment in April 2019, combined with expert knowledge and hand searching of reference lists.

cSVD-focused MRI substudies investigated the effects of a multidomain lifestyle intervention, comprehensive vascular care, antihypertensives, statins, and intensive glucose control (Table 1). A systematic review of 4 trials found that antihypertensives reduced WMH progression (standardized mean difference, −0.19 [95% CI, −0.32 to −0.06]).16 The recently published SPRINT-MIND trial (Systolic Blood Pressure Intervention Trial - Mind Substudy) found that intensive systolic blood pressure lowering to <120 mm Hg compared with <140 mm Hg reduced WMH progression17 (Table 1) and the combined end point of mild cognitive impairment and dementia (hazard ratio, 0.85 [95% CI, 0.74−0.97]).18

Table 1. Published Substudies of Cerebral Small Vessel Disease Progression Embedded Within Prevention Trials

TrialYearPopulationInterventionnDurationOutcome
PreDIVA192017CommunityNurse-led vascular care1953 yNo difference in WMH progression or new infarcts
EVA202010AD with WMHAspirin, vascular care652 yLess progression of WMH by visual rating score; no difference in lacunes
FINGER212019Older, at risk for cognitive declineMultidomain: diet, exercise, cognitive training, vascular care1222 yNo difference in WMH progression
SPRINT172018High blood pressureIntensive BP control (systolic <120 mm Hg)4544.0 yLess progression of WMH difference with intensive treatment; no difference in brain volume
SCOPE222007Older, hypertensiveCandesartan1332 yFewer patients with high WMH increase (fifth quintile) in candesartan vs placebo
PROGRESS232004StrokePerindopril plus indapamide6673.9 yNo difference in new infarcts
PROGRESS242005StrokePerindopril plus indapamide1923.0 yLess WMH increase
PROFESS252012Ischemic strokeTelmisartan77128 moNo difference in WMH progression
VITATOPS262012Ischemic stroke/TIAB vitamins3592 yNo difference in WMH progression or lacune incidence; less WMH increase if severe WMH at baseline
PROSPER272005Cardiovascular riskPravastatin, 40 mg daily53533 moNo difference in WMH progression or change in infarct volume
ROCAS282009TIASimvastatin, 20 mg daily2082 yNo difference in WMH progression; less WMH increase if severe WMH at baseline
ACCORD292011Diabetes mellitusIntensive glycemic control (HbA1c, <6.0%)50340 moLess 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.

Early Phase Trials to Prevent cSVD Progression

New approaches to preventing cSVD might target its causes, its consequences, or, for cognition, enhance cognitive reserve. In this review, we focus on interventions that reduce the progression of cSVD. Thus, we do not review trials of cognitive training, physical or cognitive rehabilitation after stroke, cognitive enhancing medications, or the safety of antithrombotics and anticoagulants.

The additional benefit to be gained from more aggressive conventional risk factor management is unclear; as summarized in a recent review: “vascular prophylaxis, as appropriate for large artery disease and cardioembolism, includes antithrombotics, and blood pressure and lipid lowering; however, these strategies may not be effective for small vessel disease, or are already used routinely so precluding further detailed study.”30 As outlined earlier, intensive blood pressure lowering may reduce cSVD and cognitive impairment. New trials to prevent cSVD progression should also look to different choices of agents (eg, different antihypertensive classes) or different pathways, in addition to stricter treatment targets.

Early phase trials to prevent cSVD are tabulated separately for patients with lacunar stroke (Table 2), progressive chronic cSVD (Table 3), and CAA (Table 4). Interventions can be divided into 5 broad categories: lifestyle and behavioral, optimizing conventional vascular risk reduction strategies or targets, novel drugs, remote ischemic conditioning (RIC), and interventions to reduce amyloid accumulation in CAA (Table 3).

Table 2. Completed and Ongoing Early Phase Trials Targeting Lacunar Stroke

InterventionName/RegistrationPopulationSizeKey OutcomesDurationResults or Expected Completion Date
Lifestyle and behavior
 High-intensity trainingHITPALS/NCT02731235History of lacunar stroke84WMH volume1 yEstimated completion: 2019
New drugs
 Cilostazol31ECLIPSE/NCT00741286Lacunar stroke130WMH volume90 dNo difference in WMH volume change
 Cilostazol, 100 mg BID, and isosorbide mononitrate, 25 mg BID32LACI-1/NCT02481323Lacunar stroke57MRI CO2 reactivity11 wkWell 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 BIDLACI-2/NCT03451591Lacunar stroke400Combined stroke, myocardial infarction, death, cognitive impairment, dependency1 yEstimated completion: November 2020
RIC
 RICREM-PROTECT/NCT02169739Lacunar stroke60WMH volume1 yEstimated 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

InterventionName/RegistrationPopulationSizeKey OutcomesDurationResults or Expected Completion Date
Lifestyle and behavior
 Aerobic dance trainingADTSVD/NCT02730065≥2 lacunes or early confluent or confluent WMH11030-min cognitive battery, TCD pulsatility index6 moEstimated completion: 2019
 Aerobic exercise33,34NCT01027858WMH with neurological signs and cognitive impairment70ADAS-Cog, WMH volume6 moCompared 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 exerciseRISE-2/NCT02068391High WMH39CBF, gray matter density6 moFinal data, March 2018; not yet published
 Moderate-intensity aerobic exercise35AIBLSubjective memory complaints or MCI with ≥1 vascular risk factor98WMH volume2 yNo difference in WMH volume at 24 mo
 Resistance training twice weekly or once weekly36NCT00426881Cognitively not impaired with WMH on MRI54WMH volume, Stroop test1 yEnd-study WMH volume lower in the twice-weekly group compared with stretching
 Resistance trainingReshaping the Path of Vascular Cognitive Impairment/NCT02669394Subcortical ischemic vascular cognitive impairment88ADAS-Cog subscale plus; WMH volume; MRI DTI1 yEstimated completion: December 2020
Optimizing vascular risk reduction
 Telmisartan, 80 mg per day, and rosuvastatin, 10 mg per day37NAHypertensive732WMH volume; MMSE5 yTwo-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 Hg38,39PRESERVEHypertensive, lacunar stroke with confluent WMH111DTI MRI; CBF by ASL MRI (n=62)12 wkNo difference in DTI white matter damage between intensive and standard BP lowering; CBF preserved at lower target in substudy
 Telemetric BP monitoringPROHIBIT ICH/NCT03863665Primary ICH with systolic >130 mm Hg112WMH volume1 yEstimated completion: December 2021
 Amlodipine, losartan, and atenololTREAT-SVDS/NCT03082014Lacunar stroke, cognitive impairment with WMH, or CADASIL105MRI-measured vascular reactivity to CO24 wk of treatment with each (crossover design)Estimated completion: March 2020
Pharmacological
 Allopurinol, 300 mg BIDXILO-FIST/NCT02122718Recent ischemic stroke or TIA464WMH volume2 yEstimated completion: September 2020
 DL-3-n-butylphthalide, 200 mg TID40NASubcortical ischemic vascular cognitive impairment281ADAS-Cog, CIBIC-plus6 moChange in ADAS-Cog and CIBIC-plus favored treatment arm
 DL-3-n-butylphthalide, 200 mg TIDNCT03906123Subcortical ischemic vascular dementia64WMH volume, CBF on ASL MRI, neuropsychological testing48 wkEstimated completion: December 2019
 Tadalafil41PASTIS/NCT02450253Lacunar stroke or TIA with MRI lacunes or WMH55CBF by ASL MRISingle doseCompleted but not yet published
RIC
 RIC42,43NCT01658306Lacunar infarction or generalized WMH36WMH volume, MoCA1 yReduced 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

InterventionName/RegistrationPopulationSizeKey OutcomesDurationResults or Expected Completion Date
Ponezumab44NCT01821118CAA by Boston criteria36MRI visual BOLD activation, MRI microbleed count90 dNo difference in MRI BOLD activation or microbleed count
Tramiprosate45NCT00056238CAA by Boston criteria24MRI microbleed count12 wkNo 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.

Trials of Lifestyle and Behavior Interventions

Two completed and 4 ongoing small trials are testing the effects of aerobic exercise, resistance training, or high-intensity training on cognition and imaging measures of cSVD (Tables 2 and 3). Hypothesized mechanisms of effect include improved cardiovascular health, improved cerebrovascular reactivity, increased angiogenesis, neuroprotection, reduced inflammation, and increased sensitivity to insulin.46

Trials Optimizing Conventional Vascular Risk Reduction Strategies or Targets

There has been concern that in patients with extensive cSVD, in whom reduced cerebral blood flow and cerebral autoregulation has been demonstrated, intensive blood pressure lowering could decrease perfusion further increasing ischemic damage.47 That this is not the case is supported by the recent cerebral blood flow substudy within the PRESERVE trial (How Intensively Should We Treat Blood Pressure in Established Cerebral Small Vessel Disease?),38 which showed that intensive lowering (target systolic, <125 mm Hg) was associated with no reduction in cerebral blood flow, and more recently by the full PRESERVE results showing no increase in white matter damage assessed by diffusion tensor imaging MRI (Hugh Markus personal communication; Table 3).

Trials of New Drugs for cSVD

We identified 4 new drugs that are being tested: allopurinol, cilostazol, DL-3-n-butylphthalide, and tadalafil (Table 3).

Allopurinol—a xanthine oxidase inhibitor—reduces uric acid levels, oxidative stress, and inflammation and improves cerebral NO bioavailability.48

Cilostazol is a phosphodiesterase 3 inhibitor that inhibits platelet aggregation and improves endothelial dysfunction,49 making it an attractive potential treatment to test in cSVD. It is already approved in major markets for other indications and has been the subject of several large trials in ischemic stroke (not limited to cSVD) primarily in Asia, where in some it appeared to have lower bleeding risk than other antithrombotics.50,51 In animal models of hypoperfusion (bilateral carotid artery occlusion or spontaneously hypertensive stroke-prone rat), cilostazol reduced blood-brain barrier permeability, reduced white matter microglial activation, reduced white matter demyelination, and improved endothelial function.52–57

DL-3-n-butylphthalide, naturally found in celery oil, has antithrombotic, antiapoptotic, and antioxidant effects. In a rat bilateral carotid occlusion model, it improved angiogenesis, cerebral blood flow, and cognitive deficits.58

Tadalafil is a phosphodiesterase 5 inhibitor that is used to treat erectile dysfunction, benign prostatic hypertrophy, and pulmonary arterial hypertension. It vasodilates small arteries, mediated by increases in intracellular cyclic GMP in smooth muscle cells.59 A small trial is testing the effect of a single dose on cerebral blood flow.41

Trials of RIC

One completed and one ongoing trial are testing the effects of RIC (Table 3). In experimental animal models, inducing brief periods of ischemia-reperfusion can exert remote protective effects on distant organs such as the brain.60 In practice, this can be done through cycles of inflation and deflation of a blood pressure cuff. In a mouse model of cerebral hypoperfusion induced by bilateral carotid occlusion, chronic daily hindlimb RIC increased angiogenesis, increased cerebral blood flow, and preserved cerebral white matter myelin.61 cSVD may be an excellent scenario for preconditioning, as serial MRI studies suggest that patients with cSVD have frequent, recurrent silent microinfarcts.62 Another attractive feature of RIC is that it induces a broad range of humoral responses that promote cell survival and inhibit inflammatory and apoptotic pathways, potentially addressing mechanisms of cSVD progression that are independent of infarction.

Trials for Reducing β-Amyloid Accumulation in CAA

The amyloid aggregation inhibitor tramiprosate showed no safety concerns in a randomized controlled trial of 24 patients,45 but the drug is of uncertain value for Alzheimer disease63 and was not developed further for CAA. The anti–aβ-monoclonal antibody ponezumab also showed no safety concerns in a randomized controlled trial of 36 patients, but the drug failed to improve visual task–related functional MRI activation (a surrogate of vascular reactivity and the preplanned surrogate efficacy outcome), and there are no plans for further development.44

Other Possible Interventions

A recent framework for cSVD progression, supported by existing biomarker studies (predominantly neuroimaging based), proposes that early endothelial dysfunction leads to disruption of the blood-brain barrier with leakage of fluid and toxic plasma proteins into the vascular media and surrounding tissues, with secondary effects on vascular reactivity, pericyte function, oligodendrocyte proliferation, and perivascular fluid drainage pathways.13 A better understanding of the molecular pathways underlying these processes may lead to new targets for drug therapy. Similar processes appear to be at play in CAA and arteriosclerotic disease, but more research is needed on their similarities and differences. Current evidence implicates molecular processes related to endothelial dysfunction, NO synthesis, blood-brain barrier integrity, maintenance and repair of the extracellular matrix (eg, matrix metalloproteinases and their inhibitors), oxidative stress, mechanical stress, thrombosis, and inflammation.64 Proposed new therapeutic approaches could include endothelin antagonists, neurotrophins, peroxisome proliferator–activated receptor-γ agonists, and prostacyclin mimics.30

How Can We Optimize Trial Design for cSVD?

The absence of positive trials for cSVD predominantly reflects a lack of trials, not past failures. Standardized neuroimaging definitions of cSVD, important for patient selection and surrogate outcomes, have been developed only recently. Additionally, a better understanding of the basic disease mechanisms is emerging. These recent developments likely explain the expanding number of early phase trials on cSVD.

Choosing the Patient Group to Include

A modern view of cSVD pathology emphasizes that it is a diffuse, progressive disease with strokes emerging in some patients as intermittent, stochastic events. Many patients experience effects of progressive cSVD in the absence of symptomatic strokes. The implication for clinical trials is that one must consider broadening selection criteria and outcomes beyond stroke events to include the changes in cognition, mood, and gait that are frequent in cSVD.

At the same time, we need to ensure that patients in cSVD trials really do have cSVD as the underlying pathology. Clinical lacunar and cognitive syndromes have low accuracy for cSVD and thus should not be used as the sole entry criteria. Neuroimaging is essential, and ideally, trials should include MRI to confirm the diagnosis.

cSVD has different subtypes and manifestations that may differ in their pathophysiology and response to treatments. CAA is a specific subtype of cSVD that is caused by vascular β-amyloid deposition and confers the highest risk of subsequent bleeding. Trial selection criteria must identify the appropriate cSVD population to match the hypothesized mechanism of intervention.

Lacunar infarcts can have different pathogeneses and do not always occur in conjunction with diffuse cSVD. Lacunar infarcts can also occur due to embolism or branch atheromatous disease or can occur in isolation. For studies targeting the diffuse arteriopathy underlying arteriosclerotic cSVD, it would be reasonable to require additional evidence of diffuse cSVD, for example, by requiring either multiple lacunes or that a threshold of WMH burden is exceeded.

To enrich the trial with more progression events, patients with higher burden of disease can be selected at baseline. Simple MRI scores have been developed that combine different neuroimaging features of cSVD65 and may allow this. The optimal disease stage for intervention is unclear. Effective intervention at an earlier stage would preserve function in a less disabled state but would require larger sample sizes to achieve the desired number of end points. CADASIL (Cerebral Autosomal Dominant Arteriopathy With Ischemic Leukoencephalopathy) and other monogenic hereditary cSVDs offer the opportunity for more specific diagnosis and earlier stage intervention (eg, in asymptomatic mutation carriers), but their molecular pathophysiology differs from acquired arteriosclerotic disease.

Optimizing the Outcome Measure

Hard clinical end points such as recurrent stroke and dementia are ideal and are most likely to change practice if the trial results are positive. However, in small vessel disease, the recurrent stroke rate is relatively low, and the dementia incidence is also low over the next 2 to 3 years. Longer follow-up and large sample sizes are, therefore, required in definitive phase 3 trials using these end points, making them expensive and challenging to perform. This has led to increasing interest in the use of surrogate end points, particularly to screen new therapies before large phase 3 trials.

Cognitive testing has been most widely used, but there is no consensus on the optimal cognitive battery. The harmonization standards from the National Institutes of Health and Canadian Stroke Network suggested 30- and 60-minute test batteries,66 while other simple batteries sensitive to the prominent executive dysfunction and delayed processing speed seen in cSVD have also been proposed.67 However, all these batteries have been developed for diagnosis, and whether they are optimal for detection of change needs evaluating.

In practice, current cognitive batteries have been shown to be insensitive to change over the 2- to 3-year time period used in most clinical trials.68,69 However, in the SCANS cohort of lacunar stroke patients, cognitive decline could be detected after 5 years.68 This means large sample sizes are required for cognitive end points (Table I in the online-only Data Supplement). Practice effects are likely to be one of the reasons why cognitive tests are insensitive to change; an improvement in cognition over 2 and 3 years of follow-up, especially in memory domain, was seen on the SCANS cohort, consistent with this.68

Because of the large sample sizes required with cognitive testing, there is increasing interest in using MRI as a surrogate marker for phase 2 trials. Quantitative measures of change in WMH volume, brain volume, and diffusion tensor imaging metrics appear to be the most sensitive to potential treatment effects, with sample sizes of 120 to 150 per arm needed to detect a 30% treatment effect over 3 years,12 although estimated sample sizes are sensitive to the underlying assumptions70,71 (Table I in the online-only Data Supplement). Standardized imaging core laboratory protocols are critical to maintain control over image quality.72 The Harmonizing Brain Magnetic Resonance Imaging Methods for Vascular Contributions to Neurodegeneration initiative provides resources for standardizing MRI methods, available at www.harness-neuroimaging.org.73

Blood or cerebrospinal fluid biomarkers may play a role in the future. For example, neurofilament light correlates well with degree of cSVD74; whether it is a sensitive marker in longitudinal studies remains to be determined.

cSVD affects not only cognition but also behavior and mood, activities of daily living, and quality of life, and including these as end points may add sensitivity and clinical relevance, although this remains to be demonstrated.

Conclusions and Future Directions

Substudies of large cardiovascular and stroke prevention trials provide moderate-quality evidence that lowering blood pressure reduces the progression of WMH but were not large enough to link this reduction to improved cognition or reduced stroke risk. Otherwise, little is known about how to prevent progression of cSVD. There have been few trials of interventions to prevent cSVD progression, probably because it is difficult to reliably and accurately subtype cSVD on clinical grounds alone. However, the time is ripe for a new generation of cSVD trials. The advent of widespread MRI scanning with standardized lesion definitions75 enables more accurate phenotyping, for example, into acute or chronic lacunar stroke with or without diffuse cSVD, vascular cognitive impairment with diffuse cSVD, and CAA. New trials should exploit advanced quantitative imaging markers (WMH volume, diffusion tensor imaging metrics, cerebral blood flow, and cerebrovascular reactivity) as surrogate end points, as they are more sensitive to change over time than cognition or recurrent stroke. With these improved tools, the field is now much better positioned to convert new pathophysiological insights into new treatments.

Footnotes

The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.119.024150.

Correspondence to Eric E. Smith, MD, MPH, University of Calgary, Room 2941, Health Sciences Bldg, 3330 Hospital Dr NW, Calgary, AB T2N 4N1, Canada. Email

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