ORCID Profile
0000-0003-2734-5132
Current Organisation
University of Nottingham
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Publisher: Springer Science and Business Media LLC
Date: 30-11-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2006
DOI: 10.1161/01.STR.0000248763.49831.C3
Abstract: Background and Purpose— Loss of motor function is common after stroke and leads to significant chronic disability. Stem cells are capable of self-renewal and of differentiating into multiple cell types, including neurones, glia, and vascular cells. We assessed the safety of granulocyte-colony–stimulating factor (G-CSF) after stroke and its effect on circulating CD34+ stem cells. Methods— We performed a 2-center, dose-escalation, double-blind, randomized, placebo-controlled pilot trial (ISRCTN 16784092) of G-CSF (6 blocks of 1 to 10 μg/kg SC, 1 or 5 daily doses) in 36 patients with recent ischemic stroke. Circulating CD34+ stem cells were measured by flow cytometry blood counts and measures of safety and functional outcome were also monitored. All measures were made blinded to treatment. Results— Thirty-six patients, whose mean±SD age was 76±8 years and of whom 50% were male, were recruited. G-CSF (5 days of 10 μg/kg) increased CD34+ count in a dose-dependent manner, from 2.5 to 37.7 at day 5 (area under curve, P =0.005). A dose-dependent rise in white cell count ( P .001) was also seen. There was no difference between treatment groups in the number of patients with serious adverse events: G-CSF, 7/24 (29%) versus placebo 3/12 (25%), or in their dependence (modified Rankin Scale, median 4, interquartile range, 3 to 5) at 90 days. Conclusions— G-CSF is effective at mobilizing bone marrow CD34+ stem cells in patients with recent ischemic stroke. Administration is feasible and appears to be safe and well tolerated. The fate of mobilized cells and their effect on functional outcome remain to be determined.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.JSTROKECEREBROVASDIS.2015.12.016
Abstract: There is increasing interest in the use of administrative data (incorporating comorbidity index) and stroke severity score to predict ischemic stroke mortality. The aim of this study was to determine the optimal timing for the collection of stroke severity data and the minimum clinical dataset to be included in models of stroke mortality. To address these issues, we chose the Virtual International Stroke Trials Archive (VISTA), which contains National Institutes of Health Stroke Scale (NIHSS) on admission and at 24 hours, as well as outcome at 90 days. VISTA was searched for patients who had baseline and 24-hour NIHSS. Improvement in regression models was performed by the net reclassification improvement (NRI) method. The clinical data among 5206 patients were mean age, 69 ± 13 comorbidity index, 3.3 ± .9 median NIHSS at baseline, 12 (interquartile range [IQR] 8-17) NIHSS at 24 hours, 9 (IQR 8-15) and death at 90 days in 15%. The baseline model consists of age, gender, and comorbidity index. Adding the baseline NIHSS to model 1 improved the NRI by 0.671 (95% confidence interval [CI] 0.595-0.747) [or 67.1% correct reclassification between model 1 and model 2]. Adding the 24 hour NIHSS term to model 1 (model 3) improved the NRI by 0.929 (95% CI 0.857-1.000) for model 3 versus model 1. Adding the variable thrombolysis to model 3 (model 4) improve NRI by 0.1 (95% CI 0.023-0.178) [model 4 versus model 3]. The optimal model for the prediction of mortality was achieved by adding the 24-hour NIHSS and thrombolysis to the baseline model.
Publisher: Wiley
Date: 06-09-2010
Publisher: American Medical Association (AMA)
Date: 11-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-02-2016
Publisher: Springer Science and Business Media LLC
Date: 22-08-2016
DOI: 10.1038/NCOMMS12314
Abstract: Serial femtosecond crystallography (SFX) using X-ray free-electron laser sources is an emerging method with considerable potential for time-resolved pump-probe experiments. Here we present a lipidic cubic phase SFX structure of the light-driven proton pump bacteriorhodopsin (bR) to 2.3 Å resolution and a method to investigate protein dynamics with modest s le requirement. Time-resolved SFX (TR-SFX) with a pump-probe delay of 1 ms yields difference Fourier maps compatible with the dark to M state transition of bR. Importantly, the method is very s le efficient and reduces s le consumption to about 1 mg per collected time point. Accumulation of M intermediate within the crystal lattice is confirmed by time-resolved visible absorption spectroscopy. This study provides an important step towards characterizing the complete photocycle dynamics of retinal proteins and demonstrates the feasibility of a s le efficient viscous medium jet for TR-SFX.
Publisher: SAGE Publications
Date: 22-10-2013
DOI: 10.1111/IJS.12131
Abstract: Clinical trials for acute ischemic stroke treatment require large numbers of participants and are expensive to conduct. Methods that enhance statistical power are therefore desirable. We explored whether this can be achieved by a measure incorporating both early and late measures of outcome (e.g. seven-day NIH Stroke Scale combined with 90-day modified Rankin scale). We analyzed sensitivity to treatment effect, using proportional odds logistic regression for ordinal scales and generalized estimating equation method for global outcomes, with all analyses adjusted for baseline severity and age. We ran simulations to assess relations between s le size and power for ordinal scales and corresponding global outcomes. We used R version 2·12·1 (R Development Core Team. R Foundation for Statistical Computing, Vienna, Austria) for simulations and SAS 9·2 (SAS Institute Inc., Cary, NC, USA) for all other analyses. Each scale considered for combination was sensitive to treatment effect in isolation. The mRS90 and NIHSS90 had adjusted odds ratio of 1·56 and 1·62, respectively. Adjusted odds ratio for global outcomes of the combination of mRS90 with NIHSS7 and NIHSS90 with NIHSS7 were 1·69 and 1·73, respectively. The smallest s le sizes required to generate statistical power ≥80% for mRS90, NIHSS7, and global outcomes of mRS90 and NIHSS7 combined and NIHSS90 and NIHSS7 combined were 500, 490, 400, and 380, respectively. When data concerning both early and late outcomes are combined into a global measure, there is increased sensitivity to treatment effect compared with solitary ordinal scales. This delivers a 20% reduction in required s le size at 80% power. Combining early with late outcomes merits further consideration.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2013
DOI: 10.1161/STROKEAHA.113.002794
Abstract: In previous studies, the Totaled Health Risks in Vascular Events (THRIVE) score has shown broad utility, allowing prediction of clinical outcome, death, and risk of hemorrhage after tissue-type plasminogen activator (tPA) treatment, irrespective of the type of acute stroke therapy applied to the patient. We used data from the Virtual International Stroke Trials Archive to further validate the THRIVE score in a large cohort of patients receiving tPA or no acute treatment, to confirm the relationship between THRIVE and hemorrhage after tPA, and to compare the THRIVE score with several other available outcome prediction scores. The THRIVE score strongly predicts clinical outcome (odds ratio, 0.55 for good outcome [95% CI, 0.53–0.57] P .001), mortality (odds ratio, 1.57 [95% confidence interval, 1.50–1.64] P .001), and risk of intracerebral hemorrhage after tPA (odds ratio, 1.34 [95% confidence interval, 1.22–1.46] P .001). The relationship between THRIVE score and outcome is not influenced by the independent relationship of tPA administration and outcome. In receiver operator characteristic curve analysis, the THRIVE score was superior to several other available outcome prediction scores in the prediction of clinical outcome and mortality. The THRIVE score is a simple-to-use tool to predict clinical outcome, mortality, and risk of hemorrhage after thrombolysis in patients with ischemic stroke. Despite its simplicity, the THRIVE score performs better than several other outcome prediction tools. A free Web calculator for the THRIVE score is available at www.thrivescore.org .
Publisher: Elsevier BV
Date: 02-2004
Publisher: Informa UK Limited
Date: 1994
DOI: 10.3109/09537109409005525
Abstract: Platelets are involved in atherogenesis, partly through the release of smooth muscle cell mitogens and chemoattractants such as platelet-derived growth factor (PDGF). The St Thomas' Atherosclerosis Regression Study (STARS) demonstrated that a cholesterol-lowering diet induced angiographic regression of coronary artery disease in 74 men. Serum PDGF concentrations were not different at the end of the study between patients randomised to receive diet, with or without cholestyramine: usual care (UC) median 53.6 pM (interquartile range 15.3), diet (D) 60.0 pM (29.7), diet and cholestyramine (DC) 51.5 pM (13.0), 2p = 0.23. Similarly, mean platelet volume (MPV), a marker of platelet function, did not differ between the three groups: UC 8.0 fl (1.1), D 8.6 fl (0.8), DC 9.0 fl (1.4), 2p = 0.16. PDGF concentrations and MPV did not correlate with lipid concentrations or angiographic indices of regression. These findings suggest that platelet function, as measured by PDGF and MPV, does not change during, or contribute to, dietary-induced regression of coronary artery disease.
Publisher: SAGE Publications
Date: 17-09-2008
Abstract: As a research community, we have failed to show that drugs, which show substantial efficacy in animal models of cerebral ischemia, can also improve outcome in human stroke. Accumulating evidence suggests this may be due, at least in part, to problems in the design, conduct, and reporting of animal experiments which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.
Publisher: SAGE Publications
Date: 06-2009
Abstract: Correction to: Journal of Cerebral Blood Flow & Metabolism (2009) 29, 221–223 doi:10.1038/jcbfm.2008.101 Following the publication of this article, the authors noted that Dr Buchan's first name was misspelled. The correct and complete author name is above.
Publisher: SAGE Publications
Date: 04-2008
DOI: 10.1258/JHSRP.2007.007011
Abstract: The aim of this study is to estimate the potential costs and benefits of three key interventions (computerized physician order entry [CPOE], additional ward pharmacists and bar coding) to help prioritize research to reduce medication errors. A generic model structure was developed to describe the incidence and impacts of medication errors in hospitals. The model follows pathways from medication error points at alternative stages of the medication pathway through to the outcomes of undetected errors. The model was populated from a systematic review of the medication errors literature combined with novel probabilistic calibration methods. Cost ranges were applied to the interventions, the treatment of preventable adverse drug events (pADEs), and the value of the health lost as a result of an ADE. The model predicts annual health service costs of between £0.3 million and £1 million for the treatment of pADEs in a 400-bed acute hospital in the UK. Including only health service costs, it is uncertain whether any of the three interventions will produce positive net benefits, particularly if high intervention costs are assumed. When the monetary value of lost health is included, all three interventions have a high probability of producing positive net benefits with a mean estimate of around £31.5 million for CPOE over a five-year time horizon. The results identify the potential cost-effectiveness of interventions aimed at medication errors, as well as identifying key drivers of cost-effectiveness that should be specifically addressed in the design of primary evaluations of medication error interventions.
Publisher: BMJ
Date: 02-2018
DOI: 10.1136/BMJOPEN-2017-019930
Abstract: To test whether administration of the antifibrinolytic drug tranexamic acid (TXA) in patients with spontaneous intracerebral haemorrhage (SICH) leads to increased prevalence of diffusion-weighted MRI-defined hyperintense ischaemic lesions (primary hypothesis) or reduced perihaematomal oedema volume, perihaematomal diffusion restriction and residual MRI-defined SICH-related tissue damage (secondary hypotheses). MRI substudy nested within the double-blind randomised controlled Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 trial ( ISRCTN93732214 ). International multicentre hospital-based study. Eligible adults consented and randomised in the TICH-2 trial who were also able to undergo MRI scanning. To address the primary hypothesis, a s le size of n=280 will allow detection of a 10% relative increase in prevalence of diffusion-weighted imaging (DWI) hyperintense lesions in the TXA group with 5% significance, 80% power and 5% imaging data rejection. TICH-2 MRI substudy participants will undergo MRI scanning using a standardised protocol at day ~5 and day ~90 after randomisation. Clinical assessments, randomisation to TXA or placebo and participant follow-up will be performed as per the TICH-2 trial protocol. The TICH-2 MRI substudy will test whether TXA increases the incidence of new DWI-defined ischaemic lesions or reduces perihaematomal oedema or final ICH lesion volume in the context of SICH. The TICH-2 trial obtained ethical approval from East Midlands - Nottingham 2 Research Ethics Committee (12/EM/0369) and an amendment to allow the TICH-2 MRI sub study was approved in April 2015 (amendment number SA02/15). All findings will be published in peer-reviewed journals. The primary outcome results will also be presented at a relevant scientific meeting. ISRCTN93732214 Pre-results.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-10-2021
Publisher: Public Library of Science (PLoS)
Date: 09-09-2016
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.STR.2017.07.002
Abstract: Serial protein crystallography was developed at X-ray free-electron lasers (XFELs) and is now also being applied at storage ring facilities. Robust strategies for the growth and optimization of microcrystals are needed to advance the field. Here we illustrate a generic strategy for recovering high-density homogeneous s les of microcrystals starting from conditions known to yield large (macro) crystals of the photosynthetic reaction center of Blastochloris viridis (RC
Publisher: SAGE Publications
Date: 12-01-2015
DOI: 10.1111/IJS.12427
Abstract: Over the last 10 years, there has been stagnation in the number of multinational drug trials in stroke in Europe. One important cause of this is probably the increased burden of laws and regulations that came with the European Union Clinical Trials Directive. The main objective of research regulation and governance should be to protect research participants, their tissues, and data, but the approval systems are complex, regulation is variably interpreted and enforced, and the assessment of studies is often not proportionate to the risk of the research to participants. Such unnecessary barriers should be reduced by simplifying, centralizing, and harmonizing the application process, and by applying regulatory and governance requirements in a way that is proportionate to the potential harms to the patients. The traditional functions of a regulator (in setting, monitoring, and enforcing quality standards) could also be supplemented with an aim to actively help researchers achieve these standards, for ex le, by giving advice, and ultimately with an aim to facilitate and promote research, for ex le, by integrating research in everyday clinical practice. Research networks offer one way of integrating research and clinical practice across multiple centers, and can streamline research delivery by supporting researchers deal professionally and efficiently with the regulations and governance requirements.
Publisher: SAGE Publications
Date: 02-2009
DOI: 10.1111/J.1747-4949.2009.00241.X
Abstract: As a research community, we have failed to demonstrate that drugs that show substantial efficacy in animal models of cerebral ischemia can also improve outcome in human stroke. Accumulating evidence suggests that this may be due, at least in part, to problems in the design, conduct and reporting of animal experiments, which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.
Publisher: SAGE Publications
Date: 26-05-2021
DOI: 10.1177/0271678X211018901
Abstract: Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models. Merino sheep underwent middle cerebral artery occlusion (MCAO) followed by GTN or control patch administration (0.2 mg/h). Monitoring of numerous physiologically relevant measures over 24 h showed that GTN administration was associated with decreased intracranial pressure, infarct volume, cerebral oedema and midline shift compared to vehicle treatment (p 0.05). No significant changes in blood pressure or cerebral perfusion pressure were observed. Using optical imaging spectroscopy and laser speckle imaging, the effect of varying doses of GTN (0.69–50 µg/h) on cerebral blood flow and tissue oxygenation was examined in mice. No consistent effect was found. Additional mice undergoing MCAO followed by GTN administration (doses varying from 0–60 µg/h) also showed no improvement in infarct volume or neurological score within 24 h post-stroke. GTN administration significantly improved numerous stroke-related physiological outcomes in sheep but was ineffective in mice. This suggests that, whilst GTN administration could potentially benefit patients, further research into mechanisms of action are required.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2017
Publisher: SAGE Publications
Date: 17-07-2014
DOI: 10.1111/IJS.12302
Abstract: We are entering a challenging but exciting period when many new interventions may appear for stroke based on the use of devices. Hopefully these will lead to improved outcomes at a cost that can be afforded in most parts of the world. Nevertheless, it is vital that lessons are learnt from failures in the development of pharmacological interventions (and from some early device studies), including inadequate preclinical testing, suboptimal trial design and analysis, and underpowered studies. The device industry is far more disparate than that seen for pharmaceuticals companies are very variable in size and experience in stroke, and are developing interventions across a wide range of stroke treatment and prevention. It is vital that companies work together where sales and marketing are not involved, including in understanding basic stroke mechanisms, prospective systematic reviews, and education of physicians. Where possible, industry and academics should also work closely together to ensure trials are designed to be relevant to patient care and outcomes. Additionally, regulation of the device industry lags behind that for pharmaceuticals, and it is critical that new interventions are shown to be safe and effective rather than just feasible. Phase IV postmarketing surveillance studies will also be needed to ensure that devices are safe when used in the ‘real-world’ and to pick up uncommon adverse events.
Publisher: SAGE Publications
Date: 10-2014
DOI: 10.1111/IJS.12269
Abstract: Epidemiological studies show that vascular risk factors are the same across the world but their effect vary between different race-ethnic groups. However, few studies have evaluated differences in recurrent stroke rates in various race-ethnicities. In 000 patients spanning 35 countries encompassing most race-ethnicities, we evaluated the incidence of ischemic and hemorrhagic strokes and myocardial infarction in patients within the context of the largest secondary stroke prevention trial (Prevention Regimen for Effectively Avoiding Secondary Strokes) to identify any significant differences. There were 20 332 patients with a recent ischemic stroke randomized in a factorial design to receive the antiplatelet agent clopidogrel vs. aspirin plus extended-release dipyridamole, and 80 mg of the anthypertensive telmisartan vs. placebo. The primary outcome for the trial was the time to any recurrent stroke. Statistical analysis was used to detect race-ethnic differences in recurrent vascular events. Mean patient age was 66 (±8·6) years and 36% were women. The study included 58% European/Caucasian, 33% Asians, 5% Latin/Hispanic, and 4% Black African. There were 74% of patients that were hypertensive, and average systolic and diastolic blood pressure was 144·1/83·8 mmHg. There was at least one significant difference in the overall test of all race-ethnic groups in myocardial infarction and symptomatic intracerebral hemorrhage occurrence. In the Kaplan–Meier hemorrhage and stroke-free survival curves, Asians showed a significantly higher recurrence of ischemic stroke risk in the 135–150 mmHg and greater than 150 mm Hg blood pressure groups, and a greater risk of hemorrhage recurrence in the greater than 150 mmHg blood pressure group. We found a significant difference in myocardial infarction and symptomatic intracerebral hemorrhage recurrence among different race-ethnic groups. The risk of recurrent ischemic and hemorrhagic stroke was greater in Asians with high blood pressure.
Publisher: SAGE Publications
Date: 22-10-2013
DOI: 10.1111/IJS.12148
Abstract: Benzodiazepines have been proposed both as a neuroprotectant and risk factor for pneumonia in acute stroke. Aims We assessed the impact of benzodiazepine exposure on the modified Rankin scale score distribution at 90 days as well as pneumonia rates among patients registered in a trials archive. We used an age, baseline National Institutes of Health Stroke Score, and thrombolysis-rate adjusted Cochran–Mantel–Haenszel test to test significance ( P) followed by proportional odds logistic regression analysis to estimate the odds ratios for improved modified Rankin scale score, and binary logistic regression to estimate the odds ratio for developing pneumonia. Data were available for 5938 patients, of whom 1800 received benzodiazepines. No association of benzodiazepine use and overall stroke outcome could be found (odds ratio 0·90, 95% confidence interval 0·82–1·00, P = 0·121). Pneumonia occurred in 12·8% of patients treated with benzodiazepines and in 13·6% of the controls (odds ratio 0·99, 95% confidence interval 0·83–1·18, P = 0·904). In this nonrandomized comparison, treatment with benzodiazepines as a concomitant medication had no independent impact on stroke outcome.
Publisher: BMJ
Date: 11-2022
DOI: 10.1136/BMJOPEN-2021-060211
Abstract: Ambulances offer the first opportunity to evaluate hyperacute stroke treatments. In this study, we investigated the conduct of a hyperacute stroke study in the ambulance-based setting with a particular focus on timings and logistics of trial delivery. Multicentre prospective, single-blind, parallel group randomised controlled trial. Eight National Health Service ambulance services in England and Wales 54 acute stroke centres. Paramedics enrolled 1149 patients assessed as likely to have a stroke, with Face, Arm, Speech and Time score (2 or 3), within 4 hours of symptom onset and systolic blood pressure mm Hg. Paramedics administered randomly assigned active transdermal glyceryl trinitrate or sham. Modified Rankin scale at day 90. This paper focuses on response time intervals, distances travelled and baseline characteristics of patients, compared between ambulance services. Paramedics enrolled 1149 patients between September 2015 and May 2018. Final diagnosis: intracerebral haemorrhage 13%, ischaemic stroke 52%, transient ischaemic attack 9% and mimic 26%. Timings (min) were (median (25–75 centile)): onset to emergency call 19 (5–64) onset to randomisation 71 (45–116) total time at scene 33 (26–46) depart scene to hospital 15 (10–23) randomisation to hospital 24 (16–34) and onset to hospital 97 (71–141). Ambulances travelled (km) 10 (4–19) from scene to hospital. Timings and distances differed between ambulance service, for ex le, onset to randomisation (fastest 53 min, slowest 77 min p .001), distance from scene to hospital (least 4 km, most 20 km p .001). We completed a large prehospital stroke trial involving a simple-to-administer intervention across multiple ambulance services. The time from onset to randomisation and modest distances travelled support the applicability of future large-scale paramedic-delivered ambulance-based stroke trials in urban and rural locations. ISRCTN26986053 .
Publisher: BMJ
Date: 08-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2015
DOI: 10.1161/STROKEAHA.115.009647
Abstract: Nitric oxide donors are candidate treatments for acute stroke, potentially through hemodynamic, reperfusion, and neuroprotectant effects, especially if given early. Although the large Efficacy of Nitric Oxide in Stroke (ENOS) trial of transdermal glyceryl trinitrate (GTN) was neutral, a prespecified subgroup suggested that GTN improved functional outcome if administered early after stroke onset. Prospective analysis of subgroup of patients randomized into the ENOS trial within 6 hours of stroke onset. Safety and efficacy of GTN versus no GTN were assessed using data on early and late outcomes. Two hundred seventy-three patients were randomized within 6 hours of ictus: mean (SD) age, 69.9 (12.7) years men, 154 (56.4%) ischemic stroke, 208 (76.2%) Scandinavian Stroke Scale, 32.1 (11.9) and total anterior circulation syndrome, 86 (31.5%). When compared with no GTN, the first dose of GTN lowered blood pressure by 9.4/3.3 mm Hg ( P .01, P =0.064) and shifted the modified Rankin Scale to a better outcome by day 90, adjusted common odds ratio, 0.51 (95% confidence interval, 0.32–0.80). Significant beneficial effects were also seen with GTN for disability (Barthel Index), quality of life (EuroQol-Visual Analogue Scale), cognition (telephone Mini-Mental State Examination), and mood (Zung Depression Scale). GTN was safe to administer with less serious adverse events by day 90 (GTN 18.8% versus no GTN 34.1%) and death (hazard ratio, 0.44 95% confidence interval, 0.20–0.99 P =0.047). In a subgroup analysis of the large ENOS trial, transdermal GTN was safe to administer and associated with improved functional outcome and fewer deaths when administered within 6 hours of stroke onset. URL: www.clinicaltrials.gov . Unique identifier: NCT00989716.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2017
DOI: 10.1161/STROKEAHA.116.016274
Abstract: Many patients receiving thrombolysis for acute ischemic stroke are on prior antiplatelet therapy (APT), which may increase symptomatic intracerebral hemorrhage risk. In a prespecified subgroup analysis, we report comparative effects of different doses of intravenous alteplase according to prior APT use among participants of the international multicenter ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study). Among 3285 alteplase-treated patients (mean age, 66.6 years 38% women) randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset, 752 (22.9%) reported prior APT use. Primary outcome at 90 days was the combined end point of death or disability (modified Rankin Scale [mRS] scores, 2–6). Other outcomes included mRS scores 3 to 6, ordinal mRS shift, and symptomatic intracerebral hemorrhage by various standard criteria. There were no significant differences in outcome between patients with and without prior APT after adjustment for baseline characteristics and management factors during the first week defined by mRS scores 2 to 6 (adjusted odds ratio [OR], 1.01 95% confidence interval [CI], 0.81–1.26 P =0.953), 3 to 6 (OR, 0.95 95% CI, 0.75–1.20 P =0.662), or ordinal mRS shift (OR, 1.03 95% CI, 0.87–1.21 P =0.770). Alteplase-treated patients on prior APT had higher symptomatic intracerebral hemorrhage (OR, 1.82 95% CI, 1.00–3.30 P =0.051) according to the safe implementation of thrombolysis in stroke-monitoring study definition. Although not significant ( P -trend, 0.053), low-dose alteplase tended to have better outcomes than standard-dose alteplase in those on prior APT compared with those not using APT (mRS scores of 2–6 OR, 0.84 95% CI, 0.62–1.12 versus OR, 1.16 95% CI, 0.99–1.36). Low-dose alteplase may improve outcomes in thrombolysis-treated acute ischemic stroke patients on prior APT, but this requires further evaluation in a randomized controlled trial. URL: www.clinicaltrials.gov . Unique identifier: NCT01422616.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Wiley
Date: 17-04-2018
Publisher: Frontiers Media SA
Date: 19-05-2017
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1186/S13063-021-05860-Y
Abstract: Early pre-hospital initiation of blood pressure (BP) lowering could improve outcomes for patients with acute stroke, by reducing hematoma expansion in intracerebral hemorrhage (ICH), and time to reperfusion treatment and risk of intracranial hemorrhage in ischemic stroke (IS). We present the design of the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4). A multi-center, ambulance-delivered, prospective, randomized, open-label, blinded endpoint (PROBE) assessed trial of pre-hospital BP lowering in 3116 hypertensive patients with suspected acute stroke at 50+ sites in China. Patients are randomized through a mobile phone digital system to intensive BP lowering to a target systolic BP of 140 mmHg within 30 min, or guideline-recommended BP management according to local protocols. After the collection of in-hospital clinical and management data and 7-day outcomes, trained blinded assessors conduct telephone or face-to-face assessments of physical function and health-related quality of life in participants at 90 days. The primary outcome is the physical function on the modified Rankin scale at 90 days, analyzed as an ordinal outcome with 7 categories. The s le size was estimated to provide 90% power ( α = 0.05) to detect a 22% reduction in the odds of a worse functional outcome using ordinal logistic regression. INTERACT4 is a pragmatic clinical trial to provide reliable evidence on the effectiveness and safety of ambulance-delivered hyperacute BP lowering in patients with suspected acute stroke. ClinicalTrials.gov NCT03790800. Registered on 2 January 2019 Chinese Trial Registry ChiCTR1900020534. Registered on 7 January 2019. All items can be found in this protocol paper.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-03-2021
Abstract: Antiplatelet therapy increases the risk of hematoma expansion in intracerebral hemorrhage (ICH) while the effect on functional outcome is uncertain. This is an exploratory analysis of the TICH‐2 (Tranexamic Acid in Intracerebral Hemorrhage‐2) double‐blind, randomized, placebo‐controlled trial, which studied the efficacy of tranexamic acid in patients with spontaneous ICH within 8 hours of onset. Multivariable logistic regression and ordinal regression were performed to explore the relationship between pre‐ICH antiplatelet therapy, and 24‐hour hematoma expansion and day 90 modified Rankin Scale score, as well as the effect of tranexamic acid. Of 2325 patients, 611 (26.3%) had pre‐ICH antiplatelet therapy. They were older (mean age, 75.7 versus 66.5 years), more likely to have ischemic heart disease (25.4% versus 2.7%), ischemic stroke (36.2% versus 6.3%), intraventricular hemorrhage (40.2% versus 27.5%), and larger baseline hematoma volume (mean, 28.1 versus 22.6 mL) than the no‐antiplatelet group. Pre‐ICH antiplatelet therapy was associated with a significantly increased risk of hematoma expansion (adjusted odds ratio [OR], 1.28 95% CI, 1.01–1.63), a shift toward unfavorable outcome in modified Rankin Scale (adjusted common OR, 1.58 95% CI, 1.32–1.91) and a higher risk of death at day 90 (adjusted OR, 1.63 95% CI, 1.25–2.11). Tranexamic acid reduced the risk of hematoma expansion in the overall patients with ICH (adjusted OR, 0.76 95% CI, 0.62–0.93) and antiplatelet subgroup (adjusted OR, 0.61 95% CI, 0.41–0.91) with no significant interaction between pre‐ICH antiplatelet therapy and tranexamic acid (P interaction=0.248). Antiplatelet therapy is independently associated with hematoma expansion and unfavorable functional outcome. Tranexamic acid reduced hematoma expansion regardless of prior antiplatelet therapy use. URL: www.isrctn.com Unique identifier: ISRCTN93732214.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2021
DOI: 10.1186/S12874-021-01388-6
Abstract: Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared in idual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p -value given the smallest rank. Friedman and Duncan’s multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test. Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes. Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.
Publisher: Elsevier BV
Date: 07-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-02-2020
DOI: 10.1212/WNL.0000000000011106
Abstract: This tertiary analysis from A Very Early Rehabilitation Trial (AVERT) examined fatal and nonfatal serious adverse events (SAEs) at 14 days. AVERT was a prospective, parallel group, assessor blinded, randomized international clinical trial comparing mobility training commenced hours poststroke, termed very early mobilization (VEM), to usual care (UC). Primary outcome was assessed at 3 months. Patients with ischemic or hemorrhagic stroke within 24 hours of onset were included. Treatment with thrombolytics was allowed. Patients with severe premorbid disability or comorbidities were excluded. Interventions continued for 14 days or hospital discharge if less. The primary early safety outcome was fatal SAEs within 14 days. Secondary outcomes were nonfatal SAEs classified as neurologic, immobility-related, and other. Mortality influences were assessed using binary logistic regression adjusted for baseline stroke severity (NIH Stroke Scale [NIHSS] score) and age. A total of 2,104 participants were randomized to VEM (n = 1,054) or UC (n = 1,050) with a median age of 72 years (interquartile range [IQR] 63–80) and NIHSS 7 (IQR 4–12). By 14 days, 48 had died in VEM, 32 in UC, age and stroke severity adjusted odds ratio of 1.76 (95% confidence interval 1.06–2.92, p = 0.029). Stroke progression was more common in VEM. Exploratory subgroup analyses showed higher odds of death in intracerebral hemorrhage and years subgroups, but there was no significant treatment by subgroup interaction. No difference in nonfatal SAEs was found. While the overall case fatality at 14 days poststroke was only 3.8%, mortality adjusted for age and stroke severity was increased with high dose and intensive training compared to usual care. Stroke progression was more common in VEM. Australian New Zealand Clinical Trials Registry, ACTRN12606000185561. This study provides Class I evidence that very early mobilization increases mortality at 14 days poststroke.
Publisher: Portland Press Ltd.
Date: 30-04-2018
DOI: 10.1042/CS20171620
Abstract: Cerebral small vessel disease (SVD) is a major contributor to stroke, cognitive impairment and dementia with limited therapeutic interventions. There is a critical need to provide mechanistic insight and improve translation between pre-clinical research and the clinic. A 2-day workshop was held which brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. These proceedings provide a summary of key talks at the workshop with a particular focus on animal models of cerebral vascular disease and dementia, mechanisms and approaches to improve translation. The outcomes of discussion groups on related themes to identify the gaps in knowledge and requirements to advance knowledge are summarized.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-09-2018
DOI: 10.1212/WNL.0000000000006437
Abstract: To determine the optimal cut point on the NIH Stroke Scale (NIHSS) for predicting poor 90-day clinical outcome in patients with supratentorial and infratentorial acute ischemic stroke (AIS). Data are from participants of the alteplase-dose arm of the randomized controlled trial, Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Associations between baseline characteristics of clinically defined supratentorial and infratentorial AIS patients and poor functional outcome, defined by scores 3–6 on the modified Rankin Scale, were evaluated in logistic regression models, with area under the curve (AUC) receiver operating characteristics defining the optimal NIHSS predictor cut point. Patients with infratentorial AIS (n = 289) had lower baseline NIHSS scores than those with supratentorial AIS (n = 2,613) (median 7 vs 9 p 0.001). NIHSS cut points for poor outcome were 10 (AUC 76, sensitivity 65%, specificity 73%) and 6 (AUC 69, sensitivity 72%, specificity 56%) in supratentorial and infratentorial AIS, respectively. There was no significant difference in functional outcome or symptomatic intracranial hemorrhage between AIS types. In thrombolysis-eligible AIS patients, the NIHSS may underestimate clinical severity for infratentorial compared to supratentorial lesions for a similar prognosis for recovery. Because thrombolysis treatment has low effect on stroke outcome in patients with infratentorial AIS when baseline NIHSS score is more than 6, additional treatment such as endovascular treatment should be considered to improve stroke outcome. NCT01422616.
Publisher: Elsevier BV
Date: 03-2019
Publisher: National Institute for Health and Care Research
Date: 02-2010
DOI: 10.3310/HTA14100
Abstract: To determine which of two methods of case note review--holistic (implicit) and criterion-based (explicit)--provides the most useful and reliable information for quality and safety of care, and the level of agreement within and between groups of health-care professionals when they use the two methods to review the same record. To explore the process-outcome relationship between holistic and criterion-based quality-of-care measures and hospital-level outcome indicators. Case notes of patients at randomly selected hospitals in England. In the first part of the study, retrospective multiple reviews of 684 case notes were undertaken at nine acute hospitals using both holistic and criterion-based review methods. Quality-of-care measures included evidence-based review criteria and a quality-of-care rating scale. Textual commentary on the quality of care was provided as a component of holistic review. Review teams comprised combinations of: doctors (n = 16), specialist nurses (n = 10) and clinically trained audit staff (n = 3) and non-clinical audit staff (n = 9). In the second part of the study, process (quality and safety) of care data were collected from the case notes of 1565 people with either chronic obstructive pulmonary disease (COPD) or heart failure in 20 hospitals. Doctors collected criterion-based data from case notes and used implicit review methods to derive textual comments on the quality of care provided and score the care overall. Data were analysed for intrarater consistency, inter-rater reliability between pairs of staff using intraclass correlation coefficients (ICCs) and completeness of criterion data capture, and comparisons were made within and between staff groups and between review methods. To explore the process-outcome relationship, a range of publicly available health-care indicator data were used as proxy outcomes in a multilevel analysis. Overall, 1473 holistic and 1389 criterion-based reviews were undertaken in the first part of the study. When same staff-type reviewer pairs/groups reviewed the same record, holistic scale score inter-rater reliability was moderate within each of the three staff groups [intraclass correlation coefficient (ICC) 0.46-0.52], and inter-rater reliability for criterion-based scores was moderate to good (ICC 0.61-0.88). When different staff-type pairs/groups reviewed the same record, agreement between the reviewer pairs/groups was weak to moderate for overall care (ICC 0.24-0.43). Comparison of holistic review score and criterion-based score of case notes reviewed by doctors and by non-clinical audit staff showed a reasonable level of agreement (p-values for difference 0.406 and 0.223, respectively), although results from all three staff types showed no overall level of agreement (p-value for difference 0.057). Detailed qualitative analysis of the textual data indicated that the three staff types tended to provide different forms of commentary on quality of care, although there was some overlap between some groups. In the process-outcome study there generally were high criterion-based scores for all hospitals, whereas there was more interhospital variation between the holistic review overall scale scores. Textual commentary on the quality of care verified the holistic scale scores. Differences among hospitals with regard to the relationship between mortality and quality of care were not statistically significant. Using the holistic approach, the three groups of staff appeared to interpret the recorded care differently when they each reviewed the same record. When the same clinical record was reviewed by doctors and non-clinical audit staff, there was no significant difference between the assessments of quality of care generated by the two groups. All three staff groups performed reasonably well when using criterion-based review, although the quality and type of information provided by doctors was of greater value. Therefore, when measuring quality of care from case notes, consideration needs to be given to the method of review, the type of staff undertaking the review, and the methods of analysis available to the review team. Review can be enhanced using a combination of both criterion-based and structured holistic methods with textual commentary, and variation in quality of care can best be identified from a combination of holistic scale scores and textual data review.
Publisher: Public Library of Science (PLoS)
Date: 26-11-2018
Publisher: BMJ
Date: 05-11-2020
Abstract: Nitrate-induced headache is common and may signify responsive cerebral vasculature. We assessed the relationship between nitrate headache and outcome in patients with acute stroke. Patients were those randomised to glyceryl trinitrate (GTN) versus no GTN in the efficacy of nitric oxide in stroke trial. Development of headache by end of treatment (day 7), and functional outcome (modified Rankin Scale, primary outcome) at day 90, were assessed. Analyses are adjusted for baseline prognostic factors and give OR and mean difference (MD) with 95% CI. In 4011 patients, headache was more common in GTN than control (360, 18.0% vs 170, 8.5% p .001). Nitrate-related headache was associated with: younger age, female sex, higher diastolic blood pressure, non-total anterior circulation syndrome, milder stroke and absence of dysphasia (p .05). Nitrate headache was not associated with improved functional outcome (OR 0.90, 95% CI 0.73 to 1.10, p=0.30) or death (day 90) (HR 0.64, 95% CI 0.40 to 1.02, p=0.062), but reduced death or deterioration (day 7) (OR 0.45, 95% CI 0.25 to 0.82), death in hospital (OR 0.44, 95% CI 0.22 to 0.88) and improved activities of daily living (Barthel index, MD 3.7, 95% CI 0.3 to 7.1) and cognition (telephone interview cognitive screen, MD 2.0, 95% CI 0.7 to 3.3) (day 90). Non-nitrate headache was not associated with death, disability or cognition. Development of a nitrate headache by day 7 after stroke may be associated with improved activities of daily living and cognitive impairment at day 90, which was not seen with non-nitrate headache.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2013
DOI: 10.1161/STROKEAHA.113.001126
Abstract: Quality of life (QoL) is important to stroke survivors yet is often recorded as a secondary measure in acute stroke randomized controlled trials. We examined whether commonly used stroke outcome measures captured aspects of QoL. We examined primary outcomes by National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI) and modified Rankin Scale (mRS), and QoL by Stroke Impact Scale (SIS) and European Quality of Life Scale (EQ-5D) from the Virtual International Stroke Trials Archive (VISTA). Using Spearman correlations and logistic regression, we described the relationships between QoL mRS, NIHSS, and BI at 3 months, stratified by respondent (patient or proxy). Using χ 2 analyses, we examined the mismatch between good primary outcome (mRS ≤1, NIHSS ≤5, or BI ≥95) but poor QoL, and poor primary outcome (mRS ≥3, NIHSS ≥20, or BI ≤60) but good QoL. Patient-assessed QoL had a stronger association with mRS (EQ-5D weighted score n=2987, P .0001, r =−0.7, r 2 =0.53 SIS recovery n=2970, P .0001, r =−0.71, r 2 =0.52). Proxy responses had a stronger association with BI (EQ-5D weighted score n=837, P .0001, r =0.78, r 2 =0.63 SIS recovery n=867, P .0001, r =0.68, r 2 =0.48). mRS explained more of the variation in QoL (EQ-5D weighted score=53%, recovery by SIS v3.0=52%) than NIHSS or BI and resulted in fewer mismatches between good primary outcome and poor QoL ( P .0001, EQ-5D weighted score=8.5% SIS recovery=10% SIS-16=4.4%). The mRS seemed to align closely with stroke survivors’ interests, capturing more information on QoL than either NIHSS or BI. This further supports its recommendation as a primary outcome measure in acute stroke randomized controlled trials.
Publisher: SAGE Publications
Date: 19-06-2012
DOI: 10.1111/J.1747-4949.2012.00802.X
Abstract: The main driving force behind the assessment of novel pharmacological agents in animal models of stroke is to deliver new drugs to treat the human disease rather than to increase knowledge of stroke pathophysiology. There are numerous animal models of the ischaemic process and it appears that the same processes operate in humans. Yet, despite these similarities, the drugs that appear effective in animal models have not worked in clinical trials. To date, tissue plasminogen activator is the only drug that has been successfully used at the bedside in hyperacute stroke management. Several reasons have been put forth to explain this, but the failure to consider comorbidities and risk factors common in older people is an important one. In this article, we review the impact of the risk factors most studied in animal models of acute stroke and highlight the parallels with human stroke, and, where possible, their influence on evaluation of therapeutic strategies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-12-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2003
Publisher: Elsevier BV
Date: 12-2018
Publisher: Elsevier BV
Date: 2023
DOI: 10.2139/SSRN.4314023
Publisher: SAGE Publications
Date: 10-07-2020
Abstract: Central adjudication of outcomes is common for randomised trials and should control for differential misclassification. However, few studies have estimated the cost of the adjudication process. We estimated the cost of adjudicating the primary outcome in nine randomised stroke trials (25,436 participants). The costs included adjudicators’ time, direct payments to adjudicators, and co-ordinating centre costs (e.g. uploading cranial scans and general set-up costs). The number of events corrected after adjudication was our measure of benefit. We calculated cost per corrected event for each trial and in total. The primary outcome in all nine trials was either stroke or a composite that included stroke. In total, the adjudication process associated with this primary outcome cost in excess of £100,000 for a third of the trials (3/9). Mean cost per event corrected by adjudication was £2295.10 (SD: £1482.42). Central adjudication is a time-consuming and potentially costly process. These costs need to be considered when designing a trial and should be evaluated alongside the potential benefits adjudication brings to determine whether they outweigh this expense.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2016
DOI: 10.1161/STROKEAHA.115.010368
Abstract: The Efficacy of Nitric Oxide in Stroke (ENOS) trial found that transdermal glyceryl trinitrate (GTN, a nitric oxide donor) lowered blood pressure but did not improve functional outcome in patients with acute stroke. However, GTN was associated with improved outcome if patients were randomized within 6 hours of stroke onset. In this prespecified subgroup analysis, the effect of GTN (5 mg/d for 7 days) versus no GTN was studied in 629 patients with intracerebral hemorrhage presenting within 48 hours and with systolic blood pressure ≥140 mm Hg. The primary outcome was the modified Rankin Scale at 90 days. Mean blood pressure at baseline was 172/93 mm Hg and significantly lower (difference −7.5/−4.2 mm Hg both P ≤0.05) on day 1 in 310 patients allocated to GTN when compared with 319 randomized to no GTN. No difference in the modified Rankin Scale was observed between those receiving GTN versus no GTN (adjusted odds ratio for worse outcome with GTN, 1.04 95% confidence interval, 0.78–1.37 P =0.84). In the subgroup of 61 patients randomized within 6 hours, GTN improved functional outcome with a shift in the modified Rankin Scale (odds ratio, 0.22 95% confidence interval, 0.07–0.69 P =0.001). There was no significant difference in the rates of serious adverse events between GTN and no GTN. In patients with intracerebral hemorrhage within 48 hours of onset, GTN lowered blood pressure was safe but did not improve functional outcome. Very early treatment might be beneficial but needs assessment in further studies. URL: www.isrctn.com/ISRCTN99414122 . Unique identifier: 99414122.
Publisher: SAGE Publications
Date: 02-03-2022
DOI: 10.1177/23969873221078136
Abstract: Low blood pressure (BP) in acute ischaemic stroke (AIS) is associated with poor functional outcome, death, or severe disability. Increasing BP might benefit patients with post-stroke hypotension including those with potentially salvageable ischaemic penumbra. This updated systematic review considers the present evidence regarding the use of vasopressors in AIS. We searched the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE and trial databases using a structured search strategy. We examined reference lists of relevant publications for additional studies examining BP elevation in AIS. We included 27 studies involving 1886 patients. Nine studies assessed increasing BP during acute reperfusion therapy (intravenous thrombolysis, mechanical thrombectomy, intra-arterial thrombolysis or combined). Eighteen studies tested BP elevation alone. Phenylephrine was the most commonly used agent to increase BP (n = 16 studies), followed by norepinephrine (n = 6), epinephrine (n = 3) and dopamine (n = 2). Because of small patient numbers and study heterogeneity, a meta-analysis was not possible. Overall, BP elevation was feasible in patients with fluctuating or worsening neurological symptoms, large vessel occlusion with labile BP, sustained post-stroke hypotension and ineligible for intravenous thrombolysis or after acute reperfusion therapy. The effects on functional outcomes were largely unknown and close monitoring is advised if such intervention is undertaken. Although theoretical arguments support increasing BP to improve cerebral blood flow and sustain the ischaemic penumbra in selected AIS patients, the data are limited and results largely inconclusive. Large, randomised controlled trials are needed to identify the optimal BP target, agent, duration of treatment and effects on clinical outcomes.
Publisher: Elsevier BV
Date: 2022
Publisher: Public Library of Science (PLoS)
Date: 30-03-2010
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-01-2008
Abstract: The evolutionary changes that occur over a small number of generations in natural populations often run counter to what is expected on the basis of the heritability of traits and the selective forces acting upon them. In Soay sheep, dark coat color is associated with large size, which is heritable and positively correlated with fitness, yet the frequency of dark sheep has decreased. This unexpected microevolutionary trend is explained by genetic linkage between the causal mutation underlying the color polymorphism and quantitative trait loci with antagonistic effects on size and fitness. As a consequence, homozygous dark sheep are large, but have reduced fitness relative to phenotypically indistinguishable dark heterozygotes and light sheep. This result demonstrates the importance of understanding the genetic basis of fitness variation when making predictions about the microevolutionary consequences of selection.
Publisher: SAGE Publications
Date: 04-2010
DOI: 10.1111/J.1747-4949.2010.00414.X
Abstract: The Virtual International Stroke Trials Archive was established to improve stroke care and trial design through the collation, categorization and potential access to data sets from clinical trials for the treatment of stroke. Virtual International Stroke Trials Archive currently provides access to a combined data set of 29 anonymised acute stroke trials and one acute stroke registry with data on 500 patients aged between 18 and 103 (mean 71) years. Virtual International Stroke Trials Archive has facilitated research across a broad canvas. The prognosis was poor in patients with very high blood pressure at the time of admission or with a wide variability of systolic blood pressure during the acute phase. The late occurrence of hyperthermia following an ischaemic stroke worsens the prognosis. Stroke lateralisation is not an important predictor of cardiac adverse events or 90-day mortality. Haemorrhagic transformation is seen frequently in patients with cardio-embolic strokes and is associated with a poor prognosis when occurring after the acute phase. Virtual International Stroke Trials Archive has allowed various prognostic models for patients with ischaemic or haemorrhagic stroke to be established and validated. More direct outcomes such as lesion volume can be useful in phase II clinical trials for determining whether a phase III trial should be undertaken. New outcome measures such as ‘home time’ may also strengthen future trials. On a worldwide level, the prognosis of stroke patients differs considerably between various countries. Virtual International Stroke Trials Archive provides an excellent opportunity for analysis of natural history data and prognosis. It has the potential to influence clinical trial design and implementation through exploratory data analyses.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2019
DOI: 10.1161/STROKEAHA.119.026389
Abstract: Pilot trials suggest that glyceryl trinitrate (GTN nitroglycerin) may improve outcome when administered early after stroke onset. We undertook a multicentre, paramedic-delivered, ambulance-based, prospective randomized, sham-controlled, blinded-end point trial in adults with presumed stroke within 4 hours of ictus. Participants received transdermal GTN (5 mg) or a sham dressing (1:1) in the ambulance and then daily for three days in hospital. The primary outcome was the 7-level modified Rankin Scale at 90 days assessed by central telephone treatment-blinded follow-up. This prespecified subgroup analysis focuses on participants with an intracerebral hemorrhage as their index event. Analyses are intention-to-treat. Of 1149 participants with presumed stroke, 145 (13% GTN, 74 sham, 71) had an intracerebral hemorrhage: time from onset to randomization median, 74 minutes (interquartile range, 45–110). By admission to hospital, blood pressure tended to be lower with GTN as compared with sham: mean, 4.4/3.5 mm Hg. The modified Rankin Scale score at 90 days was nonsignificantly higher in the GTN group: adjusted common odds ratio for poor outcome, 1.87 (95% CI, 0.98–3.57). A prespecified global analysis of 5 clinical outcomes (dependency, disability, cognition, quality of life, and mood) was worse with GTN Mann-Whitney difference, 0.18 (95% CI, 0.01–0.35 Wei-Lachin test). GTN was associated with larger hematoma and growth, and more mass effect and midline shift on neuroimaging, and altered use of hospital resources. Death in hospital but not at day 90 was increased with GTN. There were no significant between-group differences in serious adverse events. Prehospital treatment with GTN worsened outcomes in patients with intracerebral hemorrhage. Since these results could relate to the play of chance, confounding, or a true effect of GTN, further randomized evidence on the use of vasodilators in ultra-acute intracerebral hemorrhage is needed. URL: www.controlled-trials.com . Unique identifier: ISRCTN26986053.
Publisher: BMJ
Date: 06-2023
Publisher: S. Karger AG
Date: 2008
DOI: 10.1159/000131083
Abstract: This article represents the update of the European Stroke Initiative Recommendations for Stroke Management. These guidelines cover both ischaemic stroke and transient ischaemic attacks, which are now considered to be a single entity. The article covers referral and emergency management, Stroke Unit service, diagnostics, primary and secondary prevention, general stroke treatment, specific treatment including acute management, management of complications, and rehabilitation.
Publisher: SAGE Publications
Date: 27-05-2021
DOI: 10.1177/17474930211019568
Abstract: Improving stroke services is critical for reducing the global stroke burden. The World Stroke Organization–World Health Organization– Lancet Neurology Commission on Stroke conducted a survey of the status of stroke services in low and middle-income countries (LMICs) compared to high-income countries. Using a validated World Stroke Organization comprehensive questionnaire, we collected and compared data on stroke services along four pillars of the stroke quadrangle (surveillance, prevention, acute stroke, and rehabilitation) in 84 countries across World Health Organization regions and economic strata. The World Health Organization also conducted a survey of non-communicable diseases in 194 countries in 2019. Fewer surveillance activities (including presence of registries, presence of recent risk factors surveys, and participation in research) were reported in low-income countries than high-income countries. The overall global score for prevention was 40.2%. Stroke units were present in 91% of high-income countries in contrast to 18% of low-income countries (p 0.001). Acute stroke treatments were offered in ∼ 60% of high-income countries compared to 26% of low-income countries (p = 0.009). Compared to high-income countries, LMICs provided less rehabilitation services including in-patient rehabilitation, home assessment, community rehabilitation, education, early hospital discharge program, and presence of rehabilitation protocol. There is an urgent need to improve access to stroke units and services globally especially in LMICs. Countries with less stroke services can adapt strategies from those with better services. This could include establishment of a framework for regular monitoring of stroke burden and services, implementation of integrated prevention activities and essential acute stroke care services, and provision of interdisciplinary care for stroke rehabilitation.
Publisher: SAGE Publications
Date: 22-10-2013
DOI: 10.1111/IJS.12162
Abstract: The National Institutes of Neurological Disorders and Stroke and the European Co-operative Acute Stroke III trials enrolled a largely Caucasian population, but the results are often extrapolated onto non-Caucasians. A limited number of nonrandomized studies have proposed that non-Caucasian patients show differential response to tissue plasminogen activator. We examined if non-Caucasian patients of mixed national origin within the Virtual International Stroke Trials Archives neuroprotection trials responded differently to tissue plasminogen activator compared with Caucasians. We matched patients within each race-subtype for age, baseline National Institutes of Health Stroke Scales, and diabetes status, and excluded outliers. We tested for an interaction of race ethnicity with tissue plasminogen activator on predicting outcomes at α = 0·05. We compared 90-day ordinal outcome (modified Rankin Scale primary analysis) and dichotomized outcomes (modified Rankin Scale 0–1 modified Rankin Scale 0–2 survival) within in idual race ethnicity. One thousand nine hundred forty-six thrombolysed patients (125 Blacks, 39 Asians, and 1821 Caucasians) were matched with 1946 non-thrombolysed patients in each race ethnicity group. Postmatching, there were no imbalances in baseline National Institutes of Health Stroke Scales and age between the groups ( P 0·05). The interaction of tissue plasminogen activator with race ethnicity was nonsignificant in ordinal ( P = 0·4) and in dichotomized outcome models ( P 0·05). Ordinal odds for improved outcomes were 1·5 for all patients ( P 0·05). Ordinal odds for Caucasians were 1·5 ( P 0·05) for Blacks, 2·1 ( P 0·05) and for Asians, 1·2 ( P 0·05 1·6 after 1:2 matching with nonthrombolysed, because of small numbers). Dichotomized functional outcomes improved after thrombolysis overall, in Caucasians, in Blacks (modified Rankin Scale 0–2 only), and in Asians (after 1:2 matching P 0·05). Odds for survival were consistent across all groups. These results do not suggest a differential response to tissue plasminogen activator based on race ethnicity. Among Asians, data were particularly sparse, and results should be interpreted with caution.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2022
DOI: 10.1161/STROKEAHA.121.035191
Abstract: Seeking consent rapidly in acute stroke trials is crucial as interventions are time sensitive. We explored the association between consent pathways and time to enrollment in the TICH-2 (Tranexamic Acid in Intracerebral Haemorrhage-2) randomized controlled trial. Consent was provided by patients or by a relative or an independent doctor in incapacitated patients, using a 1-stage (full written consent) or 2-stage (initial brief consent followed by full written consent post-randomization) approach. The computed tomography-to-randomization time according to consent pathways was compared using the Kruskal-Wallis test. Multivariable logistic regression was performed to identify variables associated with onset-to-randomization time of ≤3 hours. Of 2325 patients, 817 (35%) gave self-consent using 1-stage (557 68%) or 2-stage consent (260 32%). For 1507 (65%), consent was provided by a relative (1 stage, 996 [66%] 2 stage, 323 [21%]) or a doctor (all 2-stage, 188 [12%]). One patient did not record prerandomization consent, with written consent obtained subsequently. The median (interquartile range) computed tomography-to-randomization time was 55 (38–93) minutes for doctor consent, 55 (37–95) minutes for 2-stage patient, 69 (43–110) minutes for 2-stage relative, 75 (48–124) minutes for 1-stage patient, and 90 (56–155) minutes for 1-stage relative consents ( P .001). Two-stage consent was associated with onset-to-randomization time of ≤3 hours compared with 1-stage consent (adjusted odds ratio, 1.9 [95% CI, 1.5–2.4]). Doctor consent increased the odds (adjusted odds ratio, 2.3 [1.5–3.5]) while relative consent reduced the odds of randomization ≤3 hours (adjusted odds ratio, 0.10 [0.03–0.34]) compared with patient consent. Only 2 of 771 patients (0.3%) in the 2-stage pathways withdrew consent when full consent was sought later. Two-stage consent process did not result in higher withdrawal rates or loss to follow-up. The use of initial brief consent was associated with shorter times to enrollment, while maintaining good participant retention. Seeking written consent from relatives was associated with significant delays. URL: www.isrctn.com Unique identifier: ISRCTN93732214.
Publisher: SAGE Publications
Date: 19-03-2013
DOI: 10.1111/IJS.12043
Abstract: Aphasia affects up to a third of the stroke population and is associated with poor social participation and quality of life. Yet people with aphasia may be excluded from some types of stroke research due to challenges in informing, consenting, and conducting follow-up in this population. We described the representation of those with aphasia in acute stroke clinical research, the level of inclusion across international trial sites, and whether there have been improvements in the inclusion of this population in recent clinical trials. We conducted a retrospective analysis of clinical trial data from the Virtual International Stroke Trials Archive (VISTA), defining aphasia using the Best Language (item 9) domain of the National Institutes of Health Stroke Scale. We used proportional odds modeling, adjusting for age, gender, ethnicity, stroke severity, medical history, hemisphere affected by stroke, and trial eligibility criteria, to examine the associations between year, location of enrollment, inclusion, and attrition of those with aphasia. Data were available for 8904 patients from 10 trials no trials listed aphasia as an exclusion criterion. At baseline, aphasia was present in 4039 (45·4%) severe/global aphasia was present in 2688 (30·2%). We observed no geographic or longitudinal disparity in the attrition of these patients at three-months. Centers in the Philippines recruited fewer people [ P = 0·05, odds ratio = 0·5, 95% confidence interval (0·2, 1·0)], while centers in Central and South America included more people with severe/global aphasia [ P = 0·0004, odds ratio = 2·4, 95% confidence interval (1·3, 4·3)], when compared with centers in the USA and Canada. Acute stroke trials have demonstrated the feasibility of including people with aphasia in stroke research we observed geographic variations that were not entirely explained by case mix or trial eligibility criteria. Similar levels of inclusion should be sought in nonemergency stroke trials to improve the applicability of research findings to this population.
Publisher: SAGE Publications
Date: 09-07-2016
Abstract: Outcome after intracerebral hemorrhage remains poor. Tranexamic acid is easy to administer, readily available, inexpensive, and effective in other hemorrhagic conditions. This randomized trial aims to test the hypothesis that intravenous tranexamic acid given within 8 h of spontaneous intracerebral hemorrhage reduces death or dependency. Phase III prospective double-blind randomized placebo-controlled trial. Participants within 8 h of spontaneous intracerebral hemorrhage are randomized to receive either intravenous tranexamic acid 1 g 10 min bolus followed by 1 g 8 h infusion, or placebo. A trial of 2000 participants (300 from start-up phase and 1700 from main phase) will have 90% power to detect an ordinal shift of the modified Rankin Scale with odds ratio 0.79. The primary outcome is death or dependency measured by ordinal shift analysis of the 7 level mRS at day 90. Secondary outcomes are neurological impairment at day 7 and disability, quality of life, cognition, and mood at day 90. Safety outcomes are death, serious adverse events, thromboembolic events, and seizures. Cost outcomes are length of stay in hospital, readmission, and institutionalization. This pragmatic trial is assessing efficacy of tranexamic acid after spontaneous intracerebral hemorrhage. Recruitment started in 2013 as of 15th January 2016 1355 participants have been enrolled, from 95 centers in seven countries. Recruitment is due to end in 2017. TICH-2 Trial is registered as ISRCTN93732214.
Publisher: BMJ
Date: 31-10-2012
Abstract: Current evidence suggests that the time lag from the publication of randomised clinical trial results to changes in prescribing behaviour for drugs is gradually reducing. However, the effect of results of clinical trials of devices and non-pharmacological interventions on clinical practice is less clear. Prospective data from the ongoing international 'Efficacy of Nitric Oxide Stroke' (ENOS) trial were analysed to assess the use of graduated compression stockings (GCS) for deep vein thrombus (DVT) prophylaxis in acute stroke patients before and after publication of the large 'Clots in Legs Or sTockings after Stroke' (CLOTS-1) trial. Data on GCS use were available for 1971 patients with acute stroke enrolled into ENOS from February 2003 to April 2011 of these, 498 (25.3%) wore GCS. Prior to publication of CLOTS-1, GCS use was common (>50%) in the UK, Australasia and Canada but infrequent in Asia and the rest of Europe. After publication of CLOTS-1, use of GCS in the UK declined from 398/656 (61%) to 20/567 (4%) (p<0.001) but not elsewhere (eg, in Australasia (57% before publication vs 70% after publication, p=0.24, but based on small numbers). Practice change was apparent within 3 months of the study publication and was sustained thereafter. There was no change in DVT rates before and after CLOTS-1 (0.8% vs 1.0%). GCS use declined dramatically following the reporting of the CLOTS-1 trial. The results support the notion that a neutral trial of a device can influence clinical practice rapidly, which is important with a widely used and moderately expensive (time and finance) intervention.
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/9706720
Abstract: Background. Nitric oxide (NO) donors are a candidate treatment for acute stroke and two trials have suggested that they might improve outcome if administered within 4–6 hours of stroke onset. We assessed the safety and efficacy of NO donors using in idual patient data (IPD) from completed trials. Methods. Randomised controlled trials of NO donors in patients with acute or subacute stroke were identified and IPD sought from the trialists. The effect of NO donor versus control on functional outcome was assessed using the modified Rankin scale (mRS) and death, by time to randomisation. Secondary outcomes included measures of disability, mood, and quality of life. Results. Five trials (4,197 participants) were identified, all involving glyceryl trinitrate (GTN). Compared with control, GTN lowered blood pressure by 7.4/3.3 mmHg. At day 90, GTN did not alter any clinical measures. However, in 312 patients randomised within 6 hours of stroke onset, GTN was associated with beneficial shifts in the mRS (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.34–0.78) and reduced death (OR 0.32, 95% CI 0.14–0.78). Conclusions. NO donors do not alter outcome in patients with recent stroke. However, when administered within 6 hours, NO donors might improve outcomes in both ischaemic and haemorrhagic stroke.
Publisher: Wiley
Date: 16-10-2014
DOI: 10.1111/ENE.12577
Abstract: Ischaemic stroke patients with atrial fibrillation (AF) are at risk of early recurrent stroke (RS). However, antithrombotics commenced at the acute stage may exacerbate haemorrhagic transformation, provoking symptomatic intracerebral haemorrhage (SICH). The relevance of antithrombotics on the patterns and outcome of the cohort was investigated. A non-randomized cohort analysis was conducted using data obtained from VISTA (Virtual International Stroke Trials Archive). The associations of antithrombotics with the modified Rankin Scale (mRS) outcome and the occurrence of RS and SICH (each as a combined end-point of fatal and non-fatal events) at 90 days for post-stroke patients with AF were described. Dichotomized outcomes were also considered as a secondary end-point (i.e. mortality and good outcome measure at 90 days). In all, 1644 patients were identified 1462 (89%) received antithrombotics, 157 (10%) had RS and 50 (3%) sustained SICH by day 90. Combined antithrombotic therapy (i.e. anticoagulants and antiplatelets), 782 (48%), was associated with favourable outcome on ordinal mRS and a significantly lower risk of RS, SICH and mortality by day 90, compared with the no antithrombotics group. The relative risk of RS and SICH appeared highest in the first 2 days post-stroke before attenuating to become constant over time. The risks and benefits of antithrombotics in recent stroke patients with AF appear to track together. Early introduction of anticoagulants (2-3 days post-stroke), and to a lesser extent antiplatelet agents, was associated with substantially fewer RS events over the following weeks but with no excess risk of SICH. More evidence is required to guide clinicians on this issue.
Publisher: Elsevier BV
Date: 05-2016
Publisher: SAGE Publications
Date: 02-2005
DOI: 10.1191/0269215505CR822OA
Abstract: Background and purpose: There are widespread regional variations in the institutionalization rate after stroke. This study sought to identify the factors that predict institutionalization after a primary diagnosis of stroke and determine whether institutionalization rate could be used to assess the quality of hospital care. Methods: A retrospective case note audit of 2778 consecutive admissions with stroke, between 1 September and 31 October 2000 from a randomly selected s le of 79 hospitals in England, Wales and Northern Ireland. Data were collected on demographics, case-mix, clinical outcome, organization of discharge, and place of residence at discharge and at three and six months. The figures from this audit were validated using data from the 1998 National Sentinel Audit of Stroke. Results: Overall 14% of patients previously living at home were discharged to nursing or residential homes. Using logistic regression, Barthel Index score at discharge accounted for 40% of variation. Two-thirds of patients with a discharge Barthel score of B=5 were institutionalized. Age alone explained 14% and when taken together with discharge Barthel and length of stay it accounted for 54% of variation. On admission 22% of the variation in institutionalization rate could be accounted for by total Glasgow Coma Score (15, B=15), age and ability to walk unaided. Regional variations in institutionalization rates are evident and may in part be explained by differences in ease of access to the institutions. Conclusions: Discharge disability and older age were the dominant factors determining admission to nursing and residential homes. It is not possible to predict sufficiently reliably for an in idual patient the likelihood of institutionalization at admission or at 72 h after admission, to justify early resource allocation decisions.
Publisher: Massachusetts Medical Society
Date: 07-04-2016
Publisher: BMJ
Date: 04-2008
Abstract: Models are used to adjust for case mix and to stratify treatment allocation in clinical trials and can, if accurate enough, be used to aid decision-making in in idual patients. We aimed to validate, in patients assessed within 6 hours of onset, a previously described six simple variable (SSV) model that was developed in stroke patients who were assessed sub-acutely. The explanatory variables in the model are age, living alone, independent pre-stroke, Glasgow Coma Scale verbal score, ability to lift arms and ability to walk. The six variables were collected at randomisation in the Third International Stroke Trial (IST3) trial of recombinant tissue plasminogen activator in ischaemic stroke. We assessed survival to 30 days and functional status at 6 months using the Oxford Handicap Scale. We constructed receiver operator characteristic (ROC) curves to establish the model's discriminatory performance and tested its calibration by charting predicted versus actual outcomes. 537 patients (mean age, 74 years) were included, of whom 422 (79%) survived 30 days and 179 (33%) were alive and independent at 6 months. The SSV model had an area under the ROC curve of 0.73 for 30-day survival and 0.82 for independent survival at 6 months. Calibration was satisfactory. This study confirms the external validity of the SSV model in an ischaemic stroke population assessed within 6 hours of symptom onset. The SSV model comprising easily collected variables can therefore be used to stratify patients in hyper-acute stroke trials, but probably is not accurate enough for decision-making in in idual patients.
Publisher: SAGE Publications
Date: 15-07-2014
DOI: 10.1111/IJS.12335
Abstract: The Totaled Health Risks in Vascular Events (THRIVE) score is a clinical prediction score that predicts ischemic stroke outcomes in patients receiving intravenous tissue plasminogen activator, endovascular stroke treatment, or no acute therapy. We have previously found an association between THRIVE and risk of post-tissue plasminogen activator symptomatic intracranial hemorrhage in the National Institute of Neurological Disorders and Stroke (NINDS) tissue plasminogen activator trial and risk of radiographic hemorrhage in Virtual International Stroke Trials Archive. The study aims to validate the relationship between THRIVE and symptomatic intracranial hemorrhage among tissue plasminogen activator-treated patients in the large Safe Implementation of Thrombolysis in Stroke – Monitoring Study (SITS-MOST). This is a retrospective analysis of the prospective SITS-MOST to examine the relationship between THRIVE and symptomatic intracranial hemorrhage after tissue plasminogen activator treatment. Symptomatic intracranial hemorrhage after tissue plasminogen activator was defined according to each of three standard definitions: the NINDS, European Cooperative Acute Stroke Study (ECASS), and Safe Implementation of Thrombolysis in Stroke (SITS) criteria. Multivariable logistic regression was used to confirm the relationship of THRIVE and in idual THRIVE components with the risk of symptomatic intracranial hemorrhage and to examine the relationship of THRIVE, symptomatic intracranial hemorrhage, and functional outcome. The odds ratio for symptomatic intracranial hemorrhage at each increased level of THRIVE score is 1·34 (95% CI 1·27 to 1·41, P 0·001) for symptomatic intracranial hemorrhage by NINDS criteria, 1·36 (95% CI 1·27 to 1·46, P 0·001) for symptomatic intracranial hemorrhage by ECASS criteria, and 1·21 (95% CI 1·09 to 1·36, P 0·001) for symptomatic intracranial hemorrhage by SITS criteria. In receiver-operator characteristics analysis, the C-statistic for THRIVE prediction of symptomatic intracranial hemorrhage was 0·65 (95% CI 0·62 to 0·67) for symptomatic intracranial hemorrhage by NINDS criteria, 0·66 (95% CI 0·63 to 0·69) for symptomatic intracranial hemorrhage by ECASS criteria, and 0·61 (95% CI 0·56 to 0·66) for symptomatic intracranial hemorrhage by SITS criteria. Each component of the THRIVE score predicts the risk of symptomatic intracranial hemorrhage, with independent impact of each component in multivariable analysis. The THRIVE score predicts the risk of symptomatic intracranial hemorrhage after intravenous tissue plasminogen activator administration. This external validation of the relationship between THRIVE and symptomatic intracranial hemorrhage in a prospective study further strengthens the role of the THRIVE score in the prediction of poststroke outcomes.
Publisher: Springer Science and Business Media LLC
Date: 09-06-2020
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1111/J.1538-7836.2011.04486.X
Abstract: Deep vein thrombosis (DVT) is an important complication of stroke, but the evidence to support commonly used prophylactic strategies is conflicting. To describe the incidence, extent, associated clinical features and evolution of DVT after stroke. The CLOTS trials 1 and 2 together randomized 5632 immobile stroke patients in 135 hospitals in nine countries. We screened patients for asymptomatic DVT with compression duplex ultrasound (CDU) at about 7-10 days and again at about 25-30 days after enrollment. Six hundred and forty-one (11.4%) of 5632 patients had DVT detected on the first CDU scan at a median of 8 days (interquartile range [IQR] 7-10 days) after enrollment, and an additional 176 (3.1%) had a DVT on the second CDU scan at a median of 28 days (IQR 26-30 days). Of the 817 with DVTs, 289 (35%) were symptomatic and 39 (5%) had pulmonary embolism (PE) confirmed by imaging. Six hundred and seventy-six (83%) were unilateral, 141 (17%) were bilateral, 322 (39%) were limited to calf veins, 172 (21%) were popliteal, and 323 (40%) were femoral. Among the 542 patients with DVT and a weak leg, the DVT affected the weaker leg in 396 (73%), the stronger leg in 59 (11%), and was bilateral in 87 (16%). Among the 318 patients with a DVT detected on the first CDU scan who had a second scan, the DVT regressed in 148 (47%), stayed the same in 140 (44%), and progressed in only 30 (9%). Although most DVTs develop within the first week, some develop later, and some early DVTs progress. Any prophylaxis needs to be started early but ideally continued for at least 4 weeks.
Publisher: SAGE Publications
Date: 10-11-2013
DOI: 10.1111/IJS.12178
Abstract: Clinical deficits from stroke are erse, prompting measurement in trials by a range of outcome scales. Statistical and clinical advantage can be gained by combining scales into a global outcome provided combinations are chosen with limited correlations. We aimed to clarify the interdependence of outcome scales by systematic review of published data and by novel analysis of data from completed acute trials. We systematically searched ScienceDirect and PubMed to summarize published data on correlations between stroke outcome scales. We generated new data on correlations among salient scales at 90 days poststroke in patients from the Virtual International Stroke Trials Archive (VISTA). We calculated Pearson and Spearman-Rank correlation coefficients for continuous and ordinal measures, respectively. We also assessed partial correlations, adjusted for baseline National Institute of Health Stroke Scale (NIHSS), and age. Published estimates of interdependence were limited to small single-trial cohorts and gave ergent results. From the more extensive VISTA dataset, we found that the modified Rankin Scale at 90 days poststroke explained 80.8% of the National Institute of Health Stroke Scale at 90 days poststroke and 86·5% of the European Stroke Scale. National Institute of Health Stroke Scale explained 75.9% of the Barthel Index and 81·2% of the Scandinavian Stroke Scale. After adjustment, modified Rankin Scale explained 56.6% of National Institute of Health Stroke Scale, 75.2% of Barthel Index. National Institute of Health Stroke Scale explained 60.2% of Barthel Index. Correlations and partial correlations among stroke outcome scales in trial datasets are higher than previously reported. The new estimates are more reliable for trial planning due to the s le size and ersity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-04-2023
DOI: 10.1212/WNL.0000000000207281
Abstract: Past studies on poststroke cognitive function have focused on the average performance or change over time, but few have investigated patterns of cognitive trajectories after stroke. This project used latent class growth analysis (LCGA) to identify clusters of patients with similar patterns of cognition scores over the first-year poststroke and the extent to which long-term cognitive outcome is predicted by the clusters (“trajectory groups”). Data were sought from the Stroke and Cognition consortium. LCGA was used to identify clusters of trajectories based on standardized global cognition scores at baseline (T 1 ) and at the 1-year follow-up (T 2 ). One-step in idual participant data meta-analysis was used to examine risk factors for trajectory groups and association of trajectory groups with cognition at the long-term follow-up (T 3 ). Nine hospital-based stroke cohorts with 1,149 patients (63% male mean age 66.4 years [SD 11.0]) were included. The median time assessed at T 1 was 3.6 months poststroke, 1.0 year at T 2 , and 3.2 years at T 3 . LCGA identified 3 trajectory groups, which were characterized by different mean levels of cognition scores at T 1 (low-performance, −3.27 SD [0.94], 17% medium-performance, −1.23 SD [0.68], 48% and high-performance, 0.71 SD [0.77], 35%). There was significant improvement in cognition for the high-performance group (0.22 SD per year, 95% CI 0.07–0.36), but changes for the low-performance and medium-performance groups were not significant (−0.10 SD per year, 95% CI −0.33 to 0.13 0.11 SD per year, 95% CI −0.08 to 0.24, respectively). Factors associated with the low- (vs high-) performance group include age (relative risk ratio [RRR] 1.18, 95% CI 1.14–1.23), years of education (RRR 0.61, 95% CI 0.56–0.67), diabetes (RRR 3.78, 95% CI 2.08–6.88), large artery vs small vessel strokes (RRR 2.77, 95% CI 1.32–5.83), and moderate/severe strokes (RRR 3.17, 95% CI 1.42–7.08). Trajectory groups were predictive of global cognition at T 3 , but its predictive power was comparable with scores at T 1 . The trajectory of cognitive function over the first-year poststroke is heterogenous. Baseline cognitive function ∼3.6 months poststroke is a good predictor of long-term cognitive outcome. Older age, lower levels of education, diabetes, large artery strokes, and greater stroke severity are risk factors for lower cognitive performance over the first year.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2015
DOI: 10.1161/STROKEAHA.114.006837
Abstract: National Institutes of Health Stroke Scale (NIHSS) item profiles that were recently proposed may prove useful both clinically and for research studies. We aimed to validate the NIHSS item profiles in an acute cohort. We conducted a retrospective analysis on pooled data from randomized clinical trials. We applied the latent class analysis probabilities of profile membership developed from the derivation study to obtain symptom grouping, a -NIHSS item profiles. We implemented an independent latent class analysis to derive secondary symptom grouping, b -NIHSS item profiles. Validation was performed by assessing the associations with outcomes and evaluating both sets of NIHSS item profiles’ discrimination and calibration to the data. The outcomes evaluated included modified Rankin Scale (mRS using the full distribution and dichotomized, mRS, 0–1) at day 90 and mortality by 90 days. We identified 10 271 patients. Ordinal analysis of mRS confirmed increased odds of better outcome across the profiles in a stepwise manner, adjusted for age and thrombolysis treatment, for each set of NIHSS item profiles. Similar patterns were observed for mRS 0 to 1, and inverse patterns were seen for mortality. The c -statistics of a -NIHSS and b -NIHSS item profiles for mRS 0 to 1 were similar at 0.71 (95% confidence interval, 0.70–0.72) and for mortality, 0.74 (0.73–0.75) and 0.75 (0.73–0.76), respectively. Calibration was good. These NIHSS item profiles identified using latent class analysis offer a reliable approach to capture the true response patterns that are associated with functional and outcome and mortality post stroke. This approach has the potential to enhance the clinical value of the overall NIHSS score.
Publisher: BMJ
Date: 03-11-2021
Abstract: To summarise evidence of the effects of blood pressure (BP)-lowering interventions after acute spontaneous intracerebral haemorrhage (ICH). A prespecified systematic review of the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE databases from inception to 23 June 2020 to identify randomised controlled trials that compared active BP-lowering agents versus placebo or intensive versus guideline BP-lowering targets for adults days after ICH onset. The primary outcome was function (distribution of scores on the modified Rankin scale) 90 days after randomisation. Radiological outcomes were absolute ( mL) and proportional ( %) haematoma growth at 24 hours. Meta-analysis used a one-stage approach, adjusted using generalised linear mixed models with prespecified covariables and trial as a random effect. Of 7094 studies identified, 50 trials involving 11 494 patients were eligible and 16 (32.0%) shared patient-level data from 6221 (54.1%) patients (mean age 64.2 [SD 12.9], 2266 [36.4%] females) with a median time from symptom onset to randomisation of 3.8 hours (IQR 2.6–5.3). Active/intensive BP-lowering interventions had no effect on the primary outcome compared with placebo/guideline treatment (adjusted OR for unfavourable shift in modified Rankin scale scores: 0.97, 95% CI 0.88 to 1.06 p=0.50), but there was significant heterogeneity by strategy (p interaction =0.031) and agent (p interaction .0001). Active/intensive BP-lowering interventions clearly reduced absolute ( ml, adjusted OR 0.75, 95%CI 0.60 to 0.92 p=0.0077) and relative (≥33%, adjusted OR 0.82, 95%CI 0.68 to 0.99 p=0.034) haematoma growth. Overall, a broad range of interventions to lower BP within 7 days of ICH onset had no overall benefit on functional recovery, despite reducing bleeding. The treatment effect appeared to vary according to strategy and agent. CRD42019141136.
Publisher: SAGE Publications
Date: 27-01-2020
Abstract: Approaches to economic evaluations of stroke therapies are varied and inconsistently described. An objective of the European Stroke Organisation (ESO) Health Economics Working Group is to standardise and improve the economic evaluations of interventions for stroke. The ESO Health Economics Working Group and additional experts were contacted to develop a protocol and a guidance document for data collection for economic evaluations of stroke therapies. A modified Delphi approach, including a survey and consensus processes, was used to agree on content. We also asked the participants about resources that could be shared to improve economic evaluations of interventions for stroke. Of 28 experts invited, 16 (57%) completed the initial survey, with representation from universities, government, and industry. More than half of the survey respondents endorsed 13 specific items to include in a standard resource use questionnaire. Preferred functional/quality of life outcome measures to use for economic evaluations were the modified Rankin Scale (14 respondents, 88%) and the EQ-5D instrument (11 respondents, 69%). Of the 12 respondents who had access to data used in economic evaluations, 10 (83%) indicated a willingness to share data. A protocol template and a guidance document for data collection were developed and are presented in this article. The protocol template and guidance document for data collection will support a more standardised and transparent approach for economic evaluations of stroke care.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
DOI: 10.1161/STROKEAHA.108.525386
Abstract: Background and Purpose— As a research community, we have failed to demonstrate that drugs which show substantial efficacy in animal models of cerebral ischemia can also improve outcome in human stroke. Summary of Review— Accumulating evidence suggests this may be due, at least in part, to problems in the design, conduct and reporting of animal experiments which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Conclusions— Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.
Publisher: Springer Science and Business Media LLC
Date: 10-01-2022
DOI: 10.1186/S12873-021-00560-X
Abstract: Prehospital stroke trials will inevitably recruit patients with non-stroke conditions, so called stroke mimics. We undertook a pre-specified analysis to determine outcomes in patients with mimics in the second Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial (RIGHT-2). RIGHT-2 was a prospective, multicentre, paramedic-delivered, ambulance-based, sham-controlled, participant-and outcome-blinded, randomised-controlled trial of transdermal glyceryl trinitrate (GTN) in adults with ultra-acute presumed stroke in the UK. Final diagnosis (intracerebral haemorrhage, ischaemic stroke, transient ischaemic attack, mimic) was determined by the hospital investigator. This pre-specified subgroup analysis assessed the safety and efficacy of transdermal GTN (5 mg daily for 4 days) versus sham patch among stroke mimic patients. The primary outcome was the 7-level modified Rankin Scale (mRS) at 90 days. Among 1149 participants in RIGHT-2, 297 (26%) had a final diagnosis of mimic (GTN 134, sham 163). The mimic group were younger, mean age 67 (SD: 18) vs 75 (SD: 13) years, had a longer interval from symptom onset to randomisation, median 75 [95% CI: 47,126] vs 70 [95% CI:45,108] minutes, less atrial fibrillation and a lower systolic blood pressure and Face-Arm-Speech-Time tool score than the stroke group. The three most common mimic diagnoses were seizure (17%), migraine or primary headache disorder (17%) and functional disorders (14%). At 90 days, the GTN group had a better mRS score as compared to the sham group (adjusted common odds ratio 0.54 95% confidence intervals 0.34, 0.85 p = 0.008), a difference that persisted at 365 days. There was no difference in the proportion of patients who died in hospital, were discharged to a residential care facility, or suffered a serious adverse event. One-quarter of patients suspected by paramedics to have an ultra-acute stroke were subsequently diagnosed with a non-stroke condition. GTN was associated with unexplained improved functional outcome observed at 90 days and one year, a finding that may represent an undetected baseline imbalance, chance, or real efficacy. GTN was not associated with harm. This trial is registered with International Standard Randomised Controlled Trials Number ISRCTN 26986053 .
Publisher: S. Karger AG
Date: 2018
DOI: 10.1159/000488911
Abstract: b i Background: /i /b Debate exists as to whether statin pretreatment confers an increased risk of 90-day mortality and symptomatic intracranial haemorrhage (sICH) in acute ischaemic stroke (AIS) patients treated with intravenous thrombolysis. We assessed the effects of undifferentiated lipid-lowering pretreatment on outcomes and interaction with low-dose versus standard-dose alteplase in a post hoc subgroup analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study. b i Methods: /i /b In all, 3,284 thrombolysis-eligible AIS patients (mean age 66.6 years 38% women), with information on lipid-lowering pretreatment, were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 h of symptom onset. Of the total number of patients, 615 (19%) received statin or other lipid-lowering pretreatment. The primary clinical outcome was combined endpoint of death or disability (modified Rankin Scale scores 2–6) at 90 days. b i Results: /i /b Compared with patients with no lipid-lowering pretreatment, those with lipid-lowering pretreatment were significantly older, more likely to be non-Asian and more likely to have a medical history including vascular co-morbidity. After propensity analysis assessment and adjustment for important baseline variables at the time of randomisation, as well as imbalances in management during the first 7 days of hospital admission, there were no significant differences in mortality (OR 0.85 95% CI 0.58–1.25, i /i = 0.42), or in overall 90-day death and disability (OR 0.85, 95% CI 0.67–1.09, i /i = 0.19), despite a significant decrease in sICH among those with lipid-lowering pretreatment according to the European Co-operative Acute Stroke Study 2 definition (OR 0.49, 95% CI 0.28–0.83, i /i = 0.009). No differences in key efficacy or safety outcomes were seen in patients with and without lipid-lowering pretreatment between low- and standard-dose alteplase arms. b i Conclusions: /i /b Lipid-lowering pretreatment is not associated with adverse outcome in AIS patients treated with intravenous alteplase, whether assessed by 90-day death and disability or death alone.
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000332028
Abstract: i Background: /i Atrial fibrillation (AF) is associated with worse outcomes following ischemic stroke and more frequent cardiac complications in the general population. We aimed to establish whether early cardiac complications contribute to the poorer ischemic stroke outcomes in patients with AF, independent of baseline differences in age, stroke severity and cardiovascular risk factors. This might have important implications for acute stroke management in patients with AF. i Methods: /i We searched VISTA-Acute, an academic database containing standardized data for 28,131 patients from 30 randomized-controlled acute stroke trials and 1 stroke registry, for imaging-confirmed placebo-treated patients with complete documentation of baseline demographics, cardiovascular risk factors, presence or absence of AF, neurologic impairment [National Institutes of Health Stroke Scale (NIHSS)], cardiac complications and 3-month outcome (modified Rankin Scale). A total of 2,865 patients from 6 randomized-controlled trials met the selection criteria, of whom 819 had AF. Binary logistic regression modeling was used to determine the independent effect of AF on stroke outcome and serious cardiac adverse events (SCAE), a composite end point including acute coronary syndrome, symptomatic heart failure, cardiopulmonary arrest, ventricular tachycardia, ventricular fibrillation and cardiac mortality. i Results: /i All patients were enrolled into the source trials within 24 h of stroke onset. At baseline, patients with AF were older (mean 75 vs. 67 years, p 0.001) and had greater neurologic impairment (median NIHSS 15 vs. 13, p 0.001). The median time to first cardiac adverse event was 3 days [median difference 0, 95% confidence interval (CI) 0–1, p = 0.06] for both patients with and without AF. SCAE occurred more frequently [14.2 vs. 6%, odds ratio (OR) = 2.58, 95% CI 1.97–3.37] in patients with AF, particularly cardiac mortality (4.9 vs. 2.6%, OR = 1.89, 95% CI 1.25–2.88), symptomatic heart failure (6.5 vs. 2.2%, OR = 3.01, 95% CI 2.01–4.50), and ventricular tachycardia and/or fibrillation (2.4 vs. 0.8%, OR = 3.18, 95% CI 1.64–6.16). At 3 months, AF was independently associated with SCAE (OR = 2.14, 95% CI 1.61–2.86) and early mortality (OR = 1.44, 95% CI 1.14–1.81) after adjusting for all baseline imbalances. i Conclusion: /i Early SCAE are common after stroke and are independently associated with the presence of AF. Given that many cardiac complications are potentially remediable, these results highlight the need for more rigorous surveillance for cardiac complications in acute ischemic stroke patients with AF.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2016
DOI: 10.1161/STROKEAHA.115.012455
Abstract: Dysphagia is common after stroke, associated with increased death and dependency, and treatment options are limited. Pharyngeal electric stimulation (PES) is a novel treatment for poststroke dysphagia that has shown promise in 3 pilot randomized controlled trials. We randomly assigned 162 patients with a recent ischemic or hemorrhagic stroke and dysphagia, defined as a penetration aspiration score (PAS) of ≥3 on video fluoroscopy, to PES or sham treatment given on 3 consecutive days. The primary outcome was swallowing safety, assessed using the PAS, at 2 weeks. Secondary outcomes included dysphagia severity, function, quality of life, and serious adverse events at 6 and 12 weeks. In randomized patients, the mean age was 74 years, male 58%, ischemic stroke 89%, and PAS 4.8. The mean treatment current was 14.8 (7.9) mA and duration 9.9 (1.2) minutes per session. On the basis of previous data, 45 patients (58.4%) randomized to PES seemed to receive suboptimal stimulation. The PAS at 2 weeks, adjusted for baseline, did not differ between the randomized groups: PES 3.7 (2.0) versus sham 3.6 (1.9), P =0.60. Similarly, the secondary outcomes did not differ, including clinical swallowing and functional outcome. No serious adverse device-related events occurred. In patients with subacute stroke and dysphagia, PES was safe but did not improve dysphagia. Undertreatment of patients receiving PES may have contributed to the neutral result. URL: www.controlled-trials.com . Unique identifier: ISRCTN25681641.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2022
DOI: 10.1161/STROKEAHA.121.036143
Abstract: High blood pressure (BP) is common after ischemic stroke and associated with a poor functional outcome and increased mortality. The conundrum then arises on whether to lower BP to improve outcome or whether this will worsen cerebral perfusion due to aberrant cerebral autoregulation. A number of large trials of BP lowering have failed to change outcome whether treatment was started prehospital in the community or hospital. Hence, nuances on how to manage high BP are likely, including whether different interventions are needed for different causes, the type and timing of the drug, how quickly BP is lowered, and the collateral effects of the drug, including on cerebral perfusion and platelets. Specific scenarios are also important, including when to lower BP before, during, and after intravenous thrombolysis and endovascular therapy/thrombectomy, when it may be necessary to raise BP, and when antihypertensive drugs taken before stroke should be restarted. This narrative review addresses these and other questions. Although further large trials are ongoing, it is increasingly likely that there is no simple answer. Different subgroups of patients may need to have their BP lowered (eg, before or after thrombolysis), left alone, or elevated.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
DOI: 10.1161/STROKEAHA.111.636449
Abstract: Granulocyte-colony stimulating factor (G-CSF) is neuroprotective in experimental stroke and mobilizes CD34 + peripheral blood stem cells into the circulation. We assessed the safety of G-CSF in recent stroke in a phase IIb single-center randomized, controlled trial. G-CSF (10 μg/kg) or placebo (ratio 2:1) was given SC for 5 days to 60 patients 3 to 30 days after ischemic or hemorrhagic stroke. The primary outcome was the frequency of serious adverse events. Peripheral blood counts, CD34 + count, and functional outcome were measured. MRI assessed lesion volume, atrophy, and the presence of iron-labeled CD34 + cells reinjected on day 6. Sixty patients were recruited at mean of 8 days (SD ±5) post ictus, with mean age 71 years (±12 years) and 53% men. The groups were well matched for baseline minimization rognostic factors. There were no significant differences between groups in the number of participants with serious adverse events: G-CSF 15 (37.5%) of 40 versus placebo 7 (35%) of 20, death or dependency (modified Rankin Score: G-CSF 3.3±1.3, placebo 3.0±1.3) at 90 days, or the number of injections received. G-CSF increased CD34 + and total white cell counts of 9.5- and 4.2-fold, respectively. There was a trend toward reduction in MRI ischemic lesion volume with respect to change from baseline in G-CSF–treated patients ( P =0.06). In 1 participant, there was suggestion that labeled CD34 + cells had migrated to the ischemic lesion. This randomized, double-blind, placebo-controlled trial suggests that G-CSF is safe when administered subacutely. It is feasible to label and readminister iron-labeled CD34 + cells in patients with ischemic stroke. URL: www.controlled-trials.com . Unique identifier: ISRCTN63336619.
Publisher: International Union of Crystallography (IUCr)
Date: 03-2015
DOI: 10.1107/S2052252514026487
Abstract: Lipidic cubic phases (LCPs) have emerged as successful matrixes for the crystallization of membrane proteins. Moreover, the viscous LCP also provides a highly effective delivery medium for serial femtosecond crystallography (SFX) at X-ray free-electron lasers (XFELs). Here, the adaptation of this technology to perform serial millisecond crystallography (SMX) at more widely available synchrotron microfocus beamlines is described. Compared with conventional microcrystallography, LCP-SMX eliminates the need for difficult handling of in idual crystals and allows for data collection at room temperature. The technology is demonstrated by solving a structure of the light-driven proton-pump bacteriorhodopsin (bR) at a resolution of 2.4 Å. The room-temperature structure of bR is very similar to previous cryogenic structures but shows small yet distinct differences in the retinal ligand and proton-transfer pathway.
Publisher: Elsevier BV
Date: 06-2023
Publisher: Public Library of Science (PLoS)
Date: 11-05-2015
Publisher: SAGE Publications
Date: 11-2006
DOI: 10.1111/J.1747-4949.2006.00059.X
Abstract: High blood pressure (BP) is common in acute stroke and is independently associated with a poor outcome. Many patients with acute stroke are taking antihypertensive medications. To test the safety and efficacy of 7 days of transdermal glyceryl trinitrate (GTN, 5 mg/day) vs. no GTN in patients with acute stroke patients taking antihypertensive therapy immediately before their stroke are also randomised to continue vs. stop this temporarily. ENOS is a prospective international multicentre single-blind randomised-controlled trial in 5000 patients with acute ( 48 h of onset) ischaemic or haemorrhagic stroke. The primary outcome is combined death and dependency (modified Rankin scale 2) at 90 days measured by blinded central telephone follow-up. Secondary outcomes include: BP over the 7 days of treatment death, impairment (Scandinavian stroke scale), recurrence, and neuroimaging at 7 days discharge disposition, disability (Barthel index), cognition (mini-mental status examination) and quality of life (EuroQoL). The s le size will allow an absolute difference in death/dependency of 5% to be detected with 90% power at 5% significance for GTN versus no GTN. Randomisation and data collection are performed over a secure Internet site with real-time data validation. Neuroimaging and serious adverse events are adjudicated blinded to treatment.
Publisher: Cold Spring Harbor Laboratory
Date: 19-07-2018
DOI: 10.1101/370874
Abstract: The ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines are widely endorsed but compliance is limited. We sought to determine whether journal-requested completion of an ARRIVE checklist improves full compliance with the guidelines. In a randomised controlled trial, manuscripts reporting in vivo animal research submitted to PLOS ONE (March-June 2015) were allocated to either requested completion of an ARRIVE checklist or current standard practice. We measured the change in proportion of manuscripts meeting all ARRIVE guideline checklist items between groups. We randomised 1,689 manuscripts, 1,269 were sent for peer review and 762 accepted for publication. The request to complete an ARRIVE checklist had no effect on full compliance with the ARRIVE guidelines. Details of animal husbandry (ARRIVE sub-item 9a) was the only item to show improved reporting, from 52.1% to 74.1% (X 2 =34.0, df=1, p=2.1×10 −7 ). These results suggest that other approaches are required to secure greater implementation of the ARRIVE guidelines.
Publisher: SAGE Publications
Date: 07-01-2013
DOI: 10.1111/J.1747-4949.2012.00943.X
Abstract: Approved use of intravenous alteplase for ischemic stroke offers net benefit. Pooled randomized controlled trial analysis suggests additional patients could benefit but others be harmed with treatment initiated beyond 4·5 h after stroke onset. We proposed prognostic scoring methods to identify a strategy for patient selection. We selected 500 patients treated by intravenous alteplase and 500 controls from Virtual International Stroke Trials Archive, matching modified Rankin score outcomes to those from pooled randomized controlled trial 4·5–6 h data. We ranked patients by prognostic score. We chose limits to optimize our s le for a net treatment benefit significant at P = 0·01 by Cochran–Mantel–Haenszel test and by ordinal regression. For validation, we had these applied to the pooled randomized controlled trial data for 4·5–6 h, testing for net benefit by Cochran–Mantel–Haenszel test, ordinal regression, and also by dichotomized outcomes: modified Rankin score 0–1, mortality and parenchymal hemorrhage type 2 bleeds. All analyses were adjusted for age and National Institutes of Health Stroke Scale. In the training dataset, limits of 56–95 on a prognostic score retained 714 patients in whom there was net benefit significant at P = 0·01. When applied to the 1120 patients in the pooled randomized controlled trial 4·5–6 h dataset, score limits of 56–95 retained 711 patients and gave odds ratio for improved modified Rankin score distribution of 1·13, 95% confidence interval 0·87–1·47, Cochran–Mantel–Haenszel P = 0·89. More patients achieved modified Rankin score 0–1 (odds ratio 1·44, 1·02–2·05, P = 0·04) but mortality and parenchymal hemorrhage type 2 bleeds were increased: odds ratio 1·56, 1·01–2·40, P = 0·04 odds ratio 15·6, 3·7–65·8, P = 0·0002, respectively. Selection of patients between 4·5 and 6 h based on simple clinical measures failed to deliver a population in whom the alteplase effect would be safe and effective.
Publisher: Elsevier BV
Date: 09-2010
Publisher: Springer Science and Business Media LLC
Date: 18-07-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2019
Publisher: Elsevier BV
Date: 05-2018
Publisher: SAGE Publications
Date: 11-05-2021
DOI: 10.1177/23969873211012133
Abstract: The optimal blood pressure (BP) management in acute ischaemic stroke (AIS) and acute intracerebral haemorrhage (ICH) remains controversial. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist physicians in their clinical decisions regarding BP management in acute stroke. The guidelines were developed according to the ESO standard operating procedure and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available to provide recommendations based on the GRADE approach. Despite several large randomised-controlled clinical trials, quality of evidence is generally low due to inconsistent results of the effect of blood pressure lowering in AIS. We recommend early and modest blood pressure control (avoiding blood pressure levels /105 mm Hg) in AIS patients undergoing reperfusion therapies. There is more high-quality randomised evidence for BP lowering in acute ICH, where intensive blood pressure lowering is recommended rapidly after hospital presentation with the intent to improve recovery by reducing haematoma expansion. These guidelines provide further recommendations on blood pressure thresholds and for specific patient subgroups. There is ongoing uncertainty regarding the most appropriate blood pressure management in AIS and ICH. Future randomised-controlled clinical trials are needed to inform decision making on thresholds, timing and strategy of blood pressure lowering in different acute stroke patient subgroups.
Publisher: Elsevier BV
Date: 02-2007
Publisher: Wiley
Date: 27-08-2022
DOI: 10.1002/ANA.26481
Abstract: We assessed whether hematoma expansion (HE) and favorable outcome differ according to type of intracerebral hemorrhage (ICH). Among participants with ICH enrolled in the TICH‐2 (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) trial, we assessed baseline scans for hematoma location and presence of cerebral amyloid angiopathy (CAA) using computed tomography (CT, simplified Edinburgh criteria) and magnetic resonance imaging (MRI Boston criteria) and categorized ICH as lobar CAA, lobar non‐CAA, and nonlobar. The main outcomes were HE and favorable functional outcome. We constructed multivariate regression models and assessed treatment effects using interaction terms. A total of 2,298 out of 2,325 participants were included with available CT (98.8% median age = 71 years, interquartile range = 60‐80 years 1,014 female). Additional MRI was available in 219 patients (9.5%). Overall, 1,637 participants (71.2%) had nonlobar ICH the remaining 661 participants (28.8%) had lobar ICH, of whom 202 patients had lobar CAA‐ICH (8.8%, 173 participants according to Edinburgh and 29 participants according to Boston criteria) and 459 did not (lobar non‐CAA, 20.0%). For HE, we found a significant interaction of lobar CAA ICH with time from onset to randomization (increasing risk with time, p interaction 0.001) and baseline ICH volume (constant risk regardless of volume, p interaction 0.001) but no association between type of ICH and risk of HE or favorable outcome. Tranexamic acid significantly reduced the risk of HE (adjusted odds ratio = 0.7, 95% confidence interval = 0.6–1.0, p = 0.020) without statistically significant interaction with type of ICH ( p interaction = 0.058). Tranexamic acid was not associated with favorable outcome. Risk of HE in patients with lobar CAA‐ICH was not independently increased but seems to have different dynamics compared to other types of ICH. The time window for treatment of CAA‐ICH to prevent HE may be longer. ANN NEUROL 2022 :921–930
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2007
DOI: 10.1161/STROKEAHA.106.473579
Abstract: Background and Purpose— Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses. Methods— Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing. Results— Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on 000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 69±12 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials. Conclusions— This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning.
Publisher: BMJ
Date: 07-2019
DOI: 10.1136/BMJOPEN-2019-030121
Abstract: Conflicting results from multiple randomised trials indicate that the methods and effects of blood pressure (BP) reduction after acute intracerebral haemorrhage (ICH) are complex. The Blood pressure in Acute Stroke Collaboration is an international collaboration, which aims to determine the optimal management of BP after acute stroke including ICH. A systematic review will be undertaken according to the Preferred Reporting Items for Systematic review and Meta-Analysis of In idual Participant Data (IPD) guideline. A search of Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from inception will be conducted to identify randomised controlled trials of BP management in adults with acute spontaneous (non-traumatic) ICH enrolled within the first 7 days of symptom onset. Authors of studies that meet the inclusion criteria will be invited to share their IPD. The primary outcome will be functional outcome according to the modified Rankin Scale. Safety outcomes will be early neurological deterioration, symptomatic hypotension and serious adverse events. Secondary outcomes will include death and neuroradiological and haemodynamic variables. Meta-analyses of pooled IPD using the intention-to-treat dataset of included trials, including subgroup analyses to assess modification of the effects of BP lowering by time to treatment, treatment strategy and patient’s demographic, clinical and prestroke neuroradiological characteristics. No new patient data will be collected nor is there any deviation from the original purposes of each study where ethical approvals were granted therefore, further ethical approval is not required. Results will be reported in international peer-reviewed journals. CRD42019141136.
Publisher: National Institute for Health and Care Research
Date: 07-2019
DOI: 10.3310/HTA23350
Abstract: Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage. The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH). The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial. Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK). Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset. Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality patients for whom tranexamic acid was thought to be contraindicated prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score 4) life expectancy 3 months and a Glasgow Coma Scale score of 5. Participants, allocated by randomisation, received 1 g of an intravenous tranexamic acid bolus followed by an 8-hour 1-g infusion or matching placebo (i.e. 0.9% saline). The primary outcome was functional status (death or dependency) at day 90, which was measured by the shift in the mRS score, using ordinal logistic regression, with adjustment for stratification and minimisation criteria. A total of 2325 participants (tranexamic acid, n = 1161 placebo, n = 1164) were recruited from 124 hospitals in 12 countries between 2013 and 2017. Treatment groups were well balanced at baseline. The primary outcome was determined for 2307 participants (tranexamic acid, n = 1152 placebo, n = 1155). There was no statistically significant difference between the treatment groups for the primary outcome of functional status at day 90 [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.76 to 1.03 p = 0.11]. Although there were fewer deaths by day 7 in the tranexamic acid group (aOR 0.73, 95% CI 0.53 to 0.99 p = 0.041), there was no difference in case fatality at 90 days (adjusted hazard ratio 0.92, 95% CI 0.77 to 1.10 p = 0.37). Fewer patients experienced serious adverse events (SAEs) after treatment with tranexamic acid than with placebo by days 2 ( p = 0.027), 7 ( p = 0.020) and 90 ( p = 0.039). There was no increase in thromboembolic events or seizures. Despite attempts to enrol patients rapidly, the majority of participants were enrolled and treated 4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK. Tranexamic acid did not affect a patient’s functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events. Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed. Current Controlled Trials ISRCTN93732214. This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland.
Publisher: Elsevier BV
Date: 04-2015
Publisher: SAGE Publications
Date: 29-10-2018
Abstract: Two previous pan-European consensus meetings, the 1995 and 2006 Helsingborg meetings, were convened to review the scientific evidence and the state of current services to identify priorities for research and development and to set targets for the development of stroke care for the decade to follow. Adhering to the same format, the European Stroke Organisation (ESO) prepared a European Stroke Action Plan (ESAP) for the years 2018 to 2030, in cooperation with the Stroke Alliance for Europe (SAFE). The ESAP included seven domains: primary prevention, organisation of stroke services, management of acute stroke, secondary prevention, rehabilitation, evaluation of stroke outcome and quality assessment and life after stroke. Research priorities for translational stroke research were also identified. Documents were prepared by a working group and were open to public comments. The final document was prepared after a workshop in Munich on 21–23 March 2018. Four overarching targets for 2030 were identified: (1) to reduce the absolute number of strokes in Europe by 10%, (2) to treat 90% or more of all patients with stroke in Europe in a dedicated stroke unit as the first level of care, (3) to have national plans for stroke encompassing the entire chain of care, (4) to fully implement national strategies for multisector public health interventions. Overall, 30 targets and 72 research priorities were identified for the seven domains. The ESAP provides a basic road map and sets targets for the implementation of evidence-based preventive actions and stroke services to 2030.
Publisher: Elsevier BV
Date: 2008
Publisher: American Medical Association (AMA)
Date: 05-2022
Publisher: Wiley
Date: 2019
DOI: 10.1016/J.JALZ.2018.07.222
Abstract: Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for % of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2018
DOI: 10.1007/S11910-018-0883-X
Abstract: The management of patients with acute stroke has been revolutionized in recent years with the advent of new effective treatments. In this rapidly evolving field, we provide an update on the management of acute stroke excluding thrombectomy, looking to recent, ongoing, and future trials. Large definitive trials have provided insight into acute stroke care including broadening the therapeutic window for thrombolysis, alternatives to standard dose alteplase, the use of dual antiplatelet therapy early after minor ischemic stroke, and treating elevated blood pressure in intracerebral hemorrhage. Further ongoing and future trials are eagerly awaited in this ever-expanding area. Although definitive trials have led to improvements in acute stroke care, there remains a need for further research to improve our understanding of pathophysiological mechanisms underlying different stroke types with the potential for treatments to be tailored to the in idual.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2022
DOI: 10.1186/S12877-022-03395-8
Abstract: People living in care homes have experienced devastating impact from COVID-19. As interventions to prevent the transmission of COVID-19 are developed and evaluated, there is an urgent need for researchers to agree on the outcomes used when evaluating their effectiveness. Having an agreed set of outcomes that are used in all relevant trials can ensure that study results can be compared. The aim of the study was to develop a core outcome set (COS) for trials assessing the effectiveness of pharmacological and non-pharmacological interventions for preventing COVID-19 infection and transmission in care homes. The study used established COS methodology. A list of candidate outcomes was identified by reviewing registered trials to evaluate interventions to prevent COVID-19 in care homes. Seventy key stakeholders participated in a Delphi survey, rating the candidate outcomes on a nine-point scale over two rounds, with the opportunity to propose additional outcomes. Stakeholders included care home representatives ( n = 19), healthcare professionals ( n = 20), people with personal experience of care homes ( n = 7), researchers ( n = 15) and others ( n = 9). Outcomes were eligible for inclusion if they met an a priori threshold. A consensus meeting with stakeholders resulted in agreement of the final outcome set. Following the Delphi and consensus meeting, twenty-four outcomes were recommended for inclusion. These are grouped across four domains of infection, severity of illness, mortality, and ‘other’ (intervention specific or life impact). Due to the considerable heterogeneity between care homes, residents, and interventions, the relevance and importance of outcomes may differ between trial contexts. Intervention-specific outcomes would be included only where relevant to a given trial, thus reducing the measurement burden. Using a rapid response approach, a COS for COVID-19 prevention interventions in care homes has been developed. Future work should focus on identifying instruments for measuring these outcomes, and the interpretation and application of the COS across different trial contexts. Beyond COVID-19, the outcomes identified in this COS may have relevance to other infectious diseases in care homes, and the rapid response approach may be useful as preparation for future pandemics.
Publisher: BMJ
Date: 11-12-2015
DOI: 10.1136/BMJ.H6432
Abstract: To report the number of participants needed to recruit per baby born to trial staff during AVERT, a large international trial on acute stroke, and to describe trial management consequences. Retrospective observational analysis. 56 acute stroke hospitals in eight countries. 1074 trial physiotherapists, nurses, and other clinicians. Number of babies born during trial recruitment per trial participant recruited. With 198 site recruitment years and 2104 patients recruited during AVERT, 120 babies were born to trial staff. Births led to an estimated 10% loss in time to achieve recruitment. Parental leave was linked to six trial site closures. The number of participants needed to recruit per baby born was 17.5 (95% confidence interval 14.7 to 21.0) additional trial costs associated with each birth were estimated at 5736 Australian dollars on average. The staff absences registered in AVERT owing to parental leave led to delayed trial recruitment and increased costs, and should be considered by trial investigators when planning research and estimating budgets. However, the celebration of new life became a highlight of the annual AVERT collaborators' meetings and helped maintain a cohesive collaborative group. Australian New Zealand Clinical Trials Registry no 12606000185561. Participation in a rehabilitation trial does not guarantee successful reproductive activity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2015
DOI: 10.1161/STROKEAHA.114.006573
Abstract: Our aim was to identify whether particular subgroups of patients had an unacceptably high risk of symptomatic intracranial hemorrhage or low chance of benefit when treated with alteplase (recombinant tissue-type plasminogen activator). Third International Stroke Trial was an international randomized trial of the intravenous (IV) recombinant plasminogen activator alteplase (0.9 mg/kg) versus control in 3035 (1515 versus 1520) patients. We analyzed the effect of recombinant tissue-type plasminogen activator on 6-month functional outcome, early death, and symptomatic intracranial hemorrhage (both ≤7 days). We tested for any differences in treatment effect between subgroups by a test of interaction. Our 13 protocol prespecified subgroups were time to randomization, age, sex, stroke subtype, atrial fibrillation, early ischemic change (clinician and expert panel), prior antiplatelet use, stroke severity, diastolic and systolic blood pressure at randomization, center’s thrombolysis experience, and trial phase. Analyses were adjusted for key baseline prognostic factors. There were no significant interactions in the subgroups analyzed that were consistent across all 3 outcomes. Treatment with recombinant tissue-type plasminogen activator increased the odds of symptomatic intracranial hemorrhage by a greater amount in patients taking prior antiplatelets than those who were not ( P =0.019 for test of interaction), but had no clear detrimental effect on functional outcome at 6 months in this group ( P =0.781 for test of interaction). Among the types of patient in the Third International Stroke Trial, this secondary analysis did not identify any subgroups for whom treatment should be avoided. Given the limitations of the analysis, we found no clear evidence to avoid treatment in patients with prior ischemic stroke, diabetes mellitus, or hypertension. URL: www.controlled-trials.com . Unique identifier: ISRCTN25765518. www.controlled-trials.com/ISRCTN25765518 .
Publisher: SAGE Publications
Date: 03-11-2010
DOI: 10.1111/J.1747-4949.2010.00485.X
Abstract: Stroke rehabilitation is a complex intervention. Many factors influence the interaction between the patient and the elements of the intervention. Rehabilitation interventions are aimed at altering different domains of patient outcome including body functions, activity and participation. As a consequence, randomised clinical trials in this area are difficult to design. We developed an archive of stroke rehabilitation trials (VISTA-Rehab) to act as a resource to help trialists model and design future rehabilitation studies. We developed specific eligibility criteria for the entry of stroke rehabilitation trials into the archive. We established a Steering Committee to oversee projects and publications and commenced the recruitment of rehabilitation trials into this resource. As of August 2009, VISTA-Rehab contains data from 23 stroke rehabilitation trials ( patients). Demographic data, including age [median=73, interquartile range (63,79)], gender (male=53%) and initial dependency [median baseline Barthel index score=6, interquartile range ( 9 , 19 )], are available for all patients. Outcome measures include the modified Rankin Scale, Barthel Index, Rivermead Motor Assessment, Fugl-Meyer Assessment, General Health Questionnaire and Nottingham Extended Activities of Daily Living Scale. VISTA-Rehab expands the Virtual International Stroke Trials Archive to include rehabilitation trials. Anonymised data can be used to examine questions specific to stroke rehabilitation and to generate novel hypotheses.
Publisher: SAGE Publications
Date: 12-2009
DOI: 10.1111/J.1747-4949.2009.00348.X
Abstract: Poststroke complications such as pulmonary embolism, deep vein thrombosis and pneumonia can impact outcome by causing deterioration in general health, delaying or preventing rehabilitation. While stroke carries a direct risk of complications, some events may be unrelated to index stroke severity and could confound outcome. We examined whether the presence of complications ‘unrelated’ to index stroke at later time-points could confound outcome, and if this could be minimised through altering study end-points. We analysed 531 placebo-treated patients from the Virtual International Stroke Trials Archive who had experienced an acute ischaemic stroke and at least one poststroke complication during the 90-day follow-up period. We categorised complications into those deemed ‘related’ or ‘unrelated’ to index stroke severity. We examined modified Rankin Scale at 30 and 90 days, stratified by type of complication and assessed the impact of eliminating ‘unrelated’ complications on functional outcome (modified Rankin Scale) at 30 and 90 days using logistic regression (accounting for age and baseline National Institutes of Health Stroke Scale). The majority of complications in the early acute period after index stroke were ‘stroke related’ (30·2%). Patients did not have a better modified Rankin Scale profile at 30 days when compared with 90 days, regardless of the type of complications experienced. The absence of ‘stroke unrelated’ complications was associated with a worse outcome at 30 days [ P = 0·04, adjusted odds ratio for good functional outcome = 0·54, 95% confidence interval (0·3, 0·96)], and had no significant effect on outcome at 90 days. We identified complications, which we deemed not to have occurred as a direct consequence of index stroke, but found that the absence of these events did not beneficially alter outcome at either short-term (30 days) or long-term (90 days) follow-up periods. Our analyses did not support the shortening of trial follow-up periods with the aim of minimising the risk of stroke-unrelated complications.
Publisher: Wiley
Date: 23-09-2022
DOI: 10.1002/ANA.26495
Abstract: The purpose of this study was to test e‐ASPECTS software in patients with stroke. Marketed as a decision‐support tool, e‐ASPECTS may detect features of ischemia or hemorrhage on computed tomography (CT) imaging and quantify ischemic extent using Alberta Stroke Program Early CT Score (ASPECTS). Using CT from 9 stroke studies, we compared software with masked experts. As per indications for software use, we assessed e‐ASPECTS results for patients with/without middle cerebral artery (MCA) ischemia but no other cause of stroke. In an analysis outside the intended use of the software, we enriched our dataset with non‐MCA ischemia, hemorrhage, and mimics to simulate a representative “front door” hospital population. With final diagnosis as the reference standard, we tested the diagnostic accuracy of e‐ASPECTS for identifying stroke features (ischemia, hyperattenuated arteries, and hemorrhage) in the representative population. We included 4,100 patients (51% women, median age = 78 years, National Institutes of Health Stroke Scale [NIHSS] = 10, onset to scan = 2.5 hours). Final diagnosis was ischemia (78%), hemorrhage (14%), or mimic (8%). From 3,035 CTs with expert‐rated ASPECTS, most (2084/3035, 69%) e‐ASPECTS results were within one point of experts. In the representative population, the diagnostic accuracy of e‐ASPECTS was 71% (95% confidence interval [CI] = 70–72%) for detecting ischemic features, 85% (83–86%) for hemorrhage. Software identified more false positive ischemia (12% vs 2%) and hemorrhage (14% vs %) than experts. On independent testing, e‐ASPECTS provided moderate agreement with experts and overcalled stroke features. Therefore, future prospective trials testing impacts of artificial intelligence (AI) software on patient care and outcome are required before widespread implementation of stroke decision‐support software. ANN NEUROL 2022 :943–957
Publisher: Georg Thieme Verlag KG
Date: 06-2023
Abstract: The aim of this review is to provide an overview of the use of antiplatelet medication in neurointervention, with a focus on the clinical indications for antiplatelet use in both preventing and reducing platelet aggregation. This review will cover current antiplatelet medications, pharmacokinetics, and pharmacodynamics. We will provide an overview of different endovascular devices and discuss the antiplatelet regimes in neurointervention, highlighting gaps in evidence and scope for future studies. Two randomized controlled trials have evaluated antiplatelet use in the setting of acute large vessel occlusion stroke, with neither demonstrating benefit in their overall cohorts. Evidence on antiplatelet medication for both acute and elective stenting for acute stroke and treatment of cerebral aneurysms is currently based on large case series, and practice in neurointervention has increasingly utilized dual antiplatelet regimes with clopidogrel and second-line agents like prasugrel and ticagrelor. Clopidogrel function testing has an increasing role in neurointerventional procedures, particularly for high metal surface area stents such as the braided flow erter type stents. Intravenous glycoprotein IIB/IIIA inhibitors have been utilized for both acute bridging and rescue therapy. Antiplatelet decision making is complex, and there are few randomized control trials to guide clinical practice. Comparative trials to guide decision making remain important in both the acute and elective settings. Standardised protocols incorporating platelet function testing may play a role in assisting decision making until more robust clinical evidence is available, particularly in the context of acute neurointerventional stenting for stroke and ruptured cerebral aneurysms.
Publisher: Wiley
Date: 25-08-2014
DOI: 10.1111/ENE.12548
Abstract: There are concerns that systemic thrombolysis might not achieve clinically important outcome amongst chronic heart failure (CHF) patients with acute ischaemic stroke. Our aim was to investigate the relevance of CHF on the outcome of acute stroke patients who received thrombolysis. A non-randomized cohort analysis was conducted using data obtained from the Virtual International Stroke Trials Archive. The association of outcome amongst CHF patients with thrombolysis treatment was described using the modified Rankin scale (mRS) distribution at day 90, stratified by the presence of atrial fibrillation. Dichotomized outcomes were considered as a secondary end-point. 5677 patients were identified, of whom 2366 (41.7%) received thombolysis. Five hundred and three (8.9%) patients had CHF, of whom 209 (41.6%) received thrombolysis. The presence of CHF was associated with a negative impact on overall stroke outcome [odds ratio (OR) 0.73 (95% confidence interval (CI) 0.62-0.87), P < 0.001]. However, thrombolysis treatment was associated with favourable functional outcome using ordinal mRS, irrespective of CHF status, after adjustment for age and baseline National Institutes of Health Stroke Scale [OR 1.44 (95% CI 1.04-2.01, P = 0.029) for CHF patients versus OR 1.50 (95% CI 1.36-1.66, P < 0.001) for non-CHF patients]. CHF patients had higher mortality at day 90 than non-CHF patients. There was no significant difference for recurrent stroke or symptomatic intracerebral haemorrhage within 7 days of the initial stroke between CHF and thrombolysis groups. Chronic heart failure was associated with a worse outcome with or without thrombolysis. However, acute stroke patients who received thrombolysis had more favourable outcome regardless of CHF status, compared with their untreated peers. Our findings should reassure clinicians considering systemic thrombolysis treatment in hyperacute ischaemic stroke patients with CHF.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2019
DOI: 10.1161/STROKEAHA.118.023190
Abstract: Increased blood pressure (BP), heart rate, and their derivatives (variability, pulse pressure, rate-pressure product) are associated with poor clinical outcome in acute stroke. We assessed the effects of glyceryl trinitrate (GTN) on hemodynamic parameters and these on outcome in participants in the ENOS trial (Efficacy of Nitric Oxide in Stroke). Four thousand and eleven patients with acute stroke and raised BP were randomized within 48 hours of onset to transdermal GTN or no GTN for 7 days. Peripheral hemodynamics were measured at baseline (3 measures) and daily (2 measures) during treatment. Between-visit BP variability over days 1 to 7 (as SD) was assessed in quintiles. Functional outcome was assessed as modified Rankin Scale and cognition as telephone mini-mental state examination at day 90. Analyses were adjusted for baseline prognostic variables. Data are mean difference or odds ratios with 95% CI. Increased baseline BP (diastolic, variability), heart rate, and rate-pressure product were each associated with unfavorable functional outcome at day 90. Increased between-visit systolic BP variability was associated with an unfavourable shift in modified Rankin Scale (highest quintile adjusted odds ratio, 1.65 95% CI, 1.37–1.99), worse cognitive scores (telephone mini-mental state examination: highest quintile adjusted mean difference, −2.03 95% CI, −2.84 to −1.22), and increased odds of death at day 90 (highest quintile adjusted odds ratio, 1.57 95% CI, 1.12–2.19). GTN lowered BP and rate-pressure product and increased heart rate at day 1 and reduced between-visit systolic BP variability. Increased between-visit BP variability was associated with poor functional and cognitive outcomes and increased death 90 days after acute stroke. In addition to lowering BP and rate-pressure product, GTN reduced between-visit systolic BP variability. Agents that lower BP variability in acute stroke require further study.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-08-2017
DOI: 10.1212/WNL.0000000000004289
Abstract: To develop and externally validate a prediction model for major bleeding in patients with a TIA or ischemic stroke on antiplatelet agents. We combined in idual patient data from 6 randomized clinical trials (CAPRIE, ESPS-2, MATCH, CHARISMA, ESPRIT, and PRoFESS) investigating antiplatelet therapy after TIA or ischemic stroke. Cox regression analyses stratified by trial were performed to study the association between predictors and major bleeding. A risk prediction model was derived and validated in the PERFORM trial. Performance was assessed with the c statistic and calibration plots. Major bleeding occurred in 1,530 of the 43,112 patients during 94,833 person-years of follow-up. The observed 3-year risk of major bleeding was 4.6% (95% confidence interval [CI] 4.4%–4.9%). Predictors were male sex, smoking, type of antiplatelet agents (aspirin-clopidogrel), outcome on modified Rankin Scale ≥3, prior stroke, high blood pressure, lower body mass index, elderly, Asian ethnicity, and diabetes (S 2 TOP-BLEED). The S 2 TOP-BLEED score had a c statistic of 0.63 (95% CI 0.60–0.64) and showed good calibration in the development data. Major bleeding risk ranged from 2% in patients aged 45–54 years without additional risk factors to more than 10% in patients aged 75–84 years with multiple risk factors. In external validation, the model had a c statistic of 0.61 (95% CI 0.59–0.63) and slightly underestimated major bleeding risk. The S 2 TOP-BLEED score can be used to estimate 3-year major bleeding risk in patients with a TIA or ischemic stroke who use antiplatelet agents, based on readily available characteristics. The discriminatory performance may be improved by identifying stronger predictors of major bleeding.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.JSTROKECEREBROVASDIS.2019.05.010
Abstract: Uncertainty persists over the effects of blood pressure-lowering treatment in acute intracerebral hemorrhage (ICH). We assessed the effects of treatment with candesartan in acute ICH and according to different types of hematoma. Post-hoc analysis of the Scandinavian Candesartan Acute Stroke Trial, a randomized- and placebo-controlled, double-masked trial of candesartan in patients with any stroke within the acute phase (<30 hours) and high systolic blood pressure (≥140 mm Hg). We collected baseline computed tomography scans of participants with ICH, and characterized hematoma volume (planimetric approach), location (deep versus lobar or infratentorial), hemisphere side, and presence of intraventricular hemorrhage. The trial's 2 coprimary effect variables were the composite endpoint of vascular death, stroke or myocardial infarction, and functional outcome at 6 months according to the modified Rankin scale. We used Cox, ordinal, and binary logistic regression for analysis and adjusted for key, predefined prognostic variables. Of 274 participants with ICH, computed tomography scans were available in 205 patients (74.8%). There were no significant differences between the candesartan and placebo groups with respect to hematoma volume (median 15.6 mL versus 13.5 mL, P = .96), deep location (77% versus 72%, P = .64), right hemisphere (49% versus 51%, P = .46), and presence of intraventricular hemorrhage (18% versus 11%, P = .22). Candesartan was associated with a significant increase in poor functional outcome in patients with deep hematoma (adjusted common odds ratio 2.27, 95% confidence interval 1.23-4.18, P = .009, P for interaction .015), but there was no differential effect on functional outcome or vascular events in any of the other imaging subgroups. Candesartan was not associated with any beneficial effect when initiated in the acute phase of ICH, a possible adverse effect on functional outcome in patients with deep hematomas cannot be ruled out by this study alone.
Publisher: SAGE Publications
Date: 04-06-2015
DOI: 10.1111/IJS.12529
Abstract: The Totaled Health Risks in Vascular Events (THRIVE) score is a previously validated ischemic stroke outcome prediction tool. Although simplified scoring systems like the THRIVE score facilitate ease-of-use, when computers or devices are available at the point of care, a more accurate and patient-specific estimation of outcome probability should be possible by computing the logistic equation with patient-specific continuous variables. We used data from 12 207 subjects from the Virtual International Stroke Trials Archive and the Safe Implementation of Thrombolysis in Stroke – Monitoring Study to develop and validate the performance of a model-derived estimation of outcome probability, the THRIVE-c calculation. Models were built with logistic regression using the underlying predictors from the THRIVE score: age, National Institutes of Health Stroke Scale score, and the Chronic Disease Scale (presence of hypertension, diabetes mellitus, or atrial fibrillation). Receiver operator characteristics analysis was used to assess model performance and compare the THRIVE-c model to the traditional THRIVE score, using a two-tailed Chi-squared test. The THRIVE-c model performed similarly in the randomly chosen development cohort ( n = 6194, area under the curve = 0·786, 95% confidence interval 0·774–0·798) and validation cohort ( n = 6013, area under the curve = 0·784, 95% confidence interval 0·772–0·796) ( P = 0·79). Similar performance was also seen in two separate external validation cohorts. The THRIVE-c model (area under the curve = 0·785, 95% confidence interval 0·777–0·793) had superior performance when compared with the traditional THRIVE score (area under the curve = 0·746, 95% confidence interval 0·737–0·755) ( P 0·001). By computing the logistic equation with patientspecific continuous variables in the THRIVE-c calculation, outcomes at the in idual patient level are more accurately estimated. Given the widespread availability of computers and devices at the point of care, such calculations can be easily performed with a simple user interface.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2022
DOI: 10.1161/STROKEAHA.121.034580
Abstract: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients. Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150–180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130–140 mm Hg) or guideline-recommended (target SBP mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1–24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage. Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71–0.82] P .001 and 0.86 [95% CI, 0.76–0.98] P =0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93–1.04] P =0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06–1.31] P =0.002 and 1.34 [1.11–1.62] P =0.002) but not with magnitude of SBP reduction (1.05 [0.98–1.14] P =0.184). Attaining early and consistent low levels in SBP mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed acute ischemic stroke patients. URL: www.clinicaltrials.gov Unique identifier: NCT01422616.
Publisher: SAGE Publications
Date: 02-04-2015
DOI: 10.1111/IJS.12486
Abstract: Controversy exists over the optimal dose of intravenous (iv) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0·6 mg/kg) is more efficacious than standard-dose (0·9 mg/kg) iv rt-PA, and guidelines recommend reducing systolic BP to mmHg before and mmHg after use of iv rt-PA, despite observational studies indicating better outcomes at much lower ( mmHg) systolic BP levels in this patient group. The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0·6 mg/kg body weight maximum 60 mg) iv rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0·9 mg/kg body weight maximum 90 mg) iv rt-PA and (ii) early intensive BP lowering (systolic target 130–140 mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target 180 mmHg). The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent, 2 × 2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] ‘rt-PA dose’ and/or Arm [B] ‘BP control’, using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately. The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2–6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift (‘improvement’) in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs. Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required s le sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide % power to detect non-inferiority of low-dose iv rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. Low-dose iv rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.
Publisher: SAGE Publications
Date: 05-09-2013
DOI: 10.1111/IJS.12123
Abstract: Reliable estimates of intracluster correlation coefficients (ICCs) for specific outcome measures are crucial for s le size calculations of future cluster randomized trials. ICCs indicate the proportion of data variability that is explained by defined levels of clustering. In this manuscript, we present potentially valuable and reliable estimates of ICCs for specific baseline and follow-up data. ICCs were estimated from linear and generalized linear mixed models using maximum likelihood estimation for common measures used in stroke research, including modified Rankin Scale (mRS), National Institutes of Health Stroke Scale (NIHSS), and Barthel Index (BI). Data were available for 11 841 patients with ischemic stroke from 11 randomized trials. After adjusting for age, thrombolysis, and baseline NIHSS, the median ICC for follow-up data, using center as the level of clustering, ranged from 0·007 to 0·041. The ICCs using trial, continent or year of enrollment as level of clustering were distinctly lower. Less than 1% of the variability of mRS, NIHSS, and BI was explained by any of these three cluster levels. This compendium of relevant ICC estimates should assist trial planning. For ex le, the s le size for a cluster trial with 150 patients per center using ordinal analysis of mRS should be inflated by 2·0 due to the ICC of 0·007 whereas the ICC of 0·031 using mRS dichotomized above mRS 0–1, requires inflation by 5·6. The low contribution of trials, year or continent of enrollment to overall variation in outcome offers reassurance that analyses using pooled data from multiple trials in VISTA are unlikely to suffer from bias from these sources.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-12-2019
DOI: 10.1212/WNL.0000000000008881
Abstract: To assess the association of baseline imaging markers of cerebral small vessel disease (SVD) and brain frailty with clinical outcome after acute stroke in the Efficacy of Nitric Oxide in Stroke (ENOS) trial. ENOS randomized 4,011 patients with acute stroke ( hours of onset) to transdermal glyceryl trinitrate (GTN) or no GTN for 7 days. The primary outcome was functional outcome (modified Rankin Scale [mRS] score) at day 90. Cognition was assessed via telephone at day 90. Stroke syndrome was classified with the Oxfordshire Community Stroke Project classification. Brain imaging was adjudicated masked to clinical information and treatment and assessed SVD (leukoaraiosis, old lacunar infarcts/lacunes, atrophy) and brain frailty (leukoaraiosis, atrophy, old vascular lesions/infarcts). Analyses used ordinal logistic regression adjusted for prognostic variables. In all participants and those with lacunar syndrome (LACS 1,397, 34.8%), baseline CT imaging features of SVD and brain frailty were common and independently associated with unfavorable shifts in mRS score at day 90 (all participants: SVD score odds ratio [OR] 1.15, 95% confidence interval [CI] 1.07–1.24 brain frailty score OR 1.25, 95% CI 1.17–1.34 those with LACS: SVD score OR 1.30, 95% CI 1.15–1.47, brain frailty score OR 1.28, 95% CI 1.14–1.44). Brain frailty was associated with worse cognitive scores at 90 days in all participants and in those with LACS. Baseline imaging features of SVD and brain frailty were common in lacunar stroke and all stroke, predicted worse prognosis after all acute stroke with a stronger effect in lacunar stroke, and may aid future clinical decision-making. ISRCTN99414122.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2007
Abstract: Amphetamine enhances recovery after experimental ischaemia and has shown promise in small clinical trials when combined with motor or sensory stimulation. Amphetamine, a sympathomimetic, might have haemodynamic effects in stroke patients, although limited data have been published. Subjects were recruited 3-30 days post-ischaemic stroke into a phase II randomized (1:1), double-blind, placebo-controlled trial. Subjects received dex hetamine (5 mg initially, then 10 mg for 10 subsequent doses with 3- or 4-day separations) or placebo in addition to inpatient physiotherapy. Recovery was assessed by motor scales (Fugl-Meyer (FM)), and functional scales (Barthel index (BI) and modified Rankin score (mRS)). Peripheral blood pressure (BP), central haemodynamics and middle cerebral artery blood flow velocity were assessed before, and 90 min after, the first two doses. Thirty-three subjects were recruited, aged 33-88 (mean 71) years, males 52%, 4-30 (median 15) days post stroke to inclusion. Sixteen patients were randomized to placebo and seventeen to hetamine. Amphetamine did not improve motor function at 90 days mean (s.d.) FM 37.6 (27.6) vs control 35.2 (27.8) (P=0.81). Functional outcome (BI, mRS) did not differ between treatment groups. Peripheral and central systolic BP, and heart rate (HR), were 11.2 mm Hg (P=0.03), 9.5 mm Hg (P=0.04) and 7 beats per minute (P=0.02) higher, respectively, with hetamine, compared with control. A nonsignificant reduction in myocardial perfusion (BUI) was seen with hetamine. Other cardiac and cerebral haemodynamics were unaffected. Amphetamine did not improve motor impairment or function after ischaemic stroke but did significantly increase BP and HR without altering cerebral haemodynamics.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2019
DOI: 10.1161/STROKEAHA.119.025019
Abstract: In randomized stroke trials, central adjudication of a trial’s primary outcome is regularly implemented. However, recent evidence questions the importance of central adjudication in randomized trials. The aim of this review was to compare outcomes assessed by central adjudicators with outcomes assessed by site investigators. We included randomized stroke trials where the primary outcome had undergone an assessment by site investigators and central adjudicators. We searched MEDLINE, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, PsycINFO, and Google Scholar for eligible studies. We extracted information about the adjudication process as well as the treatment effect for the primary outcome, assessed both by central adjudicators and by site investigators. We calculated the ratio of these treatment effects so that a ratio of these treatment effects indicated that central adjudication resulted in a more beneficial treatment effect than assessment by the site investigator. A random-effects meta-analysis model was fitted to estimate a pooled effect. Fifteen trials, comprising 69 560 participants, were included. The primary outcomes included were stroke (8/15, 53%), a composite event including stroke (6/15, 40%) and functional outcome after stroke measured on the modified Rankin Scale (1/15, 7%). The majority of site investigators were blind to treatment allocation (9/15, 60%). On average, there was no difference in treatment effect estimates based on data from central adjudicators and site investigators (pooled ratio of these treatment effects=1.02 95% CI, [0.95–1.09]). We found no evidence that central adjudication of the primary outcome in stroke trials had any impact on trial conclusions. This suggests that potential advantages of central adjudication may not outweigh cost and time disadvantages in stroke studies if the primary purpose of adjudication is to ensure validity of trial findings.
Publisher: SAGE Publications
Date: 08-04-2019
Abstract: Randomized controlled trials provide high-level evidence, but the necessity to include selected patients may limit the generalisability of their results. Comparisons were made of baseline and outcome data between patients with acute ischemic stroke (AIS) recruited into the alteplase-dose arm of the international, multi-center, Enhanced Control of Hypertension and Thrombolysis Stroke study (ENCHANTED) in the United Kingdom (UK), and alteplase-treated AIS patients registered in the UK Sentinel Stroke National Audit Programme (SSNAP) registry, over the study period June 2012 to October 2015. There were 770 AIS patients (41.2% female mean age 72 years) included in ENCHANTED at sites in England and Wales, which was 19.5% of alteplase-treated AIS patients registered in the SSNAP registry. Trial participants were significantly older, had lower baseline neurological severity, less likely Asian, and had more premorbid symptoms, hypertension and atrial fibrillation. Although ENCHANTED participants had higher rates of symptomatic intracerebral hemorrhage than those in SSNAP, there were no differences in onset-to-treatment time, levels of disability (assessed by the modified Rankin scale) at hospital discharge, and mortality over 90 days between groups. Despite the high level of participation, equipoise over the dose of alteplase among UK clinician investigators favored the inclusion of older, frailer, milder AIS patients in the ENCHANTED trial. Clinical Trial Registration-URL: www.clinicaltrials.gov . Unique identifier: NCT01422616
Publisher: BMJ
Date: 03-2019
Abstract: There is concern that blood pressure (BP) lowering in acute stroke may compromise cerebral perfusion and worsen outcome in the presence of carotid stenosis. We assessed the effect of glyceryl trinitrate (GTN) in patients with carotid stenosis using data from the Efficacy of Nitric Oxide in Stroke (ENOS) Trial. ENOS randomised 4011 patients with acute stroke and raised systolic BP (140–220 mm Hg) to transdermal GTN or no GTN within 48 hours of onset. Those on prestroke antihypertensives were also randomised to stop or continue their medication for 7 days. The primary outcome was the modified Rankin Scale (mRS) at day 90. Ipsilateral carotid stenosis was split: % 30– % 50– % ≥70%. Data are ORs with 95% CIs adjusted for baseline prognostic factors. 2023 (60.5%) ischaemic stroke participants had carotid imaging. As compared with %, ≥70% ipsilateral stenosis was associated with an unfavourable shift in mRS (worse outcome) at 90 days (OR 1.88, 95% CI 1.44 to 2.44, p .001). Those with ≥70% stenosis who received GTN versus no GTN had a favourable shift in mRS (OR 0.56, 95% CI 0.34 to 0.93, p=0.024). In those with 50– % stenosis, continuing versus stopping prestroke antihypertensives was associated with worse disability, mood, quality of life and cognition at 90 days. Clinical outcomes did not differ across bilateral stenosis groups. Following ischaemic stroke, severe ipsilateral carotid stenosis is associated with worse functional outcome at 90 days. GTN appears safe in ipsilateral or bilateral carotid stenosis, and might improve outcome in severe ipsilateral carotid stenosis.
Publisher: Elsevier BV
Date: 06-2012
Publisher: Massachusetts Medical Society
Date: 16-06-2016
Publisher: SAGE Publications
Date: 06-2021
DOI: 10.1177/23969873211026998
Abstract: The optimal blood pressure (BP) management in acute ischaemic stroke (AIS) and acute intracerebral haemorrhage (ICH) remains controversial. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist physicians in their clinical decisions regarding BP management in acute stroke. The guidelines were developed according to the ESO standard operating procedure and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available to provide recommendations based on the GRADE approach. Despite several large randomised-controlled clinical trials, quality of evidence is generally low due to inconsistent results of the effect of blood pressure lowering in AIS. We recommend early and modest blood pressure control (avoiding blood pressure levels /105 mm Hg) in AIS patients undergoing reperfusion therapies. There is more high-quality randomised evidence for BP lowering in acute ICH, where intensive blood pressure lowering is recommended rapidly after hospital presentation with the intent to improve recovery by reducing haematoma expansion. These guidelines provide further recommendations on blood pressure thresholds and for specific patient subgroups. There is ongoing uncertainty regarding the most appropriate blood pressure management in AIS and ICH. Future randomised-controlled clinical trials are needed to inform decision making on thresholds, timing and strategy of blood pressure lowering in different acute stroke patient subgroups.
Publisher: Elsevier BV
Date: 06-2012
Publisher: Springer Science and Business Media LLC
Date: 19-10-2016
DOI: 10.1038/SREP35279
Abstract: Phytochromes are a family of photoreceptors that control light responses of plants, fungi and bacteria. A sequence of structural changes, which is not yet fully understood, leads to activation of an output domain. Time-resolved serial femtosecond crystallography (SFX) can potentially shine light on these conformational changes. Here we report the room temperature crystal structure of the chromophore-binding domains of the Deinococcus radiodurans phytochrome at 2.1 Å resolution. The structure was obtained by serial femtosecond X-ray crystallography from microcrystals at an X-ray free electron laser. We find overall good agreement compared to a crystal structure at 1.35 Å resolution derived from conventional crystallography at cryogenic temperatures, which we also report here. The thioether linkage between chromophore and protein is subject to positional ambiguity at the synchrotron, but is fully resolved with SFX. The study paves the way for time-resolved structural investigations of the phytochrome photocycle with time-resolved SFX.
Publisher: Wiley
Date: 06-1995
DOI: 10.1111/J.1365-2796.1995.TB00885.X
Abstract: To test whether serum von Willebrand factor (vWf) would be lower in men with atherosclerosis who had been consuming a lipid-lowering diet for 3 years than in a control group of men with atherosclerosis who had been following their normal diet. A randomized, population-based case-control study. A tertiary health care referral centre at a University Hospital. Men age less than 66 years with angiographically proven coronary atherosclerosis and a cholesterol level > 6 mmol L-1. Sixty started the study and 50 completed it. Subjects were randomized to a lipid-lowering diet or to taking their normal diet for approximately 3 years. The components of the subjects' diets were assessed and blood was obtained for total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and for vWf. Men on the lipid-lowering diet consumed less total, saturated and monounsaturated fats (all P < 0.001), cholesterol and retinol (both P < 0.002) but increased polyunsaturated fats (P < 0.001), fibre, vitamin E (both P < 0.005) and carbohydrate (P < 0.05). Those on the lipid-lowering diet also had lower serum levels of total and LDL cholesterol (P < 0.002 and P < 0.05, respectively), triglycerides (P < 0.02) and vWf (P < 0.05) than the men on their normal diet. There was no difference in HDL cholesterol. Levels of vWf correlated with both total cholesterol (P < 0.005) and inversely with dietary polyunsaturated fats (P < 0.02). von Willebrand factor, a possible indicator of endothelial cell damage, decreases during long-term compliance with a lipid-lowering diet.
Publisher: SAGE Publications
Date: 02-2008
Publisher: SAGE Publications
Date: 20-01-2012
DOI: 10.1111/J.1747-4949.2011.00735.X
Abstract: Analysis of reliable registry data can direct future research to influence clinical care. Data from the Virtual International Stroke Trials Archive have been used to test hypotheses and inform trial design. We sought to expand Virtual International Stroke Trials Archive into a broader stroke resource with new opportunities for research and international collaboration. Using procedures initially developed for an acute stroke trial archive, we invited trialists to lodge data on rehabilitation, secondary prevention, intracerebral haemorrhage, imaging, and observational stroke studies. We have extended Virtual International Stroke Trials Archive into six subsections: Virtual International Stroke Trials Archive-Acute ( n = 28 190 patients’ data), Virtual International Stroke Trials Archive-Rehab ( n = 10 194), Virtual International Stroke Trials Archive-intracerebral haemorrhage ( n = 1829), Virtual International Stroke Trials Archive-Prevention, Virtual International Stroke Trials Archive-Imaging ( n = 1300), and Virtual International Stroke Trials Archive-Plus ( n = 6573). Enrollment continues, with commitments for the contribution of six further trials to Virtual International Stroke Trials Archive-Prevention, 13 trials to Virtual International Stroke Trials Archive-Rehab, and one registry to Virtual International Stroke Trials Archive-Plus. Data on age, type of stroke, medical history, outcomes by modified Rankin scale and Barthel Index (BI), mortality, and adverse events are available for analyses. The Virtual International Stroke Trials Archive network encourages the development of young investigators and provides opportunities for international peer review and collaboration. Application of the original Virtual International Stroke Trials Archive concepts beyond acute stroke trials can extend the value of clinical research at low cost, without threatening commercial or intellectual property interests. This delivers valuable research output to inform the efficiency of future stroke research. We invite stroke researchers to participate actively in Virtual International Stroke Trials Archive and encourage the extension of Virtual International Stroke Trials Archive principles to other disease areas.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2004
DOI: 10.1161/01.STR.0000137766.17092.FB
Abstract: Background and Purpose— Trials of occupational therapy for stroke patients living in the community have varied in their findings. It is unclear why these discrepancies have occurred. Methods— Trials were identified from searches of the Cochrane Library and other sources. The primary outcome measure was the Nottingham Extended Activities of Daily Living (NEADL) score at the end of intervention. Secondary outcome measures included the Barthel Index or the Rivermead ADL (Personal ADL), General Health Questionnaire (GHQ), Nottingham Leisure Questionnaire (NLQ), and death. Data were analyzed using linear or logistic regression with a random effect for trial and adjustment for age, gender, baseline dependency, and method of follow-up. Subgroup analyses compared any occupational therapy intervention with control. Results— We included 8 single-blind randomized controlled trials incorporating 1143 patients. Occupational therapy was associated with higher NEADL scores at the end of intervention (weighted mean difference [WMD], 1.30 points, 95% confidence intervals [CI], 0.47 to 2.13) and higher leisure scores at the end of intervention (WMD, 1.51 points 95% CI, 0.24 to 2.79). Occupational therapy emphasizing activities of daily living (ADL) was associated with improved end of intervention NEADL (WMD, 1.61 points 95% CI, 0.72 to 2.49) and personal activities of daily living (odds ratio [OR], 0.65 95% CI, 0.46 to 0.91), but not NLQ. Leisure-based occupational therapy improved end of intervention NLQ (WMD, 1.96 points 95% CI, 0.27 to 3.66) but not NEADL or PADL. Conclusions— Community occupational therapy significantly improved personal and extended activities of daily living and leisure activity in patients with stroke. Better outcomes were found with targeted interventions.
Publisher: Wiley
Date: 08-2016
Publisher: American Medical Association (AMA)
Date: 16-11-2011
Abstract: Recurrent stroke prevention guidelines suggest that larger reductions in systolic blood pressure (SBP) are positively associated with a greater reduction in the risk of recurrent stroke and define an SBP level of less than 120 mm Hg as normal. However, the association of SBP maintained at such levels with risk of vascular events after a recent ischemic stroke is unclear. To assess the association of maintaining low-normal vs high-normal SBP levels with risk of recurrent stroke. Post hoc observational analysis of a multicenter trial involving 20,330 patients (age ≥50 years) with recent non-cardioembolic ischemic stroke patients were recruited from 695 centers in 35 countries from September 2003 through July 2006 and followed up for 2.5 years (follow-up ended on February 8, 2008). Patients were categorized based on their mean SBP level: very low-normal (<120 mm Hg), low-normal (120-<130 mm Hg), high-normal (130-<140 mm Hg), high (140-<150 mm Hg), and very high (≥150 mm Hg). The primary outcome was first recurrence of stroke of any type and the secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. The recurrent stroke rates were 8.0% (95% CI, 6.8%-9.2%) for the very low-normal SBP level group, 7.2% (95% CI, 6.4%-8.0%) for the low-normal SBP group, 6.8% (95% CI, 6.1%-7.4%) for the high-normal SBP group, 8.7% (95% CI, 7.9%-9.5%) for the high SBP group, and 14.1% (95% CI, 13.0%-15.2%) for the very high SBP group. Compared with patients in the high-normal SBP group, the risk of the primary outcome was higher for patients in the very low-normal SBP group (adjusted hazard ratio [AHR], 1.29 95% CI, 1.07-1.56), in the high SBP group (AHR, 1.23 95% CI, 1.07-1.41), and in the very high SBP group (AHR, 2.08 95% CI, 1.83-2.37). Compared with patients in the high-normal SBP group, the risk of secondary outcome was higher for patients in the very low-normal SBP group (AHR, 1.31 95% CI, 1.13-1.52), in the low-normal SBP group (AHR, 1.16 95% CI, 1.03-1.31), in the high SBP group (AHR, 1.24 95% CI, 1.11-1.39), and in the very high SBP group (AHR, 1.94 95% CI, 1.74-2.16). Among patients with recent non-cardioembolic ischemic stroke, SBP levels during follow-up in the very low-normal (<120 mm Hg), high (140-<150 mm Hg), or very high (≥150 mm Hg) range were associated with increased risk of recurrent stroke. clinicaltrials.gov Identifier: NCT00153062.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2006
End Date: 2009
Funder: Medical Research Council
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