Summary Background Raised blood pressure is common after acute stroke and is associated with an adverse prognosis. We sought to assess the feasibility, safety, and effects of two regimens for ...lowering blood pressure in patients who have had a stroke. Methods Patients who had cerebral infarction or cerebral haemorrhage and were hypertensive (systolic blood pressure SBP >160 mm Hg) were randomly assigned by secure internet central randomisation to receive oral labetalol, lisinopril, or placebo if they were non-dysphagic, or intravenous labetalol, sublingual lisinopril, or placebo if they had dysphagia, within 36 h of symptom onset in this double-blind pilot trial. The doses were titrated up if target blood pressure was not reached. Analysis was by intention to treat. This trial is registered with the National Research Register, number N0484128008. Findings 179 patients (mean age 74 SD 11 years; SBP 181 SD 16 mm Hg; diastolic blood pressure DBP 95 SD 13 mm Hg; median National Institutes of Health stroke scale NIHSS score 9 IQR 5–16 points) were randomly assigned to receive labetolol (n=58), lisinopril (n=58), or placebo (n=63) between January, 2005, and December, 2007. The primary outcome—death or dependency at 2 weeks—occurred in 61% (69) of the active and 59% (35) of the placebo group (relative risk RR 1·03, 95% CI 0·80–1·33; p=0·82). There was no evidence of early neurological deterioration with active treatment (RR 1·22, 0·33–4·54; p=0·76) despite the significantly greater fall in SBP within the first 24 h in this group compared with placebo (21 17–25 mm Hg vs 11 5–17 mm Hg; p=0·004). No increase in serious adverse events was reported with active treatment (RR 0·91, 0·69–1·12; p=0·50) but 3-month mortality was halved (9·7% vs 20·3%, hazard ratio HR 0·40, 95% CI 0·2–1·0; p=0·05). Interpretation Labetalol and lisinopril are effective antihypertensive drugs in acute stroke that do not increase serious adverse events. Early lowering of blood pressure with lisinopril and labetalol after acute stroke seems to be a promising approach to reduce mortality and potential disability. However, in view of the small sample size, care must be taken when these results are interpreted and further evaluation in larger trials is needed. Funding UK National Health Service Research and Development Health Technology Assessment Programme.
Background Recurrent vascular events remain a major source of morbidity and mortality after stroke or transient ischemic attack (TIA). The IRIS Trial is evaluating an approach to secondary prevention ...based on the established association between insulin resistance and increased risk for ischemic vascular events. Specifically, IRIS will test the effectiveness of pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class, for reducing the risk for stroke and myocardial infarction (MI) among insulin resistant, nondiabetic patients with a recent ischemic stroke or TIA. Design Eligible patients for IRIS must have had insulin resistance defined by a Homeostasis Model Assessment–Insulin Resistance >3.0 without meeting criteria for diabetes. Within 6 months of the index stroke or TIA, patients were randomly assigned to pioglitazone (titrated from 15 to 45 mg/d) or matching placebo and followed for up to 5 years. The primary outcome is time to stroke or MI. Secondary outcomes include time to stroke alone, acute coronary syndrome, diabetes, cognitive decline, and all-cause mortality. Enrollment of 3,876 participants from 179 sites in 7 countries was completed in January 2013. Participant follow-up will continue until July 2015. Summary The IRIS Trial will determine whether treatment with pioglitazone improves cardiovascular outcomes of nondiabetic, insulin-resistant patients with stroke or TIA. Results are expected in early 2016.
To explore the physiological factors affecting exercise-induced changes in peak oxygen consumption and function poststroke.
Single-center, single-blind, randomized controlled pilot trial.
Community ...stroke services.
Adults (N=40; age>50y; independent with/without stick) with stroke (diagnosed >6mo previously) were recruited from 117 eligible participants. Twenty participants were randomized to the intervention group and 20 to the control group. No dropouts or adverse events were reported.
Intervention group: 19-week (3times/wk) progressive mixed (aerobic/strength/balance/flexibility) community group exercise program. Control group: Matched duration home stretching program.
(1) Pre- and postintervention: maximal cardiopulmonary exercise testing with noninvasive (bioreactance) cardiac output measurements; and (2) functional outcome measures: 6-minute walk test; timed Up and Go test, and Berg Balance Scale.
Exercise improved peak oxygen consumption (18±5 to 21±5mL/(kg⋅min); P<.01) and peak arterial-venous oxygen difference (9.2±2.7 to 11.4±2.9mL of O2/100mL of blood; P<.01), but did not alter cardiac output (17.2±4 to 17.7±4.2L/min; P=.44) or cardiac power output (4.8±1.3 to 5.0±1.35W; P=.45). A significant relation existed between change in peak oxygen consumption and change in peak arterial-venous oxygen difference (r=.507; P<.05), but not with cardiac output. Change in peak oxygen consumption did not strongly correlate with change in function.
Exercise induced peripheral muscle, but not cardiac output, adaptations after stroke. Implications for stroke clinical care should be explored further in a broader cohort.
Coronary artery disease remains the leading cause of death in developed countries despite significant progress in primary prevention and treatment strategies. Older patients are at particularly high ...risk of poor outcomes following acute coronary syndrome and impaired nutrition, including low vitamin D levels, may play a role. The extraskeletal effects of vitamin D, in particular, its role in maintaining a healthy cardiovascular system are receiving increased attention. Longitudinal studies have demonstrated increased cardiovascular mortality and morbidity associated with vitamin D deficiency. Low vitamin D levels have been linked to inflammation, higher coronary artery calcium scores, impaired endothelial function and increased vascular stiffness. However, so far, few randomized controlled trials have investigated the potential benefits of vitamin D supplementation in preventing cardiovascular events, and most available trials have tested low doses of supplementation in relatively low-risk populations. Whether vitamin D supplementation will be beneficial among patients with coronary artery disease, including high risk older patients presenting with acute coronary syndrome, is unknown and warrants further investigation.
Study objective In the context of calls to develop better systems for out-of-hospital clinical research, we seek to understand paramedics' perceptions of involvement in research and the barriers and ...facilitators to that involvement. Methods This was a qualitative study using semistructured focus groups with 58 United Kingdom paramedics and interviews with 30 US firefighter-paramedics. The study focused on out-of-hospital research (trials of out-of-hospital treatment for stroke), whereby paramedics identified potential study subjects or obtained consent and administered study treatment in the field. Data were analyzed with a thematic and discourse approach. Results Three key themes emerged as significant facilitators and barriers to paramedic involvement in research: patient benefit, professional identity and responsibility, and time. Paramedics showed willingness and capacity to engage in research but also some reticence because of the perceived sacrifice of autonomy and challenge to their identity. Paramedics work in a time-sensitive environment and were concerned that research would increase time taken in the field. Conclusion Awareness of these perspectives will help with development of out-of-hospital research protocols and potentially facilitate greater participation.
Goal We sought to develop an instrument to screen for insulin resistance in nondiabetic patients with recent ischemic stroke or transient ischemic attack (TIA). Materials and methods Subjects were ...7262 nondiabetic patients aged greater than or equal to 40 years with ischemic strokes or TIA within the past 6 months. Features were analyzed in bivariate analysis for association with insulin resistance, measured by the homeostasis model assessment of insulin resistance (HOMA-IR). Features significantly associated with HOMA-IR ( P < .05) were entered into multivariable analysis. The magnitudes of regression coefficients from the multivariable model were used to assign point values for 2 diagnostic scoring instruments: a basic instrument and an enhanced instrument incorporating and not incorporating laboratory values, respectively. The performance of the instruments was tested using receiver operating characteristic (ROC) analysis. Findings In the basic model, 5 features were retained in the multivariable regression analysis: male gender, abdominal obesity, body mass index (BMI), elevated waist-to-hip ratio, and systolic blood pressure. In the enhanced model, 4 features were retained in the multivariable regression analysis: BMI, abdominal obesity, fasting glucose greater than or equal to 100 mg/dL, and triglyceride/high-density lipoprotein ratio. In the basic model, the area under the ROC curve (aROC) was .73 in the validation cohort. In the enhanced model, the aROC was .78 in the validation cohort. Conclusions Our 2 scoring systems performed well in identifying stroke patients with insulin resistance, but they are probably not sufficiently accurate for high-stake clinical decisions. We suggest strategies for improving the accuracy of future instruments.
Summary Background Stenting is an alternative to endarterectomy for treatment of carotid artery stenosis, but long-term efficacy is uncertain. We report long-term data from the randomised ...International Carotid Stenting Study comparison of these treatments. Methods Patients with symptomatic carotid stenosis were randomly assigned 1:1 to open treatment with stenting or endarterectomy at 50 centres worldwide. Randomisation was computer generated centrally and allocated by telephone call or fax. Major outcomes were assessed by an independent endpoint committee unaware of treatment assignment. The primary endpoint was fatal or disabling stroke in any territory after randomisation to the end of follow-up. Analysis was by intention to treat (ITT all patients) and per protocol from 31 days after treatment (all patients in whom assigned treatment was completed). Functional ability was rated with the modified Rankin scale. This study is registered, number ISRCTN25337470. Findings 1713 patients were assigned to stenting (n=855) or endarterectomy (n=858) and followed up for a median of 4·2 years (IQR 3·0–5·2, maximum 10·0). Three patients withdrew immediately and, therefore, the ITT population comprised 1710 patients. The number of fatal or disabling strokes (52 vs 49) and cumulative 5-year risk did not differ significantly between the stenting and endarterectomy groups (6·4% vs 6·5%; hazard ratio HR 1·06, 95% CI 0·72–1·57, p=0·77). Any stroke was more frequent in the stenting group than in the endarterectomy group (119 vs 72 events; ITT population, 5-year cumulative risk 15·2% vs 9·4%, HR 1·71, 95% CI 1·28–2·30, p<0·001; per-protocol population, 5-year cumulative risk 8·9% vs 5·8%, 1·53, 1·02–2·31, p=0·04), but were mainly non-disabling strokes. The distribution of modified Rankin scale scores at 1 year, 5 years, or final follow-up did not differ significantly between treatment groups. Interpretation Long-term functional outcome and risk of fatal or disabling stroke are similar for stenting and endarterectomy for symptomatic carotid stenosis. Funding Medical Research Council, Stroke Association, Sanofi-Synthélabo, European Union.
Summary Background Second-line chemotherapy for patients with oesophagogastric adenocarcinoma refractory to platinum and fluoropyrimidines has not shown benefits in health-related quality of life ...(HRQoL). We assessed whether the addition of docetaxel to active symptom control alone can improve survival and HRQoL for patients. Methods For this open-labelled, multicentre trial, we recruited patients aged 18 years or older from 30 UK centres. Patients were eligible if they had an advanced, histologically confirmed adenocarcinoma of the oesophagus, oesophagogastric junction, or stomach that had progressed on or within 6 months of treatment with a platinum-fluoropyrimidine combination. Patients could have an Eastern Cooperative Oncology Group performance status of 0–2. We randomly assigned patients using a central, computerised minimisation procedure to receive docetaxel plus active symptom control, or active symptom control alone (1:1; stratified by disease status, disease site, duration of response to previous chemotherapy, and performance status). Docetaxel was given at a dose of 75 mg/m2 by intravenous infusion every 3 weeks for up to six cycles. The primary endpoint was overall survival, analysed by intention to treat. This is the report of the planned final analysis. This study is an International Standardised Randomised Controlled Trial, number ISRCTN13366390. Findings Between April 21, 2008, and April 26, 2012, we recruited 168 patients, allocating 84 to each treatment group. After a median follow-up of 12 months IQR 10–21) and 161 (96%) deaths (80 in the docetaxel group, 81 in the active symptom control group), median overall survival in the docetaxel group was 5·2 months (95% CI 4·1–5·9) versus 3·6 months (3·3–4·4) in the active symptom control group (hazard ratio 0·67, 95% CI 0·49–0·92; p=0·01). Docetaxel was associated with higher incidence of grade 3–4 neutropenia (12 15% patients vs no patients), infection (15 19% patients vs two 3% patients), and febrile neutropenia (six 7% patients vs no patients). Patients receiving docetaxel reported less pain (p=0·0008) and less nausea and vomiting (p=0·02) and constipation (p=0·02). Global HRQoL was similar between the groups (p=0·53). Disease specific HRQoL measures also showed benefits for docetaxel in reducing dysphagia (p=0·02) and abdominal pain (p=0·01). Interpretation Our findings suggest that docetaxel can be recommended as an appropriate second-line treatment for patients with oesophagogastric adenocarcinoma that is refractory to treatment with platinum and fluoropyrimidine. Funding Cancer Research UK.
The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.
Preliminary work was performed by 7 working groups ...of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.
Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent "silo" mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a "Brain Health" concept that enables promotion of preventive measures.
To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.
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