Table 2.
Therapeutic approaches for SVD.
| Intervention | Study type | Population | Notes |
| Lifestyle interventions | |||
| Aerobic exercise | RCTNCT01027858[86,88]AIBL[87] | 70 patients with WMH and cognitive impairment98 patients with subjective memory problems or mild cognitive impairment and at least 1 vascular risk factor | No difference in WMH volume in substudy (n = 30), but improved cognitive scores at 6 monthsNo difference in WMH volume at 2 years |
| Resistance training | RCTNCT00426881[89] | 54 patients with WMH but no cognitive impairment | Reduced WMH volume at 12 months |
| Smoking | Observational studyMild Stroke Study 2 (MSS-2)[70] Paris-Munich CADASIL[71]Lothian Birth Cohort[90] | 264 patients with stroke290 patients with CADASIL504 community-dwelling older patients | Smoking increases:- SVD burden on imaging- risk of stroke and dementia- rate of cortical thinning |
| Dietary sodium | Observational studyMSS-2[69] | 264 patients with stroke | High dietary sodium increased risk of: lacunar > cortical stroke, WMH & total SVD burden on imaging. |
| Traditional stroke prevention | |||
| Antiplatelet | Meta-analysis[93]RCTSPS3 [94]RCT subgroupRESTART[97] | 42,234 patients with lacunar stroke3020 patients with lacunar stroke254 patients with spontaneous ICH taking antithrombotic therapy | Single antiplatelet therapy reduced recurrent stroke across 17 trials.Chronic aspirin + clopidogrel vs. aspirin stopped early due to excess bleeding and death in dual antiplatelet groupSingle antiplatelet therapy vs. avoiding antiplatelet therapy did not increase hazard of recurrent ICH in the presence of CMB |
| BP lowering | Meta-analysis[58]RCTSPS3[98,99]RCT subgroupSPRINT-MIND[100]RCT substudyPRESERVE[101,102] | 1369 stroke patients3020 patients with lacunar stroke454 hypertensive patients with WMH111 hypertensive patients with lacunar stroke and established SVD | Less WMH progression with intensive BP reduction.No difference in recurrent stroke or long-term cognition with intensive BP loweringLess progression of WMH but no difference in brain volume over 4 years with intensive vs. standard BP treatmentNo difference in white matter damage on DTI with intensive vs. standard BP lowering. CBF did not fall with BP reduction in a further subgroup (n = 62) |
| Lipid lowering | RCTHeart Protection Study[103]ROCAS[104]PROSPER[105]RCT SubstudyVITATOPS[106] | 20,536 patients with vascular risk factors208 patients with TIA5804 patients with vascular risk factors81 patients with stroke and pre-stroke statin | Simvastatin did not influence cognitive outcomesSimvastatin did not influence WMH progressionPravastatin did not influence cognitive function (n = 5804) or WMH progression (n = 535)Less WMH progression with pre-stroke statin |
| Pharmacological agents under investigation | |||
| Cilostazol | Meta-analysis[107]RCTLACI-1[108]LACI-2[109] (ongoing) | 10,449 patients with ischaemic stroke57 patients with lacunar strokePatients with lacunar stroke (target 400) | Cilostazol reduced recurrent stroke (ischaemic and haemorrhagic) particularly in trials with larger populations of lacunar stroke patients.Cilostazol was associated with less WMH progressionEffect of cilostazol on recurrent stroke, death and dependency, cognition and imaging SVD markers |
| NO donors | RCTENOS[110,111]LACI-1[108]LACI-2[109] (ongoing) | 4011 patients with stroke57 patients with lacunar strokePatients with lacunar stroke (target 400) | GTN given under 6 hours of onset (n = 273) was associated with improved clinical outcomes at 90 daysPilot trial of ISMN on cerebrovascular reactivityEffect of ISMN on recurrent stroke, death and dependency, cognition and imaging SVD markers |
| Vitamins | RCT SubstudyVITATOPS[112] | 359 patients with stroke | Vitamin B supplements for 2 years in patients with severe WMH had slower WMH progression |
| Allopurinol | RCTXILO-FIST (NCT02122718) | Patients with ischaemic stroke (target 464) | Effect of Allopurinol on recurrent stroke and WMH progression |
| RIC | |||
| RIC | RCTWang et al[113] | 30 patients with SVD | RIC twice daily for 1 year reduced WMH and improved visuospatial and executive function |
AIBL: Australian Imaging Biomarkers and Lifestyle study; BP: blood pressure; CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CBF: cerebral blood flow; CMB: cerebral microbleeds; DTI: diffuse tensor imaging; ENOS: Efficacy of Nitric Oxide in Stroke Trial; GTN: glyceryl trinitrate; ICH: intracerebral haemorrhage; ISMN: isosorbide mononitrate; LACI-1/2: LACunar Intervention Trial -1 or 2; MSS-2: Mild Stroke Study-2; NO: Nitric oxide; PRESERVE is the name of a trial, it is not an acronym; PROSPER: Prospective Study of Pravastatin in the Elderly at Risk; RCT: randomised controlled trial; RESTART: Restart or Stop Antithrombotics Randomised Trial; RIC: Remote ischaemic conditioning; ROCAS: Regression of Cerebral Artery Stenosis study; SPRINT-MIND: Systolic blood PRessure INtervention Trial-MIND; SPS3: Secondary Prevention of Small Subcortical Stroke Trial; SVD: small vessel disease; VITATOPS: VITAmins TO Prevent Stroke; WMH: white matter hyperintensities; XILO-FIST: Xanthine oxidase Inhibition for the Improvement of Long-term Outcomes Following Ischaemic Stroke and Transient ischaemic attack.