ORCID Profile
0000-0001-5330-8584
Current Organisation
University of Nottingham
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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: Public Library of Science (PLoS)
Date: 09-09-2016
Publisher: Springer Science and Business Media LLC
Date: 05-04-2017
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: American Medical Association (AMA)
Date: 05-2022
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: BMJ
Date: 07-2019
DOI: 10.1136/BMJOPEN-2018-028387
Abstract: We report on: (1) the proportion of patients with known atrial fibrillation (AF) and (2) demographic, clinical or radiological differences between patients with known AF (and not treated) and patients with newly diagnosed AF, in a cohort of patients who presented with ischaemic stroke or transient ischaemic attack (TIA) not previously treated with anticoagulation. We reviewed cross-sectional baseline demographic and clinical data from a prospective observational cohort study, (CROMIS-2). Patients were recruited from 79 hospital stroke centres throughout the UK and one centre in the Netherlands. Patients were eligible if they were adults who presented with ischaemic stroke or TIA and AF and had not been previously treated with oral anticoagulation. Proportion of patients with known AF before index ischaemic stroke or TIA from a cohort of patients who have not been previously treated with oral anticoagulation. Secondary analysis includes the comparison of CHA 2 DS 2 -VASc and HAS-BLED scores and other demographics and risk factors between those with newly diagnosed AF and those with previously known AF. Of 1470 patients included in the analysis (mean age 76 years (SD 10)), 622 (42%) were female 999 (68%) patients had newly diagnosed AF and 471 (32%) patients had known AF. Of the 471 patients with known AF, 68% had a strong indication for anticoagulation and 89% should have been considered for anticoagulation based upon CHA 2 DS 2 -VASc score. Patients with known AF were more likely to have a prior history of dementia (4% vs 2%, p=0.02) and had higher HAS-BLED scores (median 3 vs 2). CHA 2 DS 2 -VASc, other risk factors and demographics were similar. About 1/3 of patients who present with stroke and have AF who have not been treated with oral anticoagulation have previously known AF. Of these patients, at least 68% were not adequately treated with oral anticoagulation. NCT02513316 .
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: 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: Springer Science and Business Media LLC
Date: 05-03-2018
Publisher: Springer Science and Business Media LLC
Date: 07-03-2019
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: 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: Elsevier BV
Date: 05-2018
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: 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: National Institute for Health and Care Research
Date: 09-2019
DOI: 10.3310/HTA23470
Abstract: There is currently insufficient evidence for the clinical effectiveness and cost-effectiveness of psychological therapies for post-stroke depression. To evaluate the feasibility of undertaking a definitive trial to evaluate the clinical effectiveness and cost-effectiveness of behavioural activation (BA) compared with usual stroke care for treating post-stroke depression. Parallel-group, feasibility, multicentre, randomised controlled trial with nested qualitative research and a health economic evaluation. Acute and community stroke services in three sites in England. Community-dwelling adults 3 months to 5 years post stroke who are depressed, as determined by the Patient Health Questionnaire-9 (PHQ-9) or the Visual Analogue Mood Scales ‘Sad’ item. Exclusions: patients who are blind and/or deaf, have dementia, are unable to communicate in English, do not have mental capacity to consent, are receiving treatment for depression at the time of stroke onset or are currently receiving psychological intervention. Participants were randomised (1 : 1 ratio) to BA or usual stroke care. Randomisation was conducted using a computer-generated list with random permuted blocks of varying sizes, stratified by site. Participants and therapists were aware of the allocation, but outcome assessors were blind. The intervention arm received up to 15 sessions of BA over 4 months. BA aims to improve mood by increasing people’s level of enjoyable or valued activities. The control arm received usual care only. Primary feasibility outcomes concerned feasibility of recruitment to the main trial, acceptability of research procedures and measures, appropriateness of baseline and outcome measures, retention of participants and potential value of conducting the definitive trial. Secondary feasibility outcomes concerned the delivery of the intervention. The primary clinical outcome 6 months post randomisation was the PHQ-9. Secondary clinical outcomes were Stroke Aphasic Depression Questionnaire – Hospital version, Nottingham Leisure Questionnaire, Nottingham Extended Activities of Daily Living, Carer Strain Index, EuroQol-5 Dimensions, five-level version and health-care resource use questionnaire. Forty-eight participants were recruited in 27 centre-months of recruitment, at a recruitment rate of 1.8 participants per centre per month. The 25 participants randomised to receive BA attended a mean of 8.5 therapy sessions [standard deviation (SD) 4.4 therapy sessions] 23 participants were allocated to usual care. Outcome assessments were completed by 39 (81%) participants (BA, n = 18 usual care, n = 21). Mean PHQ-9 scores at 6-month follow-up were 10.1 points (SD 6.9 points) and 14.4 points (SD 5.1 points) in the BA and control groups, respectively, a difference of –3.8 (95% confidence interval –6.9 to –0.6) after adjusting for baseline PHQ-9 score and centre, representing a reduction in depression in the BA arm. Therapy was delivered as intended. BA was acceptable to participants, carers and therapists. Value-of-information analysis indicates that the benefits of conducting a definitive trial would be likely to outweigh the costs. It is estimated that a s le size of between 580 and 623 participants would be needed for a definitive trial. Target recruitment was not achieved, although we identified methods to improve recruitment. The Behavioural Activation Therapy for Depression after Stroke trial was feasible with regard to the majority of outcomes. The outstanding issue is whether or not a sufficient number of participants could be recruited within a reasonable time frame for a definitive trial. Future work is required to identify whether or not there are sufficient sites that are able to deliver the services required for a definitive trial. Current Controlled Trials ISRCTN12715175. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment Vol. 23, No. 47. See the NIHR Journals Library website for further project information.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Tim England.