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SummaryBackgroundResults of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.MethodsFOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.FindingsBetween Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months.InterpretationFluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.FundingUK Stroke Association and NIHR Health Technology Assessment Programme.

SummaryBackgroundIntensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy.MethodsWe did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388.Findings3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001).InterpretationAmong patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice.FundingNational Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

Summary Background Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. Funding British Heart Foundation.

There is some evidence to suggest that mealtime interventions improve behavioral symptoms in elderly people with dementia living in residential care, although weak study designs limit the generalizability of the findings. Well designed, controlled trials are needed to further understand the utility of mealtime interventions in this setting.

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Abstract-Alterations of structure and function of the microcirculation in hypertension in the elderly and changes with normotensive aging have not been fully clarified. We studied capillary pressure, density, and skin microvascular function in 46 subjects in 3 groups: elderly subjects (aged Ͼ60 years) with untreated hypertension (nϭ16), elderly normotensive subjects (nϭ16), and young normotensive subjects (age Ͻ45 years, nϭ14). In a subgroup of 19 subjects, we also studied resistance artery function in the isometric myograph. Capillary pressure was higher in both elderly groups (elderly hypertensives: 18.6Ϯ4.7 mm Hg, elderly normotensives: 17.6Ϯ4.0 mm Hg) compared with young normotensives (13.9Ϯ2.6 mm Hg, PϽ0.05), but capillary density did not differ between the groups. Skin vasodilating responses to acetylcholine were greater in young normotensives compared with both elderly groups (PϽ0.05). In isolated resistance arteries, there was a greater inhibitory effect from blockade of the L-arginine-NO pathway in elderly normotensives (PϽ0.05) and a reduction in the maximal inhibitory effect of combined blockade of NO, prostanoids, and endothelium-derived hyperpolarizing factor in elderly hypertensives (PϽ0.05). This study has demonstrated a significant effect of aging but no additional effect of hypertension on capillary pressure and no effect of either on capillary density. Our findings with both in vivo and in vitro methods suggest that normotensive aging may depend on relative preservation of NO-dependent vasodilatation in resistance arteries at the expense of a rise in capillary pressure. Key Words: microcirculation Ⅲ capillaries Ⅲ endothelium Ⅲ endothelium-derived relaxing factors Ⅲ aging A lterations of structure and function in the microcirculation are important factors in vascular disease states, such as hypertension and diabetes mellitus. 1 Capillary pressure is increased in essential hypertension, 2 and this may be because of decreased capillary numbers 3-5 or abnormalities in vascular responses at a precapillary or postcapillary level. 6,7 Both capillary rarefaction and abnormal microvascular responses have been observed before the development of clinical hypertension, 8,9 implicating these processes in pathogenesis.Aging is associated with endothelial dysfunction, possibly because of a decline in NO and prostanoid pathways, 10 -12 yet hypertension in the elderly is predominantly a systolic abnormality, 13 considered to be mainly because of altered large artery stiffness. 14 Whether microvascular structure and function is also abnormal in hypertension in the elderly has not been fully clarified. We, therefore, conducted the present study to examine whether aging, in the absence of changes in blood pressure (BP), is associated with abnormalities in the structure and function of the microcirculation, and whether, in older subjects, hypertension exacerbates any of the abnormalities observed. Methods Study SubjectsThe study was approved by the local research ethics committee and conducted according to the prin...

Background hospital level healthcare in the home guided by comprehensive geriatric assessment (CGA) might provide a less costly alternative to hospitalisation for older people. Objective to determine the cost-effectiveness of CGA admission avoidance hospital at home (HAH) compared with hospital admission. Design/intervention a cost-effectiveness study alongside a randomised trial of CGA in an admission avoidance HAH setting, compared with admission to hospital. Participants/setting older people considered for a hospital admission in nine locations across the UK were randomised using a 2:1 randomisation schedule to admission avoidance HAH with CGA (N = 700), or admission to hospital with CGA when available (N = 355). Measurements quality adjusted life years, resource use and costs at baseline and 6 months; incremental cost-effectiveness ratios were calculated. The main analysis used complete cases. Results adjusting for baseline covariates, HAH was less costly than admission to hospital from a health and social care perspective (mean −£2,265, 95% CI: −4,279 to −252), and remained less costly with the addition of informal care costs (mean difference −£2,840, 95% CI: −5,495 to −185). There was no difference in quality adjusted survival. Using multiple imputation for missing data, the mean difference in health and social care costs widened to −£2,458 (95% CI: −4,977 to 61) and societal costs remained significantly lower (−£3,083, 95% CI: −5,880 to −287). There was little change to quality adjusted survival. Conclusions CGA HAH is a cost-effective alternative to admission to hospital for selected older people.