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Öğe Central adjudication of serious adverse events did not affect trial's safety results: Data from the Efficacy of Nitric Oxide in Stroke (ENOS) trial(PUBLIC LIBRARY SCIENCE, 2018) Godolphin, Peter J.; Montgomery, Alan A.; Woodhouse, Lisa J.; Bereczki, Daniel; Berge, Eivind; Collins, Ronan; Diez-Tejedor, ExuperioBackground and purpose Central adjudication of serious adverse events (SAEs) can be undertaken in clinical trials, especially for open-label studies where outcome assessment may be at risk of bias. This study explored the effect of central adjudication of SAEs on the safety results of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial. Methods ENOS assigned patients with acute stroke at random to receive either transdermal glyceryl trinitrate (GTN) or no GTN and to Stop or Continue previous antihypertensive treatment. SAEs were reported by local investigators who were not blinded to treatment allocation. Central adjudicators, blinded to treatment allocation, reviewed the investigators reports and used evidence available to confirm or re-categorise the classification of event, likely causality, diagnosis and expectedness of event. Results Of 4011 patients enrolled in ENOS, 1473 SAEs were reported by local investigators; this was reduced to 1444 after the review by adjudicators, with 29 re-classified as not an SAE. There was fair agreement between investigators and adjudicators regarding likely causality, with 808 agreements and 644 disagreements (56% crude agreement, weighted kappa, kappa = 0.31). Agreement increased upon dichotomisation of the causality categories, with 1432 agreements and 20 disagreements (99% crude agreement, kappa = 0.54). Repeating the main trial safety analysis with investigator reported events showed that adjudication had no effect on the main trial safety conclusions. Conclusions In a large trial, with many SAEs reported, central adjudication of these events did not affect trial conclusions. This suggests that adjudication of SAEs in a clinical trial where the intervention already has a well-established safety profile may not be necessary. Potential efficiency savings (financial, logistical) can be made through not adjudicating SAEs.Öğe Effect of glyceryl trinitrate on hemodynamics in acute stroke data from the ENOS trial(LIPPINCOTT WILLIAMS & WILKINS, 2019) Appleton, Jason P.; Woodhouse, Lisa J.; Bereczki, Daniel.; Berge, Eivind.; Christensen, Hanne K.; Collins, Ronan.; Gommans, John.; Ntaios, George.; Ozturk, Serefnur.; Szatmari, Szabolcs.; Wardlaw, Joanna M.; Sprigg, Nikola.; Rothwell, Peter M.; Bath, Philip M.Background and Purpose-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). Methods-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. Results-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. Conclusions-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 betweenvisit systolic BP variability. Agents that lower BP variability in acute stroke require further study.Öğe Incidence and predictors of early seizures in intracerebral haemorrhage and the effect of tranexamic acid(SAGE PUBLICATIONS LTD, 2019) Law, Zhe Kang; England, Timothy J.; Mistri, Amit K.; Woodhouse, Lisa J.; Cala, Lesley; Dineen, Rob; Ozturk, SerefnurIntroduction Seizures are common after intracerebral haemorrhage. Tranexamic acid increases the risk of seizures in non-intracerebral haemorrhage population but its effect on post-intracerebral haemorrhage seizures is unknown. We explored the risk factors and outcomes of seizures after intracerebral haemorrhage and if tranexamic acid increased the risk of seizures in the Tranexamic acid for IntraCerebral Haemorrhage-2 trial. Patients and methods Seizures were reported prospectively up to day 90. Cox regression analyses were used to determine the predictors of seizures within 90 days and early seizures (<= 7 days). We explored the effect of early seizures on day 90 outcomes. Results Of 2325 patients recruited, 193 (8.3%) had seizures including 163 (84.5%) early seizures and 30 (15.5%) late seizures (>7 days). Younger age (adjusted hazard ratio (aHR) 0.98 per year increase, 95% confidence interval (CI) 0.97-0.99; p = 0.008), lobar haematoma (aHR 5.84, 95%CI 3.58-9.52; p < 0.001), higher National Institute of Health Stroke Scale (aHR 1.03, 95%CI 1.01-1.06; p = 0.014) and previous stroke (aHR 1.66, 95%CI 1.11-2.47; p = 0.013) were associated with early seizures. Tranexamic acid did not increase the risk of seizure within 90 days. Early seizures were associated with worse modified Rankin Scale (adjusted odds ratio (aOR) 1.79, 95%CI 1.12-2.86, p = 0.015) and increased risk of death (aOR 3.26, 95%CI 1.98-5.39; p < 0.001) at day 90. Discussion and conclusion: Lobar haematoma was the strongest independent predictor of early seizures after intracerebral haemorrhage. Tranexamic acid did not increase the risk of post-intracerebral haemorrhage seizures in the first 90 days. Early seizures resulted in worse functional outcome and increased risk of death.Öğe It is safe to use transdermal glyceryl trinitrate to lower blood pressure in patients with acute ischaemic stroke with carotid stenosis(BMJ PUBLISHING GROUP, 2019) Appleton, Jason P.; Woodhouse, Lisa J.; Belcher, Andrew; Bereczki, Daniel; Berge, Eivind; Caso, Valeria; Chang, Hui Meng; Christensen, Hanne K; Collins, Ronan; Gommans, John; Laska, Ann C; Ntaios, George; Ozturk, Serefnur; Sare, Gillian M; Szatmari, Szabolcs; Wang, Yongjun; Wardlaw, Joanna M; Sprigg, Nikola; Bath, Philip MBackground 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. Methods 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%; 30-<50%; 50-<70%; >= 70%. Data are ORs with 95% CIs adjusted for baseline prognostic factors. Results 2023 (60.5%) ischaemic stroke participants had carotid imaging. As compared with <30%, >= 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<0.001). 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-<70% 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. Conclusions 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.Öğe Route of feeding as a proxy for dysphagia ater stroke and the effect of transdermal glyceryl trinitrate: data from the efficacy of nitric oxide in stroke randomised controlled trial(SPRINGER, 2018) Woodhouse, Lisa J.; Scutt, Polly.; Hamdy, Shaheen.; Smithard, David G.; Cohen, David L.; Roffe, Christine.; Bereczki, Daniel.; Berge, Eivind.; Bladin, Christopher F.; Caso, Valeria.; Christensen, Hanne K.; Collins, Rónán.; Czlonkowska, Anna.; Silva, Asita de.; Etribi, Anwar.; Laska, Ann-Charlotte.; Ntaios, George.; Ozturk, Serefnur.; Phillips, Stephen J.; Prasad, Kameshwar.; Szatmari, Szabolcs.; Sprigg, Nikola.; Bath, Philip M.at day Post-stroke dysphagia is common, associated with poor outcome and often requires non-oral feeding/fluids. The relationship between route of feeding and outcome, as well as treatment with glyceryl trinitrate (GTN), was studied prospectively. The Efficacy of Nitric Oxide in Stroke (ENOS) trial assessed transdermal GTN (5 mg versus none for 7 days) in 4011 patients with acute stroke and high blood pressure. Feeding route (oral = normal or soft diet; non-oral = nasogastric tube, percutaneous endoscopic gastrostomy tube, parenteral fluids, no fluids) was assessed at baseline and day 7. The primary outcome was the modified Rankin Scale (mRS) measured 90. At baseline, 1331 (33.2%) patients had non-oral feeding, were older, had more severe stroke and more were female, than 2680 (66.8%) patients with oral feeding. By day 7, 756 patients had improved from non-oral to oral feeding, and 119 had deteriorated. Non-oral feeding at baseline was associated with more impairment at day 7 (Scandinavian Stroke Scale 29.0 versus 43.7; 2p < 0.001), and worse mRS (4.0 versus 2.7; 2p < 0.001) and death (23.6 versus 6.8%; 2p = 0.014) at day 90. Although GTN did not modify route of feeding overall, randomisation ae6 h of stroke was associated with a move to more oral feeding at day 7 (odds ratio = 0.61, 95% confidence intervals 0.38, 0.98; 2p = 0.040). As a proxy for dysphagia, non-oral feeding is present in 33% of patients with acute stroke and associated with more impairment, dependency and death. GTN moved feeding route towards oral intake if given very early after stroke.