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Background Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. Aims In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. Methods We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3–6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. Results Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68–83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9–21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear ( R2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08–2.87); p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63–1.45); p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11–1.42); p = 0.0004). Conclusion Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. Data access statement Anonymized summary data may be requested from the corresponding author.

The replicability of research results has been a cause of increasing concern to the scientific community. The long-held belief that experimental standardization begets replicability has also been recently challenged, with the observation that the reduction of variability within studies can lead to idiosyncratic, lab-specific results that cannot be replicated. An alternative approach is to, instead, deliberately introduce heterogeneity, known as “heterogenization” of experimental design. Here, we explore a novel perspective in the heterogenization program in a meta-analysis of variability in observed phenotypic outcomes in both control and experimental animal models of ischemic stroke. First, by quantifying interindividual variability across control groups, we illustrate that the amount of heterogeneity in disease state (infarct volume) differs according to methodological approach, for example, in disease induction methods and disease models. We argue that such methods may improve replicability by creating diverse and representative distribution of baseline disease state in the reference group, against which treatment efficacy is assessed. Second, we illustrate how meta-analysis can be used to simultaneously assess efficacy and stability (i.e., mean effect and among-individual variability). We identify treatments that have efficacy and are generalizable to the population level (i.e., low interindividual variability), as well as those where there is high interindividual variability in response; for these, latter treatments translation to a clinical setting may require nuance. We argue that by embracing rather than seeking to minimize variability in phenotypic outcomes, we can motivate the shift toward heterogenization and improve both the replicability and generalizability of preclinical research., A meta-analysis study of the variability in phenotypic outcomes in both control and experimental animal models of ischaemic stroke provides novel perspectives in which heterogeneity can be embraced to improve the reproducibility and translation of preclinical studies.

Introduction The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Quantitative data on the extent of the delays due to national or local review in randomised clinical trials is scarce. Materials and methods We assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. The primary outcome was the time from the first submission to a regulatory authority to initiation of a trial site. Secondary outcomes included time needed to complete each individual preparatory requirement and the number of patients recruited by each site in the first 6 and 12 months. Results The median time from the first submission to a regulatory authority to initiation of a trial site was 784 days (IQR: 586–1102). The single most time-consuming step was the conclusion of a clinical trial agreement between the national coordinator and the trial site, which took a median of 194 days (IQR: 93–293). A longer time to site initiation was associated with a lower patient recruitment rate in the first six months after initiation (B = –0.002; p = 0.02). Discussion Conclusion In this EU-funded clinical trial, approximately 26 months were needed to initiate a trial site for patient recruitment. The conclusion of a contract with a trial site was the most time-consuming activity. To simplify and speed up the process, we suggest that the level of detail of contracts for academic trials should be proportional to the risks and commercial interests of these trials.

Background:Concerns regarding potential neurological complications of COVID-19 are being increasingly reported, primarily in small series. Larger studies have been limited by both geography and specialty. Comprehensive characterisation of clinical syndromes is crucial to allow rational selection and evaluation of potential therapies. The aim of this study was to investigate the breadth of complications of COVID-19 across the UK that affected the brain.Methods:During the exponential phase of the pandemic, we developed an online network of secure rapid-response case report notification portals across the spectrum of major UK neuroscience bodies, comprising the Association of British Neurologists (ABN), the British Association of Stroke Physicians (BASP), and the Royal College of Psychiatrists (RCPsych), and representing neurology, stroke, psychiatry, and intensive care. Broad clinical syndromes associated with COVID-19 were classified as a cerebrovascular event (defined as an acute ischaemic, haemorrhagic, or thrombotic vascular event involving the brain parenchyma or subarachnoid space), altered mental status (defined as an acute alteration in personality, behaviour, cognition, or consciousness), peripheral neurology (defined as involving nerve roots, peripheral nerves, neuromuscular junction, or muscle), or other (with free text boxes for those not meeting these syndromic presentations). Physicians were encouraged to report cases prospectively and we permitted recent cases to be notified retrospectively when assigned a confirmed date of admission or initial clinical assessment, allowing identification of cases that occurred before notification portals were available. Data collected were compared with the geographical, demographic, and temporal presentation of overall cases of COVID-19 as reported by UK Government public health bodies.Findings:The ABN portal was launched on April 2, 2020, the BASP portal on April 3, 2020, and the RCPsych portal on April 21, 2020. Data lock for this report was on April 26, 2020. During this period, the platforms received notification of 153 unique cases that met the clinical case definitions by clinicians in the UK, with an exponential growth in reported cases that was similar to overall COVID-19 data from UK Government public health bodies. Median patient age was 71 years (range 23–94; IQR 58–79). Complete clinical datasets were available for 125 (82%) of 153 patients. 77 (62%) of 125 patients presented with a cerebrovascular event, of whom 57 (74%) had an ischaemic stroke, nine (12%) an intracerebral haemorrhage, and one (1%) CNS vasculitis. 39 (31%) of 125 patients presented with altered mental status, comprising nine (23%) patients with unspecified encephalopathy and seven (18%) patients with encephalitis. The remaining 23 (59%) patients with altered mental status fulfilled the clinical case definitions for psychiatric diagnoses as classified by the notifying psychiatrist or neuropsychiatrist, and 21 (92%) of these were new diagnoses. Ten (43%) of 23 patients with neuropsychiatric disorders had new-onset psychosis, six (26%) had a neurocognitive (dementia-like) syndrome, and four (17%) had an affective disorder. 18 (49%) of 37 patients with altered mental status were younger than 60 years and 19 (51%) were older than 60 years, whereas 13 (18%) of 74 patients with cerebrovascular events were younger than 60 years versus 61 (82%) patients older than 60 years. Interpretation:To our knowledge, this is the first nationwide, cross-specialty surveillance study of acute neurological and psychiatric complications of COVID-19. Altered mental status was the second most common presentation, comprising encephalopathy or encephalitis and primary psychiatric diagnoses, often occurring in younger patients. This study provides valuable and timely data that are urgently needed by clinicians, researchers, and funders to inform immediate steps in COVID-19 neuroscience research and health policy. Funding: None.

Background Elderly patients are at high risk of complications after stroke, such as infections and fever. The occurrence of these complications has been associated with an increased risk of death or dependency. Hypothesis: Prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first four days after stroke onset will improve functional outcome at 90 days in elderly patients with acute stroke. Design International, 3 × 2-factorial, randomised-controlled, open-label clinical trial with blinded outcome assessment (PROBE) in 3800 patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and an NIHSS score ≥ 6. Patients will be randomly allocated to any combination of oral, rectal, or intravenous metoclopramide (10 mg thrice daily); intravenous ceftriaxone (2000 mg once daily); oral, rectal, or intravenous paracetamol (1000 mg four times daily); or usual care, started within 24 h after symptom onset and continued for four days or until complete recovery or discharge from hospital, if earlier. Outcome: The primary outcome measure is the score on the modified Rankin Scale at 90 days (± 14 days), as analysed with multiple regression. Summary: This trial will provide evidence for a simple, safe and generally available treatment strategy that may reduce the burden of death or disability in patients with stroke at very low costs. Planning: First patient included in May 2016; final follow-up of the last patient by April 2020. Registration: ISRCTN, ISRCTN82217627, https://doi.org/10.1186/ISRCTN82217627

Stroke is the second highest cause of death globally and a leading cause of disability, with an increasing incidence in developing countries. Ischaemic stroke caused by arterial occlusion is responsible for the majority of strokes. Management focuses on rapid reperfusion with intravenous thrombolysis and endovascular thrombectomy, which both reduce disability but are time-critical. Accordingly, improving the system of care to reduce treatment delays is key to maximizing the benefits of reperfusion therapies. Intravenous thrombolysis reduces disability when administered within 4.5 h of the onset of stroke. Thrombolysis also benefits selected patients with evidence from perfusion imaging of salvageable brain tissue for up to 9 h and in patients who awake with stroke symptoms. Endovascular thrombectomy reduces disability in a broad group of patients with large vessel occlusion when performed within 6 h of stroke onset and in patients selected by perfusion imaging up to 24 h following stroke onset. Secondary prevention of ischaemic stroke shares many common elements with cardiovascular risk management in other fields, including blood pressure control, cholesterol management and antithrombotic medications. Other preventative interventions are tailored to the mechanism of stroke, such as anticoagulation for atrial fibrillation and carotid endarterectomy for severe symptomatic carotid artery stenosis.

Background: Artificial intelligence-based software may automatically detect ischaemic stroke lesions and provide an Alberta Stroke Program Early CT score (ASPECTS) on CT, and identify arterial occlusion and provide a collateral score on CTA. Large-scale independent testing will inform clinical use, but is lacking. We aim to test e-ASPECTS and e-CTA (Brainomix, Oxford UK) using CT scans obtained from a range of clinical studies. Methods: Using prospectively collected baseline CT and CTA scans from 10 national/international clinical stroke trials or registries (total >6600 patients), we will select a large clinically representative sample for testing e-ASPECTS and e-CTA compared to previously acquired independent expert human interpretation (reference standard). Our primary aims are to test agreement between software-derived and masked human expert ASPECTS, and the diagnostic accuracy of e-ASPECTS for identifying all causes of stroke symptoms using follow-up imaging and final clinical opinion as diagnostic ground truth. Our secondary aims are to test when and why e-ASPECTS is more or less accurate, or succeeds/fails to produce results, agreement between e-CTA and human expert CTA interpretation, and repeatability of e-ASPECTS/e-CTA results. All testing will be conducted on an intention-to-analyse basis. We will assess agreement between software and expert-human ratings and test the diagnostic accuracy of software. Conclusions: RITeS will provide comprehensive, robust and representative testing of e-ASPECTS and e-CTA against the current gold-standard, expert-human interpretation.

Background and Purpose— Because the new era of preclinical stroke research demands improvements in validity and generalizability of findings, moving from single site to multicenter studies could be pivotal. However, the conduct of magnetic resonance imaging (MRI) in stroke remains ill-defined. We sought to assess the variability in the use of MRI for evaluating lesions post stroke and to examine the possibility as an alternative to gold standard histology for measuring the infarct size. Methods— We identified animal studies of ischemic stroke reporting lesion sizes using MRI. We assessed the degree of heterogeneity and reporting of scanning protocols, postprocessing methods, study design characteristics, and study quality. Studies performing histological evaluation of infarct size were further selected to compare with corresponding MRI using meta-regression. Results— Fifty-four articles undertaking a total of 78 different MRI scanning protocols met the inclusion criteria. T 2 -weighted imaging was most frequently used (83% of the studies), followed by diffusion-weighted imaging (43%). Reporting of the imaging parameters was adequate, but heterogeneity between studies was high. Twelve studies assessed the infarct size using both MRI and histology at corresponding time points, with T 2 -weighted imaging–based treatment effect having a significant positive correlation with histology ( ; P Conclusions— Guidelines for standardized use and reporting of MRI in preclinical stroke are urgently needed. T 2 -weighted imaging could be used as an effective in vivo alternative to histology for estimating treatment effects based on the extent of infarction; however, additional studies are needed to explore the effect of individual parameters.

Fatigue is ubiquitous but it is more common and more severe in patients with acute and chronic conditions, including stroke. The reported proportion of people with fatigue after stroke ranges from 23% to 75%.1 The variation in proportion between studies reflects the heterogeneity in the studied populations, time since stroke, and assessment methods for fatigue. Fatigue is common immediately after stroke, and it tends to persist in most but not all patients. It contributes to lower quality of life and a higher risk of death.2,3 How to manage and prevent fatigue is ranked by stroke survivors and health professionals among the top 10 research priorities relating to life after stroke.4 However, there is no effective treatment, which is partly because of our lack of knowledge of its mechanisms. Fatigue after stroke may share some common underlying mechanisms with other conditions. For example, Zedlitz and colleagues found that the psychosocial profiles of stroke patients with fatigue were similar to those reported in patients with cancer, multiple sclerosis, and chronic fatigue syndrome.5 Several fatigue models have been developed for patients with other conditions; a myriad of biological,6,7 psychosocial,8,9 and behavioral factors,9 as well as other symptoms, such as pain and sleep problems,10 are involved. In this review, we explored whether these factors contribute to fatigue after stroke. We systematically reviewed studies of post-stroke fatigue (PSF) and discussed the definition of PSF, its natural history, and its associations. By drawing on literature of fatigue in other conditions alongside evidence from stroke studies, we propose a conceptual model of PSF. This model is potentially useful in understanding the mechanisms of PSF and informing the development of its treatment. In stroke studies, PSF is usually defined by cut-off scores on fatigue …

Introduction: The number of stroke patients arriving at hospital within a therapeutic timeframe is increasing, enabling earlier and more successful intervention with thrombolysis and thrombectomy. Despite promising animal data, no neuroprotectants have translated into clinical practice. Brain tissue contains a high amount of polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA), an omega-3 fatty acid essential for normal brain growth and cognitive function. As DHA plays a critical role in neuronal survival and synaptic function, and is also a potent modulator of brain inflammation, it is a strong candidate for a successful neuroprotectant in stroke. Aims: We therefore aimed to summarise the current evidence for omega-3 fatty acids as a treatment for experimental acute ischaemic stroke. Methods: A systematic literature review of papers reporting omega-3 administration in animal models of acute stroke was conducted using the CAMARADES systematic review facility (SyRF). 1173 titles were screened, 168 abstracts reviewed and data extracted from 15 studies. Data were extracted manually, and collated, organised and analysed within CAMARADES. Measures of study quality were recorded, reflecting current STAIR recommendations for pre-clinical studies. Pre-defined endpoints extracted included mortality, infarct volume and neurobehavioural score. Results: DHA reduced infarct volume with an effect size of 48.5%, (95% CI 32.2 - 65.5) compared to control treatments. Neurobehavioural score was improved by 34.8%,( 95% CI 21.8 - 47.7) in DHA treated animals. There was a decrease in mortality of 61% for DHA treated animals (OR 0.39, 95% CI 0.21-0.77(12 studies, no heterogeneity)). All studies used male animals, and no studies co-administered alteplase. Composition of omega-3 preparations was a source of significant heterogeneity (P Conclusions: Current evidence suggests that DHA administration significantly improves outcome and decreases mortality in animal models of acute ischaemic stroke, providing support for further translational studies.

BACKGROUND: Developing new medicines is a complex process where understanding the reasons for both failure and success takes us forward. One gap in our understanding of most candidate stroke drugs before clinical trial is whether they have a protective effect on human tissues. NXY-059 is a spin-trap reagent hypothesized to have activity against the damaging oxidative biology which accompanies ischemic stroke. Re-examination of the preclinical in vivo dataset for this agent in the wake of the failed SAINT-II RCT highlighted the presence of a range of biases leading to overestimation of the magnitude of NXY-059's effects in laboratory animals. Therefore, NXY-059 seemed an ideal candidate to evaluate in human neural tissues to determine whether human tissue testing might improve screening efficiency.MATERIALS AND METHODS: The aim of this randomized and blinded study was to assess the effects of NXY-059 on human stem cell-derived neurons in the presence of ischemia-like injury induced by oxygen glucose deprivation or oxidative stress induced by hydrogen peroxide or sodium nitroprusside.RESULTS: In MTT assays of cell survival, lactate dehydrogenase assays of total cell death and terminal deoxynucleotidyl transferase dUTP nick end labeling staining of apoptotic-like cell death, NXY-059 at concentrations ranging from 1 µm to 1 mm was completely without activity. Conversely an antioxidant cocktail comprising 100 µm each of ascorbate, reduced glutathione, and dithiothreitol used as a positive control provided marked neuronal protection in these assays.CONCLUSION: These findings support our hypothesis that stroke drug screening in human neural tissues will be of value and provides an explanation for the failure of NXY-059 as a human stroke drug.

Cerebral small vessel disease (SVD) is a major health challenge. Therapeutic approaches remain limited, hampered by the lack of mechanistic understanding and identification of therapeutic targets. Relevant animal models could provide a cornerstone to basic scientific studies of disease mechanisms and pre-clinical studies of potential therapies, but there is a critical need to improve the current translational gap that exists between pre-clinical research and treatments in patients. The Medical Research Council Dementias Platform UK (MRC DPUK) Vascular Experimental Medicine Theme identified that a comprehensive assessment of the latest developments in animal models and of their contribution to understanding of cerebral microvascular disease would reduce the translational gap. In response to this, a two day workshop took place in late January 2017 at the British Heart Foundation Centre of Research Excellence in Glasgow, Scotland in conjunction with MRC DPUK and brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. There were presentations from UK and international researchers and a specific focus on animal models of cerebral microvascular disease and dementia, considering vascular biology, neurogliovascular coupling, blood-brain barrier function, neuroinflammation, cerebral drainage pathways, and methodological and translational challenges (see Figure 1 for the general organisation of the meeting including the key topics and themes discussed). This overview provides a summary of the key talks, with a particular focus on mechanisms of cerebral vascular disease (see Figure 2) and improving translation. These talks were followed by related themed discussion groups on the gaps in knowledge and requirements to advance knowledge, the outcomes of which are highlighted in Table 1. Additional related articles are published in the Special Edition of Clinical Science (http://www.portlandpresspublishing.com/cc/small-vessels).

Summary Background Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p Interpretation Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. Funding National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

Background and Purpose— Fatigue is common after stroke but has no effective treatments. Psychological interventions improve fatigue in other conditions by targeting psychological factors such as mood. If psychological factors correlate with fatigue in stroke, this would justify the development of similar interventions for poststroke fatigue (PSF). We used systematic review and meta-analysis to determine psychological associations of PSF. Methods— We systematically searched for studies that reported psychological associations of PSF. We used odds ratios (ORs) to estimate the strength of associations and random-effects modeling to calculate summary estimates of ORs. We used stratified meta-analysis to investigate the impact of study design and conducted sensitivity analyses limited to studies that excluded patients with clinical depression and to studies that used depression scales without fatigue items. Results— Thirty-five studies (n=9268) reported the association between PSF and ≥1 psychological factor. For PSF and depressive symptoms, we identified 19 studies (n=6712; pooled OR=4.14; 95% confidence interval, 2.73–6.27); this association existed in patients without clinical depression (pooled OR=1.39; 95% confidence interval, 1.27–1.53) and in studies using depression scales without fatigue items (pooled OR=5.41; 95% confidence interval, 1.54–18.93). For PSF and anxiety, we identified 4 studies (n=3884; pooled OR=2.34; 95% confidence interval, 0.98–5.58). Two studies (n=123) found an association with poor coping styles and 1 study (n=167) with loss of control. Six studies (n=1978) reported other emotional or behavioral associations. Conclusions— PSF is associated with depressive symptoms, anxiety, poor coping, loss of control, emotional, and behavioral symptoms. These factors are potential targets for treatment of PSF.

The use of systematic review and meta-analysis of preclinical studies has become more common, including those of studies describing the modeling of cerebrovascular diseases. Empirical evidence suggests that too many preclinical experiments lack methodological rigor, and this leads to inflated treatment effects. The aim of this review is to describe the concepts of systematic review and meta-analysis and consider how these tools may be used to provide empirical evidence to spur the field to improve the rigor of the conduct and reporting of preclinical research akin to their use in improving the conduct and reporting of randomized controlled trials in clinical research. As with other research domains, systematic reviews are subject to bias. Therefore, we have also suggested guidance for their conduct, reporting, and critical appraisal.

Background. Regular exercise reduces the risk of a first-ever stroke and is associated with smaller infarcts. Although evidence has suggested that therapeutic exercise following stroke is beneficial, we do not yet know whether exercise reduces stroke severity and improves functional recovery. The mechanisms underlying any benefit remain unclear. Objective. To conduct a systematic review and meta-analysis of studies testing exercise in animal models of ischemic stroke where outcomes were measured as infarct volume, neurobehavioral score, neurogenesis, or a combination of these. We also sought evidence of publication bias. Methods. We searched 3 online databases for publications reporting the use of exercise in focal cerebral ischemia. We used DerSimonian and Laird normalized random-effects meta-analysis and meta-regression to determine the impact of study quality and design on the efficacy of exercise. Results. Overall, exercise reduced infarct volume by 25.2% (95% confidence interval [CI] = 19.0%-31.3%; 65 experiments and 986 animals) and improved neurobehavioral score by 38.2% (95% CI = 29.1%-47.3%; 42 experiments; n = 771). For both outcomes, larger effects were seen when exercise preceded ischemia rather than came after it. For neurobehavioral scores, we found evidence of publication bias. Reported study quality was moderate (median score 5/10). Both model-specific (eg, type of ischemia) and exercise-specific characteristics influenced reported outcome. Conclusion. Exercise, either before or after ischemia, reduced infarct volume and improved neurobehavioral score. However, overall estimates of efficacy were higher in studies at risk of bias, and for neurobehavioral outcomes, there was evidence of a substantial publication bias.

Edaravone has been used in patients with acute ischemic stroke in Japan for over 10 years but does not have marketing authorization in Europe or America. Either patients in Europe and America are not receiving an effective treatment, or those in Asia are being given a treatment which is not effective. Finding out which of these is true will require further clinical trials, and a better understanding of its efficacy in animal models may help inform the design of those trials so that it might be tested under conditions where there is the greatest prospect of success. We systematically reviewed the efficacy of edaravone in animal models of focal ischemia and summarized data using weighted mean difference DerSimonian and Laird random-effects modeling. We used stratified meta-analysis and metaregression to assess the influence of study design and methodological quality. We identified 49 experiments describing outcome in 814 animals; 30 experiments (519 animals) reported functional and 35 experiments (503 animals) reported structural outcome. Edaravone improved functional and structural outcome by 30.3% (95% confidence interval 23.4–37.2%) and 25.5% (95% confidence interval, 21.1–29.9%), respectively. For functional outcome, there was an inverse relationship between study quality and effect size ( P < 0.0017). Effect sizes were larger in studies where randomization or blinded assessment was not reported. There was no evidence of publication bias. Edaravone is a promising treatment for stroke. However, because of the methodological weakness in current animal studies, no sufficient preclinical evidence is available to optimize the study design of clinical trials. Higher quality animal studies are expected to inform further clinical study.

Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes. The recommendations cover basic requirements pre-surgery, selecting the most appropriate anaesthetic and analgesic regimen, as well as intraoperative and post-operative care. The aim is to provide support for researchers and animal care staff to refine their procedures and practices, and implement small incremental changes to improve the welfare of the animals used and to answer the scientific question under investigation. All recommendations are recapitulated in a summary poster (see supplementary information)., The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Meetings of the working group were funded by the NC3Rs. Dr. Michael J. O Neill is a full time employee of Eli Lilly & Co.

Key disparities between the timing and methods of assessment in animal stroke studies and clinical trial may be part of the reason for the failure to translate promising findings. This study investigates the development of ischemic damage after thread occlusion MCAo in the rat, using histological and behavioural outcomes. Using the adhesive removal test we investigate the longevity of behavioural deficit after ischemic stroke in rats, and examine the practicality of using such measures as the primary outcome for future studies. Ischemic stroke was induced in 132 Spontaneously Hypertensive Rats which were assessed for behavioural and histological deficits at 1, 3, 7, 14, 21, 28 days, 12 and 24 weeks (n>11 per timepoint). The basic behavioural score confirmed induction of stroke, with deficits specific to stroke animals. Within 7 days, these deficits resolved in 50% of animals. The adhesive removal test revealed contralateral neglect for up to 6 months following stroke. Sample size calculations to facilitate the use of this test as the primary experimental outcome resulted in cohort sizes much larger than are the norm for experimental studies. Histological damage progressed from a necrotic infarct to a hypercellular area that cleared to leave a fluid filled cavity. Whilst absolute volume of damage changed over time, when corrected for changes in hemispheric volume, an equivalent area of damage was lost at all timepoints. Using behavioural measures at chronic timepoints presents significant challenges to the basic science community in terms of the large number of animals required and the practicalities associated with this. Multicentre preclinical randomised controlled trials as advocated by the MultiPART consortium may be the only practical way to deal with this issue.

A quantitative and qualitative comparison of contemporary neuroprotection and thrombolytic stroke trials and their preclinical animal counterparts has been undertaken, with meta-analysis (DerSimonian and Laird, 1986) used to evaluate imaging and histological outcomes. Results from 35 clinical trials including 5,532 patients were compared with data from 3,145 pre-clinical acute-stroke experiments in 45,476 animals. While clinical trials tended to be of higher methodological quality and have larger sample sizes than animal experiments (71 patients vs. 7 animals per group), both were similarly underpowered owing to the greater variability in human stroke (average standard deviation of mean in humans 99% v 30% in animals). Proportionally, animal infarcts were almost four times larger than human infarcts in untreated control groups (27% v 8% of the hemisphere) although there was considerable variability in size owing to comorbidities and stroke type. Eighty-six percent of animal studies and 54% of clinical trials reported smaller infarcts in groups receiving treatment, with 41% of clinical trials reporting an improvement in the pre-specified hypothesis. Animal experiments were not effective in predicting individual trial results, nor the level of neuroprotection, however, there was a fair agreement between the direction of the animal and clinical outcomes when looking at the overall direction of drug outcome. As a drug screening tool, experimental stroke studies need refinement. Rational frameworks for translational research will help.

Stroke is a major burden to patients and society, and resources spent on stroke research must be used efficiently and produce good value in terms of improvements in human health. However, many instances of poor value from stroke research funding have resulted from the way in which stroke research topics have been chosen and how studies have been designed, conducted, analysed, regulated, managed, disseminated, or reported. A cooperative effort of European stroke researchers aimed to identify sources of inefficiency and waste, recommend approaches to increase value, and highlight examples of best practice in stroke research. Evidence suggests that progress has been made, but there is room for much improvement; researchers, funders, regulators, and other stakeholders in stroke research might consider these recommendations when planning new research.

Background: Malignant glioma is an aggressive tumour commonly associated with a dismal outcome despite optimal surgical and radio-chemotherapy. Since 2005 temozolomide has been established as first-line chemotherapy. We investigate the role of in vivo glioma models in predicting clinical efficacy.Methods: We searched three online databases to systematically identify publications testing temozolomide in animal models of glioma. Median survival and number of animals treated were extracted and quality was assessed using a 12-point scale; random effects meta-analysis was used to estimate efficacy. We analysed the impact of study design and quality and looked for evidence of publication bias.Results: We identified 60 publications using temozolomide in models of glioma, comprising 2443 animals. Temozolomide prolonged survival by a factor of 1.88 (95% CI 1.74-2.03) and reduced tumour volume by 50.4% (41.8-58.9) compared with untreated controls. Study design characteristics accounted for a significant proportion of between-study heterogeneity, and there was evidence of a significant publication bias.Conclusion: These data reflect those from clinical trials in that temozolomide improves survival and reduces tumour volume, even after accounting for publication bias. Experimental in vivo glioma studies of temozolomide differ from those of other glioma therapies in their consistent efficacy and successful translation into clinical medicine.

Background Hypothermia is a promising experimental treatment for acute ischemic stroke. Human trials are still at an early stage, with the focus now on using hypothermia in awake patients. Pethidine (meperidine) is the principle agent used to control shivering in humans; however, whether it has any modulating effects on the neuroprotective efficacy of hypothermia is unknown. Aim The aim of this study was to determine if pethidine influences the neuroprotective effect of hypothermia in experimental stroke. Methods Seventy-two male spontaneously hypertensive rats were anesthetized with isoflurane and randomly assigned to either normothermia (37·4°C rectal temperature); hypothermia (33°C maintained for 130 mins); normothermia plus pethidine (2·5 mg/kg); or hypothermia plus pethidine. Temporary (90 mins) endovascular occlusion of the middle cerebral artery was induced blinded to treatment allocation and was confirmed with laser Doppler flowmetry. Pethidine and cooling were started immediately after vessel occlusion. Animals in the normothermia group had active temperature management using a heat lamp and fan. Assessments of outcome were carried out 24 after the induction of injury. Results Thirteen animals met our prespecified criteria for exclusion, and data for 59 rats were presented here. Hypothermia was associated with a 63% reduction in infarct size, and pethidine had no significant impact on the efficacy of hypothermia. No effects were observed in neurobehavioral outcome or edema volume across experimental groups. Conclusions The effects of hypothermia in a model of focal ischemia are not affected by administration of pethidine.

The mortality and morbidity associated with stroke makes the development of new drugs a research priority. Recent unsuccessful clinical trials have reduced enthusiasm for the development of neuroprotective drugs. Here, we use empirical evidence derived from systematic reviews of stroke drug development to identify stages of drug development which might be improved. We then propose exemplar strategies which may be helpful, along with some basic economic modelling of what the impact of such strategies might be. This suggests that relatively straightforward measures might reduce the costs of drug development by $5.8 bn or 31%.

Combination therapy has been identified as a promising strategy to improve stroke management. We conducted a systematic review and meta-analysis of evidence from animal models of ischemic stroke to determine whether combining treatments improved efficacy. Multiple databases were searched and data were extracted from focal ischemia experiments comparing control groups, single treatments, and combination treatments. Of 11,430 papers identified, 142 met the inclusion criteria; these tested 126 treatments in 373 experiments using 8,037 animals ( I2 = 85 to 96%). Taken together, single treatments reduced infarct size by 20% and improved neurological score by 12% compared with control; a second therapy improved efficacy by an additional 18% and 25%, respectively. Publication bias may affect combination efficacy for infarct size but not neurological score. Combining thrombolysis with other therapies may extend the time window from 4.4 to 8 hours in animal models, although testing beyond 6 hours is required to confirm this. Benefits of additional therapy decreased as the efficacy of the primary treatment increased, with combination efficacy reaching a ceiling at 60% to 80% protection. Combining treatments may bring benefits and extend the time window for treatment. More evidence is needed due to potential publication bias and heterogeneity.

Background. Major advances during the past 50 years highlight the immense potential for restoration of function after neural injury, even in the damaged adult human brain. Yet, the translation of these advances into clinically useful treatments is painstakingly slow. Objective. Here, we consider why the traditional model of a “translational research pipeline” that transforms basic science into novel clinical practice has failed to improve rehabilitation practice for people after stroke. Results. We find that (1) most treatments trialed in vitro and in animal models have not yet resulted in obviously useful functional gains in patients; (2) most clinical trials of restorative treatments after stroke have been limited to small-scale studies; (3) patient recruitment for larger clinical trials is difficult; (4) the determinants of patient outcomes and what patients want remain complex and ill-defined, so that basic scientists have no clear view of the clinical importance of the problems that they are addressing; (5) research in academic neuroscience centers is poorly integrated with practice in front-line hospitals and the community, where the majority of patients are treated; and (6) partnership with both industry stakeholders and patient pressure groups is poorly developed, at least in the United Kingdom where research in the translational restorative neurosciences in stroke depends on public sector research funds and private charities. Conclusions. We argue that interaction between patients, front-line clinicians, and clinical and basic scientists is essential so that they can explore their different priorities, skills, and concerns. These interactions can be facilitated by funding research consortia that include basic and clinical scientists, clinicians and patient/carer representatives with funds targeted at those impairments that are major determinants of patient and carer outcomes. Consortia would be instrumental in developing a lexicon of common methods, standardized outcome measures, data sharing and long-term goals. Interactions of this sort would create a research-friendly, rather than only target-led, culture in front-line stroke rehabilitation services.

Background and Purpose— At least part of the failure in the transition from experimental to clinical studies in stroke has been attributed to the imprecision introduced by problems in the design of experimental stroke studies. Using a metaepidemiologic approach, we addressed the effect of randomization, blinding, and use of comorbid animals on the estimate of how effectively therapeutic interventions reduce infarct size. Methods— Electronic and manual searches were performed to identify meta-analyses that described interventions in experimental stroke. For each meta-analysis thus identified, a reanalysis was conducted to estimate the impact of various quality items on the estimate of efficacy, and these estimates were combined in a meta–meta-analysis to obtain a summary measure of the impact of the various design characteristics. Results— Thirteen meta-analyses that described outcomes in 15 635 animals were included. Studies that included unblinded induction of ischemia reported effect sizes 13.1% (95% CI, 26.4% to 0.2%) greater than studies that included blinding, and studies that included healthy animals instead of animals with comorbidities overstated the effect size by 11.5% (95% CI, 21.2% to 1.8%). No significant effect was found for randomization, blinded outcome assessment, or high aggregate CAMARADES quality score. Conclusions— We provide empirical evidence of bias in the design of studies, with studies that included unblinded induction of ischemia or healthy animals overestimating the effectiveness of the intervention. This bias could account for the failure in the transition from bench to bedside of stroke therapies.

It has recently been suggested that multicenter preclinical stroke studies should be carried out to improve translation from bench to bedside, but the accuracy of magnetic resonance imaging (MRI) scanners routinely used in experimental stroke has not yet been evaluated. We aimed to assess and compare geometric accuracy of preclinical scanners and examine the longitudinal stability of one scanner using a simple quality assurance (QA) protocol. Six 7 Tesla animal scanners across six different preclinical imaging centers throughout Europe were used to scan a small structural phantom and estimate linear scaling errors in all orthogonal directions and volumetric errors. Between-scanner imaging consisted of a standard sequence and each center's preferred sequence for the assessment of infarct size in rat models of stroke. The standard sequence was also used to evaluate the drift in accuracy of the worst performing scanner over a period of six months following basic gradient calibration. Scaling and volumetric errors using the standard sequence were less variable than corresponding errors using different stroke sequences. The errors for one scanner, estimated using the standard sequence, were very high (above 4% scaling errors for each orthogonal direction, 18.73% volumetric error). Calibration of the gradient coils in this system reduced scaling errors to within ±1.0%; these remained stable during the subsequent 6-month assessment. In conclusion, despite decades of use in experimental studies, preclinical MRI still suffers from poor and variable geometric accuracy, influenced by the use of miscalibrated systems and various types of sequences for the same purpose. For effective pooling of data in multicenter studies, centers should adopt standardized procedures for system QA and in vivo imaging.

The development of stroke drugs has been characterized by success in animal studies and subsequent failure in clinical trials. Animal studies might have overstated efficacy, or clinical trials might have understated efficacy; in either case we need to better understand the reasons for failure. Techniques borrowed from clinical trials have recently allowed the impact of publication and study-quality biases on published estimates of efficacy in animal experiments to be described. On the basis of these data, we propose minimum standards for the range and quality of pre-clinical animal data. We believe the adoption of these standards will lead to improved effectiveness and efficiency in the selection of drugs for clinical trials in stroke and in the design of those trials.

FK506 is a candidate drug for acute stroke. For such drugs, any decision to proceed to clinical trial should be based on a full and unbiased assessment of the animal data, and consideration should be given to the limitations of those data. Such an assessment should include not only the efficacy of a drug but also the in vivo characteristics and limits to that efficacy. Here we use systematic review and meta-analysis to assess the evidence for a protective effect of FK506 in animal models of stroke. In all, 29 studies were identified describing procedures involving 1759 animals. The point estimate for the effect of FK506 was a 31.3% (95% confidence interval 27.2% to 35.4%) improvement in outcome. Efficacy was higher with ketamine anaesthesia and temporary ischaemia and was lower in rats, in animals with comorbidities, and where outcome was measured as infarct size alone. Reported study quality was modest by clinical trial standards, and efficacy was lower in high-quality studies. These findings show a substantial efficacy for FK506 in experimental stroke, but raise concerns that our estimate of effect size might be too high because of factors such as study quality and possible publication bias.

Atrial fibrillation and severe carotid-artery stenosis are well-characterised risk factors for stroke; each is present in about a fifth of patients. The identification of such risk factors in patients is important because their presence calls for specific secondary prevention strategies. One region of the circulation that has received limited attention as a source of thrombus is the aortic arch. However, aortic arch atheroma is a common post-mortem finding, and it seems reasonable to speculate that atheroma might give rise to thrombi with distal embolism to the arterial tree, including the cerebral circulation. Here we review the evidence for aortic-arch atheroma as an important independent risk factor for stroke, and show that studies of the risk of stroke indicate a four times greater odds of stroke in patients with severe arch atheroma.

Background and Purpose— The extensive neuroprotective literature describing the efficacy of candidate drugs in focal ischemia has yet to lead to the development of effective stroke treatments. Ideally, the choice of drugs taken forward to clinical trial should be based on an unbiased assessment of all available data. Such an assessment might include not only the efficacy of a drug but also the in vivo characteristics and limits—in terms of time window, dose, species, and model of ischemia used—to that efficacy. To our knowledge, such assessments have not been made. Nicotinamide is a candidate neuroprotective drug with efficacy in experimental stroke, but the limits to and characteristics of that efficacy have not been fully described. Methods— Systematic review and modified meta-analysis of studies of experimental stroke describing the efficacy of nicotinamide. The search strategy ensured ascertainment of studies published in full and those published in abstract only. DerSimonian and Laird random effects meta-analysis was used to account for heterogeneity between studies. Results— Nicotinamide improved outcome by 0.287 (95% confidence interval 0.227 to 0.347); it was more effective in temporary ischemia models, after intravenous administration, in animals without comorbidities, and in studies published in full rather than in abstract. Studies scoring highly on a quality measure gave more precise estimates of the global effect. Conclusions— Meta-analysis provides an effective technique for the aggregation of data from experimental stroke studies. We propose new standards for reporting such studies and a systematic approach to aggregating data from the neuroprotective literature.

Background and aimPost-stroke fatigue (PSF) is common and distressing, but there is insufficient evidence to recommend any effective treatment for it. Psychological interventions are effective in treating fatigue in other conditions. This paper describes the development and evaluation of the feasibility of a psychological intervention for PSF.MethodsBased on psychological correlates of PSF and evidence-based psychological interventions for fatigue in other medical conditions, we developed a manualised psychological intervention for PSF, with input from stroke clinicians, psychological therapists, and stroke survivors. The intervention was delivered by a clinical psychologist to 12 participants with PSF to test its acceptability and feasibility. According to the feedback from participants and therapists, the intervention was refined for future use.ResultsThe intervention consisted of six individual, face-to-face treatment sessions, and one follow-up, telephone-delivered booster session. It included psycho-education and discussion of strategies to promote physical and social activities and to challenge unhelpful thoughts. Four participants dropped out and the remaining eight participants completed the intervention. These eight participants also completed all assessments and feedback and reported fatigue levels as lower at the end of the study than at the baseline. All participants reported favourable opinions on the intervention and suggested that the last two treatment sessions be combined and the booster session be delivered in person as opposed to telephone.ConclusionsThis psychological intervention was acceptable to stroke patients and was feasible in the local health service. These findings suggest that a randomised controlled trial to test efficacy is warranted.

Background and Purpose— Poststroke depression is a prevalent complication of stroke with unclear pathogenesis. The benefits of antidepressants in this context and their effects on stroke recovery other than effects on mood are not clearly defined, with some studies suggesting efficacy in improving functional outcome in both depressed and nondepressed stroke patients. We have analyzed the preclinical animal data on antidepressant treatment in focal cerebral ischemia, modeled±depression, to help inform clinical trial design. Methods— We performed a systematic review and meta-analysis of data from experiments testing the efficacy of antidepressants versus no treatment to reduce infarct volume or improve neurobehavioral or neurogenesis outcomes in animal models of stroke. We used random-effects metaregression to test the impact of study quality and design characteristics and used trim and fill to assess publication bias. Results— We identified 44 publications describing the effects of 22 antidepressant drugs. The median quality checklist score was 5 of a possible 10 (interquartile range, 4–7). Overall, antidepressants reduced infarct volume by 27.3% (95% confidence interval, 20.7%–33.8%) and improved neurobehavioral outcomes by 53.7% (46.4%–61.1%). There was little evidence for an effect of selective serotonin reuptake inhibitors on infarct volume. For neurobehavioral outcomes there was evidence of publication bias. Selective serotonin reuptake inhibitors were the most frequently studied antidepressant subtype and improved neurobehavioral outcome by 51.8% (38.6%–64.9%) and increased neurogenesis by 2.2 SD (1.3–3.0). Conclusions— In line with current clinical data and despite some limitations, antidepressant treatments seem to improve infarct volume and neurobehavioral outcome in animal models of ischemic stroke.

Summary Most in-hospital deaths of patients with stroke, traumatic brain injury, or postanoxic encephalopathy after cardiac arrest occur after a decision to withhold or withdraw life-sustaining treatments. Decisions on treatment restrictions in these patients are generally complex and are based only in part on evidence from published work. Prognostic models to be used in this decision-making process should have a strong discriminative power. However, for most causes of acute brain injury, prognostic models are not sufficiently accurate to serve as the sole basis of decisions to limit treatment. These decisions are also complicated because patients often do not have the capacity to communicate their preferences. Additionally, surrogate decision makers might not accurately represent the patient's preferences. Finally, in the acute stage, prediction of how a patient would adapt to a life with major disability is difficult.

Findings from laboratory experiments are often offered up to neurologists and our patients as ‘evidence’ for exciting new treatments for some of the conditions we try to manage. This is especially true for stroke, multiple sclerosis and those relentlessly progressive neurodegenerative diseases where current treatments are limited, and which largely target symptoms rather than disease progression. Whether responding to an invitation to join a randomised controlled trial or to the patient who has heard on the Today Programme on the BBC that stem cell therapies may soon be available for their disease, how confident can we be that data from animal studies are relevant to our clinical practice? There is consensus among most scientists and clinicians that much human benefit has come from understanding animal biology, and some consensus in the public mind that, that being so, animal experiments can be ethical. However, the delivery of human benefit to patients with neurological disease has been somewhat limited, and the gap between the laboratory and the clinic is large and well recognised. Even when pathological and functional characteristics of disease appear similar in animals and …

In this issue, Bath et al. use state of the art meta-analytical tools to address the pressing question of why NXY-059, a compound at the time considered to fulfil all the recommendations for the evaluation of preclinical data regarding neuroprotective drugs, has failed clinically. They demonstrate quantitatively that a negative publication bias existed, that the compound was indeed neuroprotective in experimental stroke, but that bias may have resulted in an overestimation of efficacy, and that efficacy in healthy, male, adolescent animals is a poor predictor of success in clinical trial. The study contains important messages for researchers, journal editors, the pharmaceutical industry and science policy makers. Bias is both prevalent and relevant in experiments modelling human stroke. Simple measures can reduce, perhaps substantially, the impact of such bias. The decision to proceed to clinical trial should be based on a thorough and systematic review of the animal data.

Background and Purpose— A total of 25% of strokes are lacunar, and these are pathophysiologically different from large artery strokes. Despite emerging evidence of a substantial impact on physical disability and dementia, little attention has been paid to the development of specific treatments. The optimal use of the animal models of lacunar stroke used to test candidate interventions is not known. Methods— We conducted a systematic review and meta-analysis of studies testing candidate interventions in animal models of lacunar stroke. We used random-effects meta-analysis to assess the impact of study characteristics and trim and fill to seek evidence of publication bias. Results— The efficacy of 43 distinct interventions was described in 57 publications. The median number of quality checklist items scored was 3 of 8 (interquartile range, 2–4). Many models reflected mechanisms of limited relevance to lacunar stroke. Meta-analysis of results from 27 studies showed that on average, infarct size and neurobehavioral outcome were improved by 34.2% (24.1–44.2) and 0.82 standardized mean difference (0.51–1.14), respectively. Four interventions improved both infarct size and neurobehavioral outcome but there were insufficient data for this finding to be considered robust. For infarct size, efficacy was lower in studies reporting blinding and higher in studies reporting randomization. For neurobehavior, efficacy was lower in randomized studies. For infarct size there was evidence of publication bias. Conclusions— No intervention has yet been tested in sufficient range and depth to support translation to clinical trial. There is limited reporting of measures to reduce the risk of bias and evidence for a substantial publications bias.

Rationale Cooling reduced infarct size and improved neurological outcomes in animal studies modeling ischemic stroke, and also improved outcome in randomized clinical trials in patients with hypoxic-ischemic brain injury after cardiac arrest. Cooling awake patients with ischemic stroke has been shown feasible in phase II clinical trials. Primary aim To determine whether systemic cooling to a target body temperature between 34·0 and 35·0°C, started within six-hours of symptom onset and maintained for 24 h, improves functional outcome at three-months in patients with acute ischemic stroke. Design International, multicenter, phase III, randomized, open-label clinical trial with blinded outcome assessment in 1500 patients aged 18 years or older with acute ischemic stroke and a National Institutes of Health Stroke Scale score of 6 up to and including 18. In patients randomized to hypothermia, cooling to a target body temperature of 34–35°C will be started within six-hours after symptom onset with rapid intravenous infusion of refrigerated normal saline or a surface cooling technique and maintained for 24 h with a surface or endovascular technique. Patients randomized to hypothermia will receive pethidine and buspirone to prevent shivering and discomfort. Primary outcome Score on the modified Rankin Scale at 91 days, as analyzed with ordinal logistic regression and expressed as a common odds ratio. Discussion With 750 patients per intervention group, this trial has 90% power to detect 7% absolute improvement at the 5% significance level. The full trial protocol is available at http://www.eurohyp1.eu . ClinicalTrials.gov Identifier: NCT01833312.

Translational neuroscience is in the doldrums. The stroke research community was among the first to recognize that the motivations inherent in our system of research can cause investigators to take shortcuts, and can introduce bias and reduce generalizability, all of which leads ultimately to the recurrent failure of apparently useful drug candidates in clinical trials. Here, we review the evidence for these problems in stroke research, where they have been most studied, and in other translational research domains, which seem to be bedevilled by the same issues. We argue that better scientific training and simple changes to the way that we fund, assess and publish research findings could reduce wasted investment, speed drug development, and create a healthier research environment. For 'phase III' preclinical studies--that is, those studies that build the final justification for conducting a clinical trial--we argue for a need to apply the same attention to detail, experimental rigour and statistical power in our animal experiments as in the clinical trials themselves.

Hypertension is an established target for long-term stroke prevention but procedures for management of hypertension in acute stroke are less certain. Here, we analyze basic science data to examine the impact of hypertension on candidate stroke therapies and of anti-hypertensive treatments on stroke outcome. Methods: Data were pooled from 3,288 acute ischemic stroke experiments (47,899 animals) testing the effect of therapies on infarct size (published 1978-2010). Data were combined using meta-analysis and meta-regression, partitioned on the basis of hypertension, stroke model, and therapy. Results: Hypertensive animals were used in 10% of experiments testing 502 therapies. Hypertension was associated with lower treatment efficacy, especially in larger infarcts. Overall, anti-hypertensives did not provide greater benefit than other drugs, although benefits were evident in hypertensive animals even when given after stroke onset. Fifty-eight therapies were tested in both normotensive and hypertensive animals: some demonstrated superior efficacy in hypertensive animals (hypothermia) while others worked better in normotensive animals (tissue plasminogen activator, anesthetic agents). Discussion: Hypertension has a significant effect on the efficacy of candidate stroke drugs: standard basic science testing may overestimate the efficacy which could be reasonably expected from certain therapies and for hypertensive patients with large or temporary occlusions.

Special report.-- et al.

The pharmaceutical industry is in the doldrums. Food and Drug Administration drug approvals per year are falling steadily,1 and the costs of drug development are steadily increasing.2 However, although neuroscience as a whole may not be delivering the returns on investment we would like, the state of stroke medicine has never been better. Although changing lifestyles for the better often seems intractable, pharmacotherapy has delivered effective primary prevention. Control of blood pressure, cholesterol lowering, and control of clotting in atrial fibrillation are all providing benefit. The same approaches are effective in secondary prevention, in which antiplatelet therapies already have a long-established role. We also have even come slowly to the realization that the brain is malleable, and that therapy during the long-term rehabilitative phase of stroke is likely to help patients regain useful function. Despite this, we are still struggling to make gains in acute stroke treatment. Thrombolysis was first introduced in the 1990s after the National Institute of Neurological Disorders and Stroke (NINDS) trial in a period that saw intensive evaluation of a range of lytic approaches. However, only a small proportion of the patients who might benefit from this powerful treatment receive it.3 Surprisingly, despite the clear benefit of tissue-type plasminogen activator, we have still to complete the analysis of novel thrombolytics, such as desmoteplase and tenecteplase.3 Moreover, we seem to be on the verge of abandoning neuroprotection, one of the most extensively studied concepts in neuroscience.4 For all intents and purposes, Big Pharma has already done so despite convincing proof of concept in humans; neuroprotection by hypothermia is in routine use to prevent the neurological consequences of cardiac arrest in adults5 and hypoxic-ischemic encephalopathy in neonates.6 The pessimism within the pharmacological industry seems reasonable. More than 100 clinical trials of …

There is some evidence that in animal models of acute ischaemic stroke, combinations of neuroprotective agents might be more efficacious than the same agents administered alone. Hence, we developed pragmatic, empirical criteria based on therapeutic target, cost, availability, efficacy, administration, and safety to select drugs for testing in combination in animal models of acute stroke. Magnesium sulphate, melatonin, and minocycline were chosen from a library of neuroprotective agents, and were tested in a more ‘realistic’ model favoured by the STAIR (Stroke Therapy Academic Industry Roundtable). Outcome was assessed with infarct volume, neurologic score, and two newly developed scales measuring general health and physiologic homeostasis. Owing to the failure to achieve neuroprotection in aged, hypertensive animals with drug delivery at 3 hours, the bar was lowered in successive experiments to determine whether neuroprotection could be achieved under conditions more conducive to recovery. Testing in younger animals showed more favourable homeostasis and general health scores than did testing in older animals, but infarct volume and neurologic scores did not differ with age, and treatment efficacy was again not shown. Testing with shorter occlusions resulted in smaller infarct volumes; nevertheless, treatment efficacy was still not observed. It was concluded that this combination, in these stroke models, was not effective.

Thrombolysis with recombinant tissue plasminogen activator (rtPA) improves outcome in animal models of stroke and in clinical trial, but is associated with increased intracranial hemorrhage. Here, we explore the impact of biologic and experimental design factors on efficacy and bleeding. We conducted a systematic review of studies describing the effect of tPA in thrombotic occlusion models of ischemic stroke followed by random effects meta-analysis, meta-regression, and trim and fill. We identified 202, 66, 128, and 54 comparisons reporting infarct volume, neurobehavioral score, hemorrhage, and mortality, respectively. The rtPA reduced infarct volume by 25.2% (95% confidence interval=21.8 to 28.6, 3388 animals), improved neurobehavioral score by 18.0% (12.6% to 23.3%, n=1243), increased the risk of hemorrhage (odds ratio=1.71, 1.42 to 2.07, n=2833) and had no significant effect on mortality (odds ratio=0.82, 0.62 to 1.08, n=1274). There was an absolute reduction in efficacy of 1.1% (0.7% to 1.4%) for every 10 minutes delay to treatment. Cumulative meta-analysis showed that the estimate of efficacy fell as more data became available. Publication bias inflated efficacy by 5.1% (infarct volume) and 8.1% (neurobehavioral score). This data set was large enough to be adequately powered to estimate with precision the impact of biologic and experimental factors on the efficacy and safety of rtPA.