METHODS: Blinded assessors coded baseline images for acute ischaemic signs (presence, extent, swelling and attenuation of acute lesions; and hyperattenuated arteries) and pre-existing changes (atrophy, leucoaraiosis and old ischaemic lesions). Logistic regression models assessed associations between imaging features and death at 7 and 90 days; good recovery (modified Rankin Scale scores 0-2 at 90 days) and sICH. Data are reported with adjusted ORs and 95% CIs.

RESULTS: 2916 patients (67±13 years, National Institutes of Health Stroke Scale 8 (5-14)) were included. Visible ischaemic lesions, severe hypoattenuation, large ischaemic lesion, swelling and hyperattenuated arteries were associated with 7-day death (OR (95% CI): 1.52 (1.06 to 2.18); 1.51 (1.01 to 2.18); 2.67 (1.52 to 4.71); 1.49 (1.03 to 2.14) and 2.17 (1.48 to 3.18)) and inversely with good outcome. Severe atrophy was inversely associated with 7-day death (0.52 (0.29 to 0.96)). Atrophy (1.52 (1.08 to 2.15)) and severe leucoaraiosis (1.74 (1.20 to 2.54)) were associated with 90-day death. Hyperattenuated arteries were associated with sICH (1.71 (1.01 to 2.89)). No imaging features modified the effect of alteplase dose.

Methods: We recruited independent patients with clinically confirmed lacunar ischaemic stroke without cognitive impairment to a prospective randomised clinical trial, LACunar Intervention-1 (LACI-1). We randomised patients using a central web-based system, 1:1:1:1 with minimisation, to masked ISMN 25 mg bd, cilostazol 100 mg bd, both ISMN and cilostazol started immediately, or both with start delayed. We escalated doses to target over two weeks, sustained for eight weeks. Primary outcome was the proportion achieving target dose. Secondary outcomes included symptoms, safety (haemorrhage, recurrent vascular events), cognition, haematology, vascular function, and neuroimaging. LACI-1 was powered (80%, alpha 0.05) to detect 35% (90% versus 55%) difference between the proportion reaching target dose on one versus both drugs at 55 patients. Registration ISRCTN12580546.

Findings: LACI-1 enrolled 57 participants between March 2016 and August 2017: 18 (32%) females, mean age 66 (SD 11, range 40-85) years, onset-randomisation 203 (range 6-920) days. Most achieved full (64%) or over half (87%) dose, with no difference between cilostazol vs ISMN, single vs dual drugs. Headache and palpitations increased initially then declined similarly with dual versus single drugs. There was no between-group difference in BP, pulse-wave velocity, haemoglobin or platelet function, but pulse rate was higher (mean difference, MD, 6.4, 95%CI 1.2-11.7, p = 0.02), platelet count higher (MD 35.7, 95%CI 2.8, 68.7, p = 0.03) and white matter hyperintensities reduced more (Chi-square p = 0.007) with cilostazol versus no cilostazol.

Interpretation: Cilostazol and ISMN are well tolerated when the dose is escalated, without safety concerns, in patients with lacunar stroke. Larger trials with longer term follow-up are justified.