Article Figures & Data
Figures
- Figure 1
The ‘inverted pyramid of perfection’ in trial recruitment and follow-up: effect of increasing levels of selection and follow-up methods on participant numbers and generalisability. cSVD, cerebral small vessel disease.
- Figure 2
Number of participants randomised and follow-up rate achieved in example randomised controlled trial’s that used clinical or imaging outcomes.
- Figure 3
Comparison of clinical and imaging outcomes in trials with an imaging substudy.
Tables
- Table 1
Exemplar randomised controlled trials, and substudies where relevant, targeting people with cerebral small vessel disease including those with lacunar infarcts, white matter hyperintensities or sporadic intracerebral haemorrhage
Intervention Trial Target population N Outcome FU (months) Comment Pharmacotherapy Anti-inflammatory, minocycline MINERVA69 LACI and WMH 44 BBB permeability, microglia activation 3 Completed Antiplatelet, dual vs mono SPS-36 LACI (on MRI) 2916 CASI 60 Neutral BP lowering, perindopril±indapamide PROGRESS70 Stroke (IS, ICH) 6105 Dementia, cognitive decline 47 Dementia/cognitive decline reduced PROGRESS47 71 Stroke (IS, ICH) 192 WMH 36 WMH progression reduced BP lowering, telmisartan PRoFESS54 Stroke (IS) 771 WMH 28 Neutral (but no BP difference) BP lowering, intense v guideline INFINITY43 WMH 199 Gait speed
WMH36 Neutral
ReducedLEOPOLD (NCT02472028) cSVD 820 WMH 36 Ongoing PODCAST72 IS, ICH 83 ACE-R 6–30 Neutral PRESERVE44 LACI+WMH 62/111 Cerebral perfusion 3 Neutral PRESERVE73 LACI+WMH 111 White matter diffusivity, cognition 24 Neutral (SBP −6.8 mm Hg) PROHIBIT-ICH (ISRCTN23416732) ICH 112 MoCA 12 Ongoing SPRINT-MIND74 Hypertension (no diabetes/stroke) 9361 Dementia, cognitive impairment 40 Neutral, but less cognitive impairment SPRINT-MIND50 Hypertension (no diabetes/stroke) 454 WMH 48 Less increase in WMH volume, and more decrease in total brain volume (but diuretic effect?) SPS-36 LACI (on MRI) 2916 CASI 60 Neutral GABA partial agonist (tramiprosate) (NCT00056238) CAA 24 Microbleeds 3 Neutral Lipid lowering, pravastatin PROSPER52 Vascular risk factors 535 New infarcts, WMH 33 Neutral Lipid lowering, intense v guideline PODCAST75 IS 77 ACE-R 6–30 Neutral. Post hoc analysis positive75 Neurotransmission modulators (DL-3-n-butylphthalide) (ChiCTR-TRC-09000440)76 cSVD+VCI 281 ADAS-cog, CIBIC-plus 5.5 Cognition and global functioning improved Nitric oxide donor (ISMN) LACI-111 35 77 LACI Safety, tolerability 2 Safe, tolerable LACI-210 LACI 363 Feasibility 12 Composite, cognition, function PDE3-I (cilostazol) ECLIPSE78 Acute LACI 130 Pulsatility index, WMH 3 Reduced pulsatility index. Neutral for WMH LACI-111 35 77 LACI Safety, tolerability 2 Safe, tolerable, WMH reduced LACI-210 LACI 363 Feasibility 12 Composite, cognition, function Lee et al 79 AD with WMH 36 WMH 6 Improved regional cerebral metabolism PDE5-I (tadalafil) PASTIS80 LACI/TIA+lacunes/WMH 55 Change in CBF Single dose Non-significant increase in CBF Uric acid lowering (allopurinol) XILO-FIST81 IS/TIA 464 WMH 24 Neutral, safe Device Remote ischaemic conditioning Liao82 Subcortical VaD 37 Neuropsychological profile 6 Safe but neutral Exercise Aerobic dance ADTSVD83 cSVD 110 Cognition, mood, mobility 6 Inconsistent benefits on memory and executive function Multi-domain Nurse-led multidimensional cardiovascular intervention preDIVA84 Age 70–78 years 3526 Dementia and disability, WMH 80 Neutral on all outcomes. Cluster design, 116 practices AD, Alzheimer’s disease; ADAS-cog, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-CGIC, Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change; BBB, blood-brain barrier; BMI, body mass index; BP, blood pressure; CAA, cerebral amyloid angiopathy; CASI, Cognitive Abilities Screening Instrument; CBF, cerebral blood flow; CIBIC-plus, Clinician’s Interview-Based Impression of Change Plus caregiver input; cSVD, cerebral small vessel disease; DSST, digit symbol substitution test; FU, follow-up; ICH, intracerebral haemorrhage; IS, ischaemic stroke; LDL-c, low density lipoprotein-cholesterol; MoCA, Montreal Cognitive Assessment; MRI-BOLD, MRI blood oxygenation level dependent; PDE3-I, phosphodiesterase-3 inhibition; PDE5-I, phosphodiesterase-5 inhibition; RCT, randomised controlled trial; SBP, systolic BP; TIA, transient ischaemic attack; VADAS-cog, Vascular Dementia Assessment Scale-Cognitive Subscale; WMD, white matter disease; WMH, white matter hyperintensities.
- Table 2
Trials with clinical and imaging outcomes: comparing numbers screened, randomised, centres, recruitment rates, completeness of follow-up
PROGRESS VITATOPS SPRINT/SPRINT MIND PROSPER PROFESS ACCORD/ACCORD MIND LACI-1 Clinical Imaging Clinical Imaging Clinical Imaging Clinical Imaging Clinical Imaging Clinical Imaging Clinical Imaging Screened 7121 323 N/A N/A 14 692 1267 23 770 1100 N/A N/A 19 716 N/A N/A N/A Randomised 6105 254 8164 471 9361 673 5804 646 20 333 1057 10 251 632 57 27 Follow-up complete 6102 (99.9%) 192 (75.6%) 7462 (91.4%) 359
(76.2%)8563 (91.5%) 454 (67.5%) 5147 (88.7%) 554 (85.8%) 20 208 (99.4%) 771 (72.9%) 10 201 (99.5%) 503 (79.6%) 56 (98.3%) 22 (81.5%) Centres 172 10 123 5 101 7 3 1 695 ? 77 28 2 1 Recruitment rate 1.18 0.85 0.55 3.77 3.31 3.43 113.8 38 0.86 ? 3.69 0.81 1.67 1.59 Follow-up duration 46.8 36 40.8 25 39.1 6.5 38.4 33 30 27.9 42 35 3 3 Age (mean) 64 60.8 62.6 64.3 67.9 67.3 75.4 75 66.2 65.4 62.2 62.4 66.1 68 - Table 3
Proportion and prediction of missing data for clinical outcomes assessed at 12 months in the LACI-2 trial based on key baseline variables
Outcome Participants where outcome is missing (%) Baseline predictors as covariates in models to predict missingness Age Baseline
MoCASex Prestroke mRS NIHSS Time to randomisation Education Cog 7 Level 55 (15.15%) *−0.038
(0.018)−0.185 (<0.0001) 0.721 (0.064) *Overall (0.006) −0.258 (0.057) 0.0002 (0.208) Overall
(0.257)Cog 4 Level 55 (15.15%) *−0.040
(0.018)−0.185 (<0.0001) 0.721
(0.064)*Overall (0.006) −0.258 (0.057) 0.0002 (0.208) Overall
(0.257)Modified Rankin Scale 40 (11.02%) *−0.036 (0.045) −0.010 (0.849) 0.021 (0.958) Overall (0.083) −0.187 (0.008) −0.001 (0.272) *Overall (0.015) t-MoCA 56 (15.43%) *0.036 (0.023) *0.187 (<0.0001) −0.585 (0.123) *Overall (0.017) 0.188 (0.145) −0.0004 0.168) Overall (0.364) TICS-m 50 (13.77%) *0.041 (0.012) *0.205 (<0.0001) −0.547 (0.166) *Overall (0.036) 0.343 (0.018) 0.0002 (0.669) Overall (0.536) Verbal fluency test 44 (12.12%) −0.033 (0.056) −0.189 (0.0001) 0.495 (0.226) Overall (0.051) *−0.313 (0.036) −0.0001 (0.762) Overall (0.620) Trail Making Test B† 207 (57.02%) 0.003 (0.821) 0.0001 (0.999) −0.099 (0.684) Overall (0.164) 0.137 (0.136) 0.0002 (0.506) Overall (0.146) Zung depression scale 46 (12.67%) *−0.034
(0.040)−0.063 (0.206) −0.017 (0.963) Overall (0.087) −0.190 (0.159) −0.0004 (0.378) Overall (0.092) Care home placement‡ 42 (11.57%) *−0.043 (0.013) −0.035 (0.506) 0.098 (0.802) Overall (0.067) −0.175 (0.212) −0.0006 (0.250) *Overall
(0.031)IQCODE§ 205 (56.47%) *−0.023 (0.041) 0.002 (0.958) 0.115 (0.634) Overall (0.116) 0.097 (0.280) −0.0006 (0.019) Overall (0.693) EQ-5D-5L¶ 43 (11.85%) *−0.045 (0.010) −0.055 (0.289) −0.005 (0.990) Overall (0.093) −0.166 (0.227) −0.0004 (0.380) *Overall (0.034) EQVAS¶ 43 (11.85%) *−0.045
(0.010)−0.055 (0.289) −0.005 (0.990) Overall
(0.093)−0.166 (0.227) −0.0004 (0.380) *Overall (0.034) Each row corresponds to a model using column variables as predictors.
Systolic BP and smoking did not predict missing variables (data not shown).
*estimate (p value)*=overall significant predictor variable.
†Required in-person assessment; many participants were unable to attend for assessment due to COVID-19 regulations.
‡Disposition that is, place of residence, at 12 months. A: home independent—267, H: home with carer—49, R: residential home—1, died—4, missing and null—11+35=46–4=42.
§IQCODE: information collected from a person who knows the participant well; 213 participants did not provide informant details at randomisation, 7 participants had IQCODE but no informant recorded, 1 participant had informant but IQCODE not computed due to missing values.
¶EQ-5D-5L and EQVAS—measures of quality of life.
DSM-5, Diagnostic and Statistical Manual of Mental Disorders Fifth Edition; NIHSS, National Institutes of Health Stroke Scale.
