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    Baseline characteristics of the 4011 patients recruited into the 'Efficacy of Nitric Oxide in Stroke' (ENOS) trial
    (SAGE PUBLICATIONS LTD, 2014) Bath, Philip M. W.; Adami, Alessandro; Bereczki, Daniel; Berge, Eivind; Beridze, Maia; Cala, Lesley; Casado, Ana
    Background High blood pressure is common in acute stroke and associated with a worse functional outcome. Many patients who present with acute stroke are taking prescribed antihypertensive therapy before their stroke. Aims ENOS tested whether lowering blood pressure and continuing pre-stroke antihypertensive therapy are each safe and effective. Methods This study is an international multi-centre prospective randomized single-blind blinded-endpoint parallel-group partial-factorial controlled trial of transdermal glyceryl trinitrate (a nitric oxide donor, given for seven-days) vs. no glyceryl trinitrate, and of continuing vs. stopping (temporarily for seven-days) pre-stroke antihypertensive drugs if relevant, in patients with acute ischaemic stroke or intracerebral haemorrhage and high systolic blood pressure (140-220 mmHg). Results Recruitment ran from July 2001 to October 2013. Four thousand eleven patients [2097 (52.3%) in the continue/stop arm] were recruited from 173 sites across 23 countries in 5 continents (Asia 14%, Continental Europe 16%, UK 64%). Baseline characteristics include: mean age 70 (standard deviation 12) years; male 57%; mean time from stroke to recruitment 26 (13) h; mean severity (Scandinavian Stroke Scale) 34 (13) of 58; mean blood pressure 167 (19)/90 (13) mmHg; ischaemic stroke 83%; and intracerebral haemorrhage 16%. The main trial results will be presented in May 2014. The results will also be presented in updated Cochrane systematic reviews and included in individual patient data meta-analyses of all relevant randomized controlled trials. Conclusion ENOS is a large completed international trial of blood pressure management in acute stroke and includes patients representative of many stroke services worldwide.
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    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, Exuperio
    Background 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.
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    Infections Up to 76 Days After Stroke Increase Disability and Death
    (SPRINGER, 2017) Learoyd, Annastazia E.; Woodhouse, Lisa; Shaw, Laurence; Sprigg, Nikola; Bereczki, Daniel; Berge, Eivind; Caso, Valeria
    Early infection after stroke is associated with a poor outcome. We aimed to determine whether delayed infections (up to 76 days post-stroke) are associated with poor outcome at 90 days. Data came from the international Efficacy of Nitric Oxide Stroke (ENOS, ISRCTN99414122) trial. Post hoc data on infections were obtained from serious adverse events reports between 1 and 76 days following stroke in this large cohort of patients. Regression models accounting for baseline covariates were used to analyse fatalities and functional outcomes (modified Rankin Scale (mRS), Barthel Index, Euro-Qol-5D) at 90 days, in patients with infection compared to those without infection. Of 4011 patients, 242 (6.0%) developed one or more serious infections. Infections were associated with an increased risk of death (p < 0.001) and an increased likelihood of dependency (measured by mRS) compared to those of all other patients (p < 0.001). This remained when only surviving patients were analysed, indicating that the worsening of functional outcome is not due to mortality (p < 0.001). In addition, the timing of the infection after stroke did not alter its detrimental association with fatality (p = 0.14) or functional outcome (p = 0.47). In conclusion, severe post-stroke infections, whether occurring early or late after stroke, are associated with an increased risk of death and poorer functional outcome, independent of differences in baseline characteristics or treatment. Not only are strategies needed for reducing the risk of infection immediately after stroke, but also during the first 3 months following a stroke. This study is registered: ISRCTN registry, number ISRCTN99414122, Identifier, NCT00989716.
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    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 M
    Background 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.
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    Tranexamic acid for hyperacute primary intracerebral haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial
    (ELSEVIER SCIENCE INC, 2018) Sprigg, Nikola; Flaherty, Katie; Appleton, Jason P.; Salman, Rustam Al-Shahi; Bereczki, Daniel; Beridze, Maia; Christensen, Hanne
    Background Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage. Methods We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1: 1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214. Findings We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0.88, 95% CI 0.76-1.03, p= 0.11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0.73, 0.53-0.99, p= 0.0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0.92, 95% CI 0.77-1.10, p= 0.37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]). Interpretation Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect. Funding National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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    Tranexamic acid to improve functional status in adults with spontaneous intracerebral haemorrhage: The TICH-2 RCT
    (NIHR JOURNALS LIBRARY, 2019) Sprigg, Nikola; Flaherty, Katie; Appleton, Jason P.; Al-Shahi Salman, Rustam; Bereczki, Daniel; Beridze, Maia; Ciccone, Alfonso; Collins, Ronan; Dineen, Robert A.; Duley, Lelia; Egea-Guerrero, Juan José; England, Timothy J.; Karlinski, Michal; Krishnan, Kailash; Laska, Ann Charlotte; Law, Zhe Kang; Ovesen, Christian; Öztürk, Şerefnur; Pocock, Stuart J.; Roberts, Ian; Robinson, Thompson G.; Roffe, Christine; Peters, Nils; Scutt, Polly; Thanabalan, Jegan; Werring, David; Whynes, David; Woodhouse, Lisa; Bath, Philip M.
    Background: Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage. Objective: 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). Design: The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial. Setting: Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK). Participants: Adult patients (aged >= 18 years) with ICH within 8 hours of onset. Exclusion criteria: 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. Interventions: 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). Main outcome measure: 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. Results: 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. Limitations: 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. Conclusions: 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: 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.