Tolerability, safety and intermediary pharmacological effects of cilostazol and isosorbide mononitrate, alone and combined, in patients with lacunar ischaemic stroke:The LACunar Intervention-1 (LACI-1) trial, a randomised clinical trial

BackgroundLacunar stroke, a frequent clinical manifestation of small vessel disease (SVD), differs pathologically from other ischaemic stroke subtypes and has no specific long-term secondary prevention. Licenced drugs, isosorbide mononitrate (ISMN) and cilostazol, have relevant actions to prevent SVD progression.MethodsWe 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.FindingsLACI-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.nterpretationCilostazol 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

An assessment of the cost-effectiveness of magnetic resonance, including diffusion-weighted imaging in patients with transient ischaemic attack and minor stroke : a systematic review, meta-analysis and economic evaluation

Erratum issued September 2015 Erratum DOI: 10.3310/hta18270-c201509Peer reviewedPublisher PD

Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial

Background: Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke. Methods: In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130-149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306. Findings: 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137-139) in the higher-target group and 127 mm Hg (95% CI 126-128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64-1·03, p=0·08), disabling or fatal stroke (0·81, 0·53-1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68-1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15-0·95, p=0·03). Treatment-related serious adverse events were infrequent. Interpretation: Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial

Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial

Background: Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke. Methods: In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130-149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306. Findings: 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137-139) in the higher-target group and 127 mm Hg (95% CI 126-128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64-1·03, p=0·08), disabling or fatal stroke (0·81, 0·53-1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68-1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15-0·95, p=0·03). Treatment-related serious adverse events were infrequent. Interpretation: Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial

Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial

Background: Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke. Methods: In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130-149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306. Findings: 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137-139) in the higher-target group and 127 mm Hg (95% CI 126-128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64-1·03, p=0·08), disabling or fatal stroke (0·81, 0·53-1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68-1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15-0·95, p=0·03). Treatment-related serious adverse events were infrequent. Interpretation: Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial

Clinical Correlates of Infarct Shape and Volume in Lacunar Strokes

BACKGROUND AND PURPOSE: Infarct size and location are thought to correlate with different mechanisms of lacunar infarcts. We examined the relationship between the size and shape of lacunar infarcts and vascular risk factors and outcomes. METHODS: We studied 1679 participants in the Secondary Prevention of Small Subcortical Stroke trial with a lacunar infarct visualized on DWI. Infarct volume was measured planimetrically, and shape was classified based on visual analysis after 3D reconstruction of axial MRI slices. RESULTS: Infarct shape was ovoid/spheroid in 63%, slab 12%, stick 7%, and multi- component 17%. Median infarct volume was smallest in ovoid/spheroid relative to other shapes: 0.46, 0.65, 0.54, and 0.90 ml respectively, p< 0.001. Distributions of vascular risk factors were similar across the four groups except that patients in the ovoid/spheroid and stick groups were more often diabetic and those with multi-component had significantly higher blood pressure at study entry. Intracranial stenosis did not differ among groups (p=0.2). Infarct volume was not associated with vascular risk factors. Increased volume was associated with worse functional status at baseline and 3 months. Overall, 162 recurrent strokes occurred over an average of 3.4 years of follow-up with no difference in recurrent ischemic stroke rate by shape or volume. CONCLUSION: In patients with recent lacunar stroke, vascular risk factor profile was similar amongst the different infarct shapes and sizes. Infarct size correlated with worse short- term functional outcome. Neither shape nor volume was predictive of stroke recurrence