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Biomedical subjects

Kennedy R Lees

Publications and source records attributed to Kennedy R Lees.

At least 37 records · Page 2Linked to original sources
PubMed2004

Poststroke neurological improvement within 7 days is associated with subsequent deterioration.

BACKGROUND AND PURPOSE: Improvement in the National Institutes of Health Stroke Scale (NIHSS) 24 hours after stroke has been associated with subsequent neurological deterioration. We hypothesized that a similar association would be apparent for events occurring after 7 days, when acute changes from edema and herniation are less common. We evaluated the degree of NIHSS improvement at 7 days (recovery) as a predictor of subsequent neurological deterioration from day 7 to day 90. METHODS: We studied all patients of the Glycine Antagonist (gavestinel) In Neuroprotection (GAIN) International Trial with ischemic stroke alive at day 7, excluding patients with hemorrhagic events and deaths from nonstroke-related causes. The GAIN International Trial was a randomized, double-blind, placebo-controlled, and parallel-group trial; because the study drug had no effect on stroke outcome, treatment groups were combined for this analysis. Neurological deterioration was assessed by the combined measure, including: (1) stroke-related events recorded as "serious adverse events," (2) recurrent stroke recorded on a separate case report form, and (3) any NIHSS worsening. RESULTS: Among 1187 patients included, 25% had >65% recovery. Deterioration was more prevalent in the group with >65% early recovery (15.5% versus 10.3%; P=0.01). Logistic regression modeling indicated that recovery was associated with subsequent neurological deterioration (odds ratio, 1.2; 95% CI, 1.1 to 1.3, per 10% recovery) after adjusting for age, NIHSS at 7 days, and stroke subtype. CONCLUSIONS: Substantial neurological recovery at 7 days is associated with subsequent neurological deterioration.

Aged↗
PubMed2004

Targeting neuroprotection clinical trials to ischemic stroke patients with potential to benefit from therapy.

BACKGROUND AND PURPOSE: Clinical trials of neuroprotective drugs have had limited success. We investigated whether selecting patients according to prognostic features would improve the statistical power of a trial to identify an efficacious treatment. METHODS: Using placebo data from the Glycine Antagonist in Neuroprotection (GAIN) International and National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rtPA) clinical trials, we developed and validated simple prognostic models for stroke trial end points: Barthel Index > or =95, modified Rankin Scale < or =1, National Institutes of Health Stroke Scale < or =1, and Glasgow Outcome Scale=1. Using these models, we simulated 1000 clinical trials and estimated, under several hypothetical treatment effect patterns of neuroprotection, the effect on statistical power of including only patients with moderate prognosis. We calculated the number of patients that would have to be enrolled to maintain the statistical power achieved in selecting the whole trial population. Reanalysis of actual data from the NINDS rtPA trials confirmed the results independently. RESULTS: Selecting patients with moderate prognosis (predicted probability of favorable outcome 0.2 to 0.8) enabled a sample size reduction, without loss of statistical power, of between 54.6% (51.3% to 57.6%) and 68.6% (66.0% to 71.1%), depending on the treatment effect pattern and outcome measure. These benefits were largely due to the exclusion of patients with poor prognosis. CONCLUSIONS: Targeting patients with potential to benefit enables a substantial sample size reduction without compromising statistical power or duration of recruitment. As part of a broader trial design strategy, informed use of prognostic data available acutely would help in identifying effective neuroprotective treatments.

Aged↗
PubMed2004

Impact and influences on caregiver outcomes at one year post-stroke.

BACKGROUND AND PURPOSE: Four outcome measures of carer stress and coping at one year post-stroke were identified: carer general health, anxiety, depression and perception of stress. METHODS: Each outcome was assessed using valid and reliable instruments. In addition, we collected demographic data from both carers and patients which could reasonably be expected to influence carer stress and coping (e.g. age, deprivation levels) as well as information specific to the caring role. RESULTS: Carers were found to be more anxious than previously reported. Neither satisfaction with caring nor the adoption of helpful coping strategies were associated with positive carer outcomes but, nevertheless, carers were not reluctant to care. The SF-36 is a useful predictor of carer stress, in particular the vitality score. CONCLUSIONS: Patient data are not sufficient to predict carer general health at one year. At one year, both patients and carers are more anxious than depressed. And there may be a group of patients and carers who can be characterised as borderline anxious and/or depressed and who warrant specific attention to prevent carer burnout.

Activities of Daily Living↗
PubMed2004

Elevated pulse pressure during the acute period of ischemic stroke is associated with poor stroke outcome.

BACKGROUND: It is controversial which component of blood pressure (BP) during acute period of stroke best predicts outcome. We hypothesized that elevated pulse pressure (PP), the difference between systolic BP (SBP) and diastolic BP (DBP), is independently associated with poor stroke outcome at 3 months. METHODS: We analyzed both treatment groups from the Glycine Antagonist (Gavestinel) in Neuroprotection (GAIN) International trial (1455 ischemic stroke cases of mostly moderate severity). Cox proportional hazards and logistic regression modeling corrected for demography, medical history, heart rate, stroke severity, and clinical subtype. RESULTS: Elevated weighted average PP during the first 60 hours was associated with poor outcome by mortality, Barthel index, National Institutes of Health Stroke Score (NIHSS) and Rankin scores. Elevated baseline PP was associated with Barthel index and Rankin score. CONCLUSIONS: Elevated PP is associated with poor stroke outcome at 3 months.

Acute Disease↗
PubMed2004

The effect of losartan on global and focal cerebral perfusion and on renal function in hypertensives in mild early ischaemic stroke.

BACKGROUND: Secondary prevention of stroke with antihypertensive drugs is now standard practice, but it is unclear how soon after a cerebrovascular event antihypertensive therapy should be initiated or re-started. Due to impaired cerebral autoregulation, changes in systemic blood pressure may be reflected in cerebral perfusion, especially in hypertensive patients immediately post-stroke. Conversely, early initiation in hospital may better assure continued long-term treatment. We have investigated the effect of the angiotensin II receptor antagonist (ARA) losartan on mean arterial blood pressure (MABP), global and focal cerebral blood flow (CBF), and glomerular filtration rate (GFR) in hypertensive patients 2-7 days after stroke. METHODS: Twenty-four patients without occlusive carotid disease but with MABP between 110 and 145 mmHg were studied within 2-7 days of ischaemic stroke/transient ischaemic attack (TIA). They were randomized to receive either placebo or losartan (25 or 50 mg daily). MABP and internal carotid artery (ICA) flow were measured at baseline, over the following 24 h and at 2 weeks. Brain hexamethylpropyleneamine oxime single photon emission computed tomography (HMPAO SPECT) was performed before dosing and at the estimated time of peak drug effect (6-8 h after the first dose). GFR was measured at baseline and at 2 weeks. RESULTS: The mean National Institutes of Health (NIH) score of randomized patients was 2.6; losartan was generally well tolerated and no patient suffered a deterioration in neurological function. A mean placebo-corrected intra-subject reduction in MABP of 9.5 mmHg was observed in treated patients from 1-12 h (P = 0.0001), with a maximal fall of 18.1 mmHg at 9 h post-dose (P = 0.002). No change occurred in ICA flow, or cortical or hemispheric CBF measured by HMPAO SPECT. No significant change in GFR was seen within or between groups. DISCUSSION: Losartan may be introduced within 2-7 days of mild stroke in hypertensive patients in whom significant carotid occlusive disease has been excluded without affecting global or regional CBF, or affecting GFR.

Aged↗
PubMed2004

Informal carers' experience of caring for stroke survivors.

BACKGROUND: Stroke is the third most common cause of death in industrialized countries and a major cause of adult disability. However, the burden of caring for stroke survivors usually rests with family members who have neither chosen nor volunteered for the role of 'carer'. AIMS: This paper reports on a study which aimed to describe the experience of caring for a stroke survivor at one year after stroke in Scotland. STUDY DESIGN: Semi-structured, taped interviews were conducted with 90 carers of stroke survivors one year after stroke and the data analysed using NUD*IST. The interviews were part of a larger study, which included the administration of a range of valid and reliable multidimensional instruments to both carers and stroke survivors. The interview prompt schedule had been developed and tested in a previous study. FINDINGS: Although a medical emergency, stroke was not always diagnosed or treated as such by either the public or general practitioners. Initially most carers found that they lacked the knowledge and skills to care for the stroke survivor at home and so they had to learn how to obtain the information and assistance required. Carers had to adapt to the changes that stroke effected in the stroke survivor and seek alternative ways of securing the resources they needed for managing their lives. They thought that they had not been prepared adequately for the caring role or assessed satisfactorily in terms of whether they could manage given their skill level, age and/or health status. CONCLUSIONS: A public health campaign to educate and inform that stroke is a medical emergency is required if stroke disability is to be minimized. The use of new technologies should be considered in facilitating carers' learning how to care. There is a need to test alternative models of stroke follow-up in multi-centre studies that are holistic and place the carer-stroke survivor at the centre of care.

Adaptation, Psychological↗
PubMed2003

How a sequential design would have affected the GAIN International Study of gavestinel in stroke.

While planning the GAIN International Study of gavestinel in acute stroke, a sequential triangular test was proposed but not implemented. Before the trial commenced it was agreed to evaluate the sequential design retrospectively to evaluate the differences in the resulting analyses, trial durations and sample sizes in order to assess the potential of sequential procedures for future stroke trials. This paper presents four sequential reconstructions of the GAIN study made under various scenarios. For the data as observed, the sequential design would have reduced the trial sample size by 234 patients and shortened its duration by 3 or 4 months. Had the study not achieved a recruitment rate that far exceeded expectation, the advantages of the sequential design would have been much greater. Sequential designs appear to be an attractive option for trials in stroke.

Acute Disease↗
PubMed2003

Effect of area-based deprivation on the severity, subtype, and outcome of ischemic stroke.

BACKGROUND AND PURPOSE: Markers of low socioeconomic status (deprivation) are associated with stroke and its causes. In the United Kingdom, area-based deprivation measures are available routinely through links with postal codes. We hypothesized that deprivation is associated with ischemic stroke risk factors, severity, subtype, and outcome. METHODS: We studied 2026 patients, each with at least 2 years of outcome follow-up by record linkage after first admission with ischemic stroke to an acute stroke unit. Baseline factors recorded routinely were age, sex, medical history, blood pressure, and stroke severity and subtype. Deprivation was assessed by the Womersley score (WS) and Murray score (MS). RESULTS: Higher WS and MS were associated with stroke at younger age (eg, WS linear regression coefficient (r)=-0.26; 95% confidence interval [CI], -0.51 to -0.01 per additional point), smoking (odds ratio [OR], 1.12; 95% CI, 1.08 to 1.17), and claudication (OR, 1.09; 95% CI, 1.01 to 1.17); WS was associated with higher systolic blood pressure (r=0.13; 95% CI, 0.02 to 0.24); and MS was associated with severe stroke. Deprivation was not associated with case fatality in univariate analysis or after correction for all baseline factors. Deprivation was associated with readmission to hospital as a result of any vascular event in univariate analysis (hazard ratio [HR], 1.05; 95% CI, 1.02 to 1.09) and after correction for all baseline factors (HR, 1.06; 95% CI, 1.02 to 1.10). CONCLUSIONS: Tackling health inequalities in stroke should focus on stroke primary prevention by tackling deprivation, including promoting changes in lifestyle.

Aged↗
PubMed2003

Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke.

BACKGROUND AND PURPOSE: UK-279,276 (neutrophil inhibitory factor) reduced infarct volume in a rat middle cerebral artery occlusion reperfusion model. ASTIN (Acute Stroke Therapy by Inhibition of Neutrophils) was an adaptive phase 2 dose-response-finding, proof-of-concept study to establish whether UK-279,276 improves recovery in acute ischemic stroke. The prime objective was to determine the dose that gave a clinically relevant effect in patients. METHODS: A Bayesian sequential design with real-time efficacy data capture and continuous reassessment of the dose response allowed double-blind, randomized, adaptive allocation to 1 of 15 doses (dose range, 10 to 120 mg) or placebo and early termination for efficacy or futility. The primary end point was change from baseline to day 90 on the Scandinavian Stroke Scale (DeltaSSS), adjusted for baseline SSS, aiming for a 3-point additional mean recovery above placebo. RESULTS: Nine hundred sixty-six acute stroke patients (887 ischemic, 204 cotreated with intravenous tissue plasminogen activator; mean baseline SSS score, 28; range, 10 to 40) were treated within 6 hours of symptom onset. Mean DeltaSSS was approximately +17 points of improvement on SSS for the overall evaluable population. There was no treatment effect for UK-279,276 (posterior probability of futility, 0.89). The trial was stopped early for futility. Post hoc analysis indicated a mean 1.6-point additional improvement on DeltaSSS in the tissue plasminogen activator-treated subset (credible interval=0.5, 2.6). UK-279,276 was generally well tolerated, with no increased incidence of infections. CONCLUSIONS: UK-279,276 did not improve recovery in acute ischemic stroke patients but was devoid of serious side effects. The adaptive design facilitated early termination for futility.

Acute Disease↗
PubMed2003

Strengthening acute stroke trials through optimal use of disability end points.

BACKGROUND AND PURPOSE: Suboptimal choices of primary end point for acute stroke trials may have contributed to inconclusive results. The Barthel Index (BI) and Rankin Scale (RS) have been widely used and analyzed in various ways. We sought to investigate the most powerful end point for use in acute stroke trials. METHODS: Data from the Glycine Antagonist in Neuroprotection (GAIN) International Trial were used to simulate 24 000 clinical trials exploring various patterns and magnitudes of treatment effect and thus to estimate the statistical power for a range of end points based on the BI or RS. RESULTS: RS end points were more powerful than BI end points. End points dichotomized toward the favorable extreme of either scale or adjusted according to baseline prognosis ("patient-specific" end point) were among the most powerful. Combining RS and BI in a "global" end point was also successful. Improvements in statistical power indicated that using a RS end point instead of BI > or =60 could reduce the sample size by up to 84% (95% CI, 80% to 87%), 73% (95% CI, 68% to 79%) for a patient-specific BI end point, or 81% (95% CI, 76% to 85%) for a global end point. CONCLUSIONS: The RS and global end points are preferable to BI end points; the position of the cut point is also important. Better choices of end point substantially strengthen trial power for a given trial size or allow reduced sample sizes without loss of statistical power.

Acute Disease↗
PubMed2003

Effect of blood pressure during the acute period of ischemic stroke on stroke outcome: a tertiary analysis of the GAIN International Trial.

BACKGROUND AND PURPOSE: The effects of blood pressure (BP) and its fluctuations during the acute phase on the clinical course of ischemic stroke are incompletely understood. We tested the hypotheses that baseline mean arterial BP [MAP=(2xdiastolic BP+systolic BP)/3], weighted average MAP, and an increase or decrease of >30% from baseline MAP are independently associated with stroke outcome. METHODS: We studied the 1455 patients with ischemic stroke in the Glycine Antagonist (Gavestinel) in Neuroprotection (GAIN) International Trial. BP management was at the discretion of investigators and was measured at 0, 0.5, 4, 12, 12.25, 60, and 60.25 hours. Outcome was assessed by mortality, Barthel Index (dead or 0 to 55 versus 60 to 90 versus > or =95), National Institutes of Health Stroke Scale (NIHSS) score (dead or > or =2), and Rankin Scale (dead or > or =2). Cox proportional-hazards and stepwise logistic regression modeling corrected for demography, medical history, stroke severity, and clinical subtype. RESULTS: Elevated weighted average MAP was associated with poor outcome assessed by mortality at 3 months (hazard ratio, 1.16; 1.06 to 1.27 per 10 mm Hg), NIHSS score (odds ratio [OR] 1.14; 95% confidence interval [CI], 1.01 to 1.28), and Barthel Index at 1 month (OR, 1.12; 95% CI, 1.03 to 1.23). A 30% increase from baseline MAP was associated with poor outcome assessed by NIHSS score and Barthel Index at 1 and 3 months and by Rankin score at 1 month (OR, 2.01; 95% CI, 1.16 to 3.49 to OR, 3.03; 95% CI, 1.30 to 7.02). CONCLUSIONS: Baseline MAP was not associated with poor ischemic stroke outcome. However, variables describing the course of BP over the first 2.5 days have a marked and independent relationship with 1- and 3-month outcome.

Acute Disease↗
PubMed2003

Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke.

BACKGROUND AND PURPOSE: Serum urate concentration is associated with cardiovascular disease, and hyperuricemia predicts first-ever stroke. We explored the association of admission urate level with mortality, placement, and risk of further vascular events after acute stroke. METHODS: In patients with ischemic stroke or primary intracranial hemorrhage, we determined the association of urate level with 90-day placement (alive at home, good outcome; dead or living in care, poor outcome) and with the subsequent occurrence of ischemic stroke, myocardial infarction, or vascular death. In multivariate analysis (logistic regression for 90-day placement, proportional-hazards regression for time to further vascular event), we adjusted for stroke severity (modified National Institutes of Health stroke scale) and other clinical, biochemical, and radiological variables known to influence stroke outcome. RESULTS: We studied 3731 patients and measured serum urate in 2498. Elevated urate level predicted a lower chance of good 90-day outcome (odds ratio, 0.78 per additional 0.1 mmol/L; 95% confidence interval [CI], 0.67 to 0.91) independently of stroke severity and other prognostic factors. Vascular event risk increased with urate level (relative hazard, 1.27 per additional 0.1 mmol/L; 95% CI, 1.18 to 1.36). Higher urate levels have a greater effect on vascular event rates in the presence of diabetes (additional relative hazard, 1.22 per additional 0.1 mmol/L; 95% CI, 1.06 to 1.41). CONCLUSIONS: Independently of other prognostic factors, higher serum urate levels predicted poor outcome (dead or in care) and higher vascular event rates. The role of urate in stroke pathophysiology remains uncertain, but intervention to lower urate may be worth considering.

Acute Disease↗
PubMed2003

UK-279,276, a neutrophil inhibitory glycoprotein, in acute stroke: tolerability and pharmacokinetics.

BACKGROUND AND PURPOSE: UK-279,276, a recombinant glycoprotein, binds selectively to the CD11b/CD18 integrin on neutrophils and has the potential to modulate the neuroinflammation associated with acute stroke. After preclinical evidence of neuroprotection, UK-279,276 has entered clinical development. The purposes of this study were to evaluate the safety and tolerability of UK-279,276 and to examine its pharmacokinetics and pharmacodynamics (binding to neutrophil CD11b) in patients with acute stroke. METHODS: This was a multicenter, double-blind, dose-escalation study in 176 patients randomized to a single intravenous dose of UK-279,276 (6 cohorts: 0.06, 0.1, 0.2, 0.5, 1.0, 1.5 mg/kg) or placebo (3:1 randomization within each cohort) within 12 hours of stroke onset. RESULTS: Age and stroke severity were well balanced across groups, with a mean age of 70 years (range, 39 to 92 years) and moderate baseline stroke severity (mean Scandinavian Stroke Scale score, 36.5 to 43.2; mean National Institutes of Health Stroke Scale score, 6.3 to 8.5). UK-279,276 was well tolerated at doses up to 1.5 mg/kg. There was no evidence of a relationship between dose of UK-279,276 and adverse events or clinical chemistry or hematology laboratory tests, or of an increased incidence of infection-related adverse events with the study drug. A dose-dependent UK-279,276-specific IgG antibody response was observed in patients treated with the 1.0- and 1.5-mg/kg doses. UK-279,276 displayed nonlinear pharmacokinetics across the dose range investigated. The duration of CD11b saturation was dose dependent, with >80% saturation achieved for at least 7 days after treatment with UK-279,276 1.0 and 1.5 mg/kg. CONCLUSIONS: UK-279,276 was well tolerated in acute stroke patients at single doses up to 1.5 mg/kg. Further clinical investigation of UK-279,276 is ongoing.

Acute Disease↗
PubMed2003

Comparison of stratification and adaptive methods for treatment allocation in an acute stroke clinical trial.

Achieving balance on prognostic factors between treatment groups in a clinical trial is important to ensure that any observed treatment effect may be attributed to the treatment itself. Improving the balance on prognostic factors also potentially increases the statistical power attained in a trial. Substantial imbalances may occur by chance if simple randomization is used. Allocation of the treatment according to stratified random blocks based on clinical features is the conventional approach to obtain treatment groups that are as similar as possible. An alternative approach, known as minimization (or more generally as adaptive stratification), has also been proposed. We assessed the feasibility of adaptive stratification in the context of a clinical trial of insulin to control plasma glucose level following acute stroke. We determined suitable settings for the parameters in the adaptive stratification procedure by simulation studies. Specifically, we assessed: the optimal probability for allocating a patient to the preferred (leading to least imbalance on prognostic factors) treatment group; the number of variables that could be incorporated in the adaptive stratification algorithm; the weighting that should be given to each variable; and whether interactions between variables should be included. We then compared the statistical power, across a range of simulated treatment effects, between trials where treatments were allocated by stratified random blocks and by adaptive stratification. Finally, we considered the importance of the method of analysis in realizing the gain in power which may potentially be achieved by allocating treatments using stratified random blocks or adaptive stratification.

Aged↗
PubMed2003

Design of future acute-stroke treatment trials.

Very few trials of acute stroke treatments show efficacy of a tested agent on the prespecified primary outcome. We can learn many lessons from the studies that achieve only neutral results. Preclinical studies have been flawed by use of models of transient not permanent brain ischaemia, treatments that aim to protect cerebral grey matter independently of white matter, delivery of the study drug within too short a time window after ischaemic insult, use of surrogate outcome measures in the short term instead of function in the long-term, and small sample sizes. Clinical trials have been hampered by heterogeneity in causes of stroke and inability to classify subtypes of cause; the short time available to rescue ischaemic brain tissue; the haemorrhagic transformation that can cause severe functional consequences seen frequently in infarcted brain tissue; the lack of valid, reliable, sensitive, and simple tools for assessment of functional outcome; and, above all, small treatment effects that are difficult to detect or refute. In this review, we look at the designs and results of all controlled trials of treatments for ischaemic stroke, and try to identify opportunities to improve future treatment assessment.

Clinical Trials as Topic↗
PubMed2003

Stroke: trial by jury.

Trials of pharmacological intervention for acute stroke show several points of similarity with legal trials by jury. The relationships between sponsoring organisation and regulatory authorities and the roles of the many other participants are described. Only through a partnership can the common aim of developing improved treatment for patients with stroke be realised. Excellent structures and procedures have recently developed which minimise the risk of undertaking impractical, invalid or unreported trials. This will lead to greater confidence in our ability to identify a successful treatment and to discount worthless approaches.

Clinical Trials as Topic↗
PubMed2003

Acute stroke: trial by jury. The toothless tiger (role of the principal investigator).

All trials require a principal investigator to take the lead role and act as main contact amongst the various groups of participants. His role ranges from assistance in protocol design; through selection of investigators, monitoring of study conduct and responding to Safety Committee recommendations; to involvement in study reporting and in maintaining access to the data set after the conclusion of the trial. This article describes the role of the principal investigator and Steering Committee in more detail and discusses the issues that arise out of the organisational requirements of modern clinical trials and the potential tensions between the various participating groups.

Acute Disease↗