Search

ImportanceCerebral small vessel disease (SVD) causes a quarter of strokes and is the most common pathology underlying vascular cognitive impairment and dementia. An important step to developing new treatments is better trial methodology. Disease mechanisms in SVD differ from other stroke etiologies; therefore, treatments need to be evaluated in cohorts in which SVD has been well characterized. Furthermore, SVD itself can be caused by a number of different pathologies, the most common of which are arteriosclerosis and cerebral amyloid angiopathy. To date, there have been few sufficiently powered high-quality randomized clinical trials in SVD, and inconsistent trial methodology has made interpretation of some findings difficult.ObservationsTo address these issues and develop guidelines for optimizing design of clinical trials in SVD, the Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE) was created under the auspices of the International Society of Vascular Behavioral and Cognitive Disorders. Experts in relevant aspects of SVD trial methodology were convened, and a structured Delphi consensus process was used to develop recommendations. Areas in which recommendations were developed included optimal choice of study populations, choice of clinical end points, use of brain imaging as a surrogate outcome measure, use of circulating biomarkers for participant selection and as surrogate markers, novel trial designs, and prioritization of therapeutic agents using genetic data via Mendelian randomization.Conclusions and RelevanceThe FINESSE provides recommendations for trial design in SVD for which there are currently few effective treatments. However, new insights into understanding disease pathogenesis, particularly from recent genetic studies, provide novel pathways that could be therapeutically targeted. In addition, whether other currently available cardiovascular interventions are specifically effective in SVD, as opposed to other subtypes of stroke, remains uncertain. FINESSE provides a framework for design of trials examining such therapeutic approaches.

BackgroundCerebral small vessel disease (SVD) causes lacunar strokes (25% of all ischaemic strokes), physical frailty and cognitive impairment and vascular and mixed dementia. There is no specific treatment to prevent progression of SVD.MethodsThe LACunar Intervention Trial-2 (LACI-2) is an investigator-initiated prospective randomised open-label blinded-endpoint (PROBE) phase II feasibility study assessing cilostazol and isosorbide mononitrate for preventing SVD progression. We aimed to recruit 400 patients with clinically-evident lacunar ischaemic stroke and randomised to cilostazol, isosorbide mononitrate, both or neither, in addition to guideline secondary ischaemic stroke prevention, in a partial factorial design. The primary outcome is feasibility of recruitment and adherence to medication; key secondary outcomes include: drug tolerability; recurrent vascular events, cognition and function at one year after randomisation; and safety (bleeding, falls, death). Data are number (%), and median [interquartile range].ResultsThe trial commenced on 5th of February 2018 and ceased recruitment on 31st of May 2021 with 363 patients randomised, with the following baseline characteristics: average age 64 [56.0, 72.0] years, female 112 (30.9%), stroke onset to randomisation 79.0 [27.0, 244.0] days, hypertension 267 (73.6%), median blood pressures 143.0 [130.0, 157.0]/83.0 [75.0, 90.0] mmHg, current smokers 67 (18.5%), educationally achieved end of school examinations (A-level) or higher 118 (32.5%), modified Rankin scale 1.0 [0.0, 1.0], National Institutes Health stroke scale (NIHSS) 1.0 (1.4), Montreal Cognitive Assessment 26.0 [23.0, 28.0] and total SVD score on brain imaging 1.0 [0.0, 2.0]. This publication summarises the baseline data and presents the statistical analysis plan.SummaryThe trial is currently in follow-up which will complete on 31 May 2022 with results expected in October 2022.

BackgroundThe effectiveness and safety of endovascular thrombectomy (EVT) in the late window (6–24 hours) for acute ischemic stroke (AIS) patients selected without advanced imaging is undetermined. We aimed to assess clinical outcomes and the relationship with time-to-EVT treatment beyond 6 hours of stroke onset without advanced neuroimaging.MethodsPatients who underwent EVT selected with non-contrast CT/CT angiography (without CT perfusion or MR imaging), between October 2015 and March 2020, were included from a national stroke registry. Functional and safety outcomes were assessed in both early (ResultsAmong 3278 patients, 2610 (79.6%) and 668 (20.4%) patients were included in the early and late windows, respectively. In the late window, for every hour delay, there was no significant association with shift towards poorer functional outcome (modified Rankin Scale (mRS)) at discharge (adjusted common OR 0.98, 95% CI 0.94 to 1.01, p=0.27) or change in predicted functional independence (mRS ≤2) (24.5% to 23.3% from 6 to 24 hours; aOR 0.99, 95% CI0.94 to 1.04, p=0.85). In contrast, predicted functional independence was time sensitive in the early window: 5.2% reduction per-hour delay (49.4% to 23.5% from 1 to 6 hours, p=0.0001). There were similar rates of symptomatic intracranial hemorrhage (sICH) (3.4% vs 4.6%, p=0.54) and in-hospital mortality (12.9% vs 14.6%, p=0.33) in the early and late windows, respectively, without a significant association with time.ConclusionIn this real-world study, there was minimal change in functional disability, sICH and in-hospital mortality within and across the late window. While confirmatory randomized trials are needed, these findings suggest that EVT remains feasible and safe when performed in AIS patients selected without advanced neuroimaging between 6–24 hours from stroke onset.

We read with interest the authors’ systematic review and meta-analysis of pharyngeal electrical stimulation (PES) and neuromuscular electrical stimulation (NMES) in patients with oropharyngeal dysphagia (OD) [...]

Purpose: Information on reliability of outcome measures used to assess the effectiveness of interventions in dysphagia rehabilitation is lacking, particularly when used by different research groups. Here, we report on reliability of the penetration–aspiration scale (PAS) and temporal and clearance measures, determined using videofluoroscopy. Method: Secondary analysis used videofluoroscopies from the Swallowing Treatment using Electrical Pharyngeal Stimulation trial in subacute stroke. PAS scores (719 scores from 18 participants) were evaluated and compared to the original PAS scores from the trial. Five conditions were assessed, including reliability for every swallow and overall mean of the worst PAS score. Operational rules for assessing temporal and clearance measures were also developed using the same data, and reliability of these rules was assessed. Reliability of component-level and derivative-level scores was assessed using the intraclass correlation coefficient (ICC) and weighted kappa. Results: Image quality was variable. Interrater reliability for the overall mean of the worst PAS score was excellent (ICC = .914, 95% confidence interval [CI] [.853, .951]) but moderate for every swallow in the bolus (ICC = .743, 95% CI [.708, .775]). Intrarater reliability for PAS was excellent (all conditions). Excellent reliability (both inter- and intrarater > .90) was seen for temporal measures of stage transition duration (ICC = .998, 95% CI [.993, .999] and ICC = .995, 95% CI [.987, .998], respectively) as well as initiation of laryngeal closure and pharyngeal transit time and all individual swallow events. Strong scores were obtained for some clearance measures; others were moderate or weak. Conclusions: Interrater reliability for PAS is acceptable but depends on how the PAS scores are handled in the analysis. Interrater reliability for most temporal measures was high, although some measures required additional training. No clearance measures had excellent reliability. Supplemental Material: https://doi.org/10.23641/asha.19090088

ObjectiveTo summarise evidence of the effects of blood pressure (BP)-lowering interventions after acute spontaneous intracerebral haemorrhage (ICH).MethodsPre-specified systematic review of the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE databases from inception to 23 June 2020 to identify randomised controlled trials that compared active BP-lowering agents vs. placebo or intensive vs. guideline BP-lowering targets for adults 6mL) and proportional (>33%) haematoma growth at 24 hours. Meta-analysis used a one-stage approach, adjusted for pre-specified covariables and trial.ResultsOf 7094 studies identified, 50 trials involving 11,494 patients were eligible and 16 (32.0%) shared patient-level data from 6,221 (54.1%) patients (mean age 64.2 [SD 12.9], 2,266 [36.4%] females) with a median time from symptom onset to randomisation of 3.8 hours (IQR 2.6−5.3). Active/intensive BP-lowering had no effect on the primary outcome compared to placebo/guideline treatment (adjusted OR for unfavourable shift in modified Rankin scale scores: 0.97, 95%CI 0.88−1.06; p=0.50), but there was signifi- cant heterogeneity by strategy (pinteraction=0.031) and agent (pinteractionInterpretation: Overall, a broad range of interventions to lower BP within 7 days of ICH had no benefit on functional recovery, despite reducing bleeding. The treatment effect appeared to vary according to strategy and agent.tom.moullaali@ed.ac.uk

Background Inter-observer variability in stroke aetiological classification may have an effect on trial power and estimation of treatment effect. We modelled the effect of misclassification on required sample size in a hypothetical cardioembolic (CE) stroke trial. Methods We performed a systematic review to quantify the reliability (inter-observer variability) of various stroke aetiological classification systems. We then modelled the effect of this misclassification in a hypothetical trial of anticoagulant in CE stroke contaminated by patients with non-cardioembolic (non-CE) stroke aetiology. Rates of misclassification were based on the summary reliability estimates from our systematic review. We randomly sampled data from previous acute trials in CE and non-CE participants, using the Virtual International Stroke Trials Archive. We used bootstrapping to model the effect of varying misclassification rates on sample size required to detect a between-group treatment effect across 5000 permutations. We described outcomes in terms of survival and stroke recurrence censored at 90 days. Results From 4655 titles, we found 14 articles describing three stroke classification systems. The inter-observer reliability of the classification systems varied from ‘fair’ to ‘very good’ and suggested misclassification rates of 5% and 20% for our modelling. The hypothetical trial, with 80% power and alpha 0.05, was able to show a difference in survival between anticoagulant and antiplatelet in CE with a sample size of 198 in both trial arms. Contamination of both arms with 5% misclassified participants inflated the required sample size to 237 and with 20% misclassification inflated the required sample size to 352, for equivalent trial power. For an outcome of stroke recurrence using the same data, base-case estimated sample size for 80% power and alpha 0.05 was n = 502 in each arm, increasing to 605 at 5% contamination and 973 at 20% contamination. Conclusions Stroke aetiological classification systems suffer from inter-observer variability, and the resulting misclassification may limit trial power. Trial registration Protocol available at reviewregistry540. Electronic supplementary material The online version of this article (10.1186/s13063-019-3222-x) contains supplementary material, which is available to authorized users.

Background and aim The availability and access of hospital administrative data [coding for Charlson comorbidity index (CCI)] in large data form has resulted in a surge of interest in using this information to predict mortality from stroke. The aims of this study were to determine the minimum clinical data set to be included in models for predicting disability after ischemic stroke adjusting for CCI and clinical variables and to evaluate the impact of CCI on prediction of outcome. Method We leverage anonymized clinical trial data in the Virtual International Stroke Trials Archive. This repository contains prospective data on stroke severity and outcome. The inclusion criteria were patients with available stroke severity score such as National Institutes of Health Stroke Scale (NIHSS), imaging data, and outcome disability score such as 90-day Rankin Scale. We calculate CCI based on comorbidity data in this data set. For logistic regression, we used these calibration statistics: Nagelkerke generalised R2 and Brier score; and for discrimination we used: area under the receiver operating characteristics curve (AUC) and integrated discrimination improvement (IDI). The IDI was used to evaluate improvement in disability prediction above baseline model containing age, sex, and CCI. Results The clinical data among 5,206 patients (55% males) were as follows: mean age 69 ± 13 years, CCI 4.2 ± 0.8, and median NIHSS of 12 (IQR 8, 17) on admission and 9 (IQR 5, 15) at 24 h. In Model 2, adding admission NIHSS to the baseline model improved AUC from 0.67 (95% CI 0.65–0.68) to 0.79 (95% CI 0.78–0.81). In Model 3, adding 24-h NIHSS to the baseline model resulted in substantial improvement in AUC to 0.90 (95% CI 0.89–0.91) and increased IDI by 0.23 (95% CI 0.22–0.24). Adding the variable recombinant tissue plasminogen activator did not result in a further change in AUC or IDI to this regression model. In Model 3, the variable NIHSS at 24 h explains 87.3% of the variance of Model 3, follow by age (8.5%), comorbidity (3.7%), and male sex (0.5%). Conclusion Our results suggest that prediction of disability after ischemic stroke should at least include 24-h NIHSS and age. The variable CCI is less important for prediction of disability in this data set.

Background and Purpose— Controversy persists over statins and risk of intracerebral hemorrhage. We determined associations of premorbid lipid-lowering therapy and outcomes among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials (INTERACT). Methods— The pooled data of INTERACT 1 and 2 (international, multicenter, prospective, open, blinded end point, randomized controlled trials of patients with intracerebral hemorrhage [ Results— Among 204 patients (6.5%) with baseline lipid-lowering treatment, 90-day clinical outcomes were not significantly different after adjustment for confounding variables including region and age. In the computed tomographic substudy, 24-hour hematoma growth was greater in 124 patients (9%) with, compared with those without, prior lipid-lowering therapy. However, this association was not significant between groups (9.2 versus 6.8 mL; P Conclusions— No independent associations were found between lipid-lowering medication and adverse outcomes in patients with intracerebral hemorrhage. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00226096 and NCT00716079.

Background and Purpose— Many stroke trials have provided neutral results. Suboptimal statistical analyses may be failing to detect effective interventions. Adjusting outcomes for baseline prognostic factors in the analysis may improve the efficiency of analysis of outcomes. Methods— Data from 23 stroke trials (25 674 patients) assessing functional outcome were included. The prognostic variables considered were age, sex, and baseline severity. Unadjusted and adjusted ordinal logistic regression models were compared using simulated data from each trial (10 000 simulations per trial). Three levels of treatment effect were assessed with ORs of 0.95, 0.74, and 0.57. The reduction in sample size gained from using the adjusted models, as compared with an unadjusted model, was then calculated as a reflection of the increase in statistical power. Results— Adjusting outcome for baseline factors led to a reduction in sample size, which was similar across all 3 treatment effects (median percentage reduction, interquartile range): OR=0.95: 35.3% (21.0 to 42.1); OR=0.74: 38.4% (29.4 to 42.7); and OR=0.57: 38.4% (27.4 to 42.2). As the treatment effect increased, the proportion of simulations in which the treatment effect for the adjusted model was greater than for the unadjusted model also increased. Conclusion— Adjusting for prognostic factors in stroke trials can reduce sample size by at least 20% to 30% (the lower interquartile range) for a given power. Conversely, trialists may want to power for an unadjusted analysis and then increase statistical power by adjusting for prognostic factors.

Background Many acute stroke trials have given neutral results. Sub-optimal statistical analyses may be failing to detect efficacy. Methods which take account of the ordinal nature of functional outcome data are more efficient. We compare sample size calculations for dichotomous and ordinal outcomes for use in stroke trials. Methods Data from stroke trials studying the effects of interventions known to positively or negatively alter functional outcome – Rankin Scale and Barthel Index – were assessed. Sample size was calculated using comparisons of proportions, means, medians (according to Payne), and ordinal data (according to Whitehead). The sample sizes gained from each method were compared using Friedman 2 way ANOVA. Results Fifty-five comparisons (54 173 patients) of active vs. control treatment were assessed. Estimated sample sizes differed significantly depending on the method of calculation ( PConclusions Choosing an ordinal rather than binary method of analysis allows most trials to be, on average, smaller by approximately 28% for a given statistical power. Smaller trial sample sizes may help by reducing time to completion, complexity, and financial expense. However, ordinal methods may not be optimal for interventions which both improve functional outcome and cause hazard in a subset of patients, e.g. thrombolysis.

Background and Purpose\ud Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene, is the most common monogenic disorder causing lacunar stroke and cerebral small vessel disease (SVD). Fabry disease (FD) due to mutations in the GLA gene has been suggested as an underdiagnosed cause of stroke, and one feature is SVD. Previous studies reported varying prevalence of CADASIL and FD in stroke, likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence in a well-defined, MRI-verified cohort of apparently sporadic patients with lacunar infarct.\ud \ud Methods\ud Caucasian patients with lacunar infarction, aged ≤70 years (mean age 56.7 (SD8.6)), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. Patients with a previously confirmed monogenic cause of stroke were excluded. All MRI’s and clinical histories were reviewed centrally. Screening was performed for NOTCH3 and GLA mutations.\ud \ud Results\ud Of 994 subjects five had pathogenic NOTCH3 mutations (R169C, R207C, R587C, C1222G and C323S) all resulting in loss or gain of a cysteine in the NOTCH3 protein. All five patients had confluent leukoaraiosis (Fazekas grade ≥2). CADASIL prevalence overall was 0.5% (95% CI 0.2%-1.1%) and among cases with confluent leukoaraiosis 1.5% (95% CI 0.6%-3.3%). No classic pathogenic FD mutations were found; one patient had a missense mutation (R118C), associated with late-onset FD.\ud \ud Conclusion\ud CADASIL cases are rare and only detected in SVD patients with confluent leukoaraiosis. No definite FD cases were detected.

BACKGROUND: Extracranial carotid and vertebral artery dissection is an important cause of stroke, especially in young people. In some observational studies it has been associated with a high risk of recurrent stroke. Both antiplatelet drugs and anticoagulant drugs are used to reduce risk of stroke but whether one treatment strategy is more effective than the other is unknown. We compared their efficacy in the Cervical Artery Dissection in Stroke Study (CADISS), with the additional aim of establishing the true risk of recurrent stroke. METHODS: We did this randomised trial at hospitals with specialised stroke or neurology services (39 in the UK and seven in Australia). We included patients with extracranial carotid and vertebral dissection with onset of symptoms within the past 7 days. Patients were randomly assigned (1:1) by an automated telephone randomisation service to receive antiplatelet drugs or anticoagulant drugs (specific treatment decided by the local clinician) for 3 months. Patients and clinicians were not masked to allocation, but investigators assessing endpoints were. The primary endpoint was ipsilateral stroke or death in the intention-to-treat population. The trial was registered with EUDract (2006-002827-18) and ISRN (CTN44555237). FINDINGS: We enrolled 250 participants (118 carotid, 132 vertebral). Mean time to randomisation was 3·65 days (SD 1·91). The major presenting symptoms were stroke or transient ischaemic attack (n=224) and local symptoms (headache, neck pain, or Horner's syndrome; n=26). 126 participants were assigned to antiplatelet treatment versus 124 to anticoagulant treatment. Overall, four (2%) of 250 patients had stroke recurrence (all ipsilateral). Stroke or death occurred in three (2%) of 126 patients versus one (1%) of 124 (odds ratio [OR] 0·335, 95% CI 0·006-4·233; p=0·63). There were no deaths, but one major bleeding (subarachnoid haemorrhage) in the anticoagulant group. Central review of imaging failed to confirm dissection in 52 patients. Preplanned per-protocol analysis excluding these patients showed stroke or death in three (3%) of 101 patients in the antiplatelet group versus one (1%) of 96 patients in the anticoagulant group (OR 0·346, 95% CI 0·006-4·390; p=0·66). INTERPRETATION: We found no difference in efficacy of antiplatelet and anticoagulant drugs at preventing stroke and death in patients with symptomatic carotid and vertebral artery dissection but stroke was rare in both groups, and much rarer than reported in some observational studies. Diagnosis of dissection was not confirmed after review in many cases, suggesting that radiographic criteria are not always correctly applied in routine clinical practice. FUNDING: Stroke Association.

Introduction: The THRIVE score is a validated ischemic stroke outcome prediction tool. While simplified systems like the THRIVE score facilitate ease-of-use, when computers or devices are available at the point of care, a more accurate estimation of outcome probability is possible by computing the logistic equation with patient-specific continuous variables. Methods: We used data from 12,207 subjects from the Virtual International Stroke Trials Archive (VISTA) and the Safe Implementation of Thrombolysis in Stroke - Monitoring Study (SITS-MOST) study to develop and validate the performance of a model-derived estimation of outcome probability, the THRIVE-c calculation. Models were built with logistic regression using the underlying predictors from the THRIVE score: age, NIH Stroke Scale (NIHSS) score, and the Chronic Disease Scale (presence of hypertension, diabetes mellitus, or atrial fibrillation). Receiver-Operator Characteristics (ROC) analysis was used to assess model performance and compare the THRIVE-c model to the traditional THRIVE score. Results: The THRIVE-c model performed similarly in the randomly chosen development cohort (n=6194, AUC = 0.786, 95% CI 0.774-0.798) and validation cohort (n=6013, AUC = 0.784, 95% CI 0.772-0.796) (P=0.79). The THRIVE-c model (AUC = 0.785, 95% CI 0.777-0.793) had superior performance when compared to the traditional THRIVE score (AUC = 0.746, 95% CI 0.737-0.755), (P Conclusion: By computing the logistic equation with patient-specific continuous variables in the THRIVE-c calculation, patient outcomes are more accurately estimated. Given the widespread availability of the computers and devices at the point of care, such calculations can be easily performed with a simple user interface. A web calculator for THRIVE-c is available at www.thrivescore.org.

BACKGROUND: Thrombolysis is of net benefit in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4·5 h of onset. The third International Stroke Trial (IST-3) sought to determine whether a wider range of patients might benefit up to 6 h from stroke onset. METHODS: In this international, multicentre, randomised, open-treatment trial, patients were allocated to 0·9 mg/kg intravenous recombinant tissue plasminogen activator (rt-PA) or to control. The primary analysis was of the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0-2 at 6 months. The study is registered, ISRCTN25765518. FINDINGS: 3035 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0-2; adjusted odds ratio [OR] 1·13, 95% CI 0·95-1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI -20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10-1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07-11·8; absolute excess 58/1000, 95% CI 44-72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22-2·08, p=0·001; absolute increase 37/1000, 95% CI 17-57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group). INTERPRETATION: For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients. FUNDING: UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, Arbetsmarknadens Partners Forsakringsbolag (AFA) Insurances Sweden, Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, the Australian Heart Foundation, Australian National Health and Medical Research Council (NHMRC), Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita, Regione dell'Umbria, Italy, and Danube University.

BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS:At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P

Background Headache is a common adverse event in patients treated with dipyridamole (DP) for secondary stroke prevention. The headache resembles migraine, possibly indicating that vessel walls and endothelium of cerebral vessels are still intact and able to dilate. Purpose We hypothesized that patients who develop headache on DP will have a lower risk of recurrent stroke compared to patients without headache. Methods We analysed data from PROFESS (N=20,332) comparing aspirin plus DP with clopidogrel. Prospective data on headache as an adverse event within 7 days of start of medication or reason for discontinuation of study drug and recurrent stroke incidence were collected. We compared the relative risk of recurrent stroke in patients who did and did not get headache and who did or did not discontinue study medication due to headache. Analyses were repeated in the smaller ESPS 2 study (N=6,602) investigating aspirin, aspirin plus DP, DP or placebo in secondary stroke prevention. Results In PROFESS 3067 patients taking aspirin plus DP complained of headache in the first 7 days while 6988 did not. In the aspirin plus DP group, the recurrent stroke risk after 2.5 years was 8.2% in patients with and 9.4% in patients without headache resulting in a RR of 0.90 (95% CI 0.81-1.01, p= 0.07). In the clopidogrel treated group there was no difference in stroke risk between patients with and without headache RR = 1.00 (95% CI 0.82-1.23). In PROFESS, 518 patients taking aspirin plus DP discontinued treatment due to headache in the first 90 days. Their risk of recurrent stroke was 5.0%. In patients who did not discontinue aspirin plus DP due to headache in the first 90 days, the recurrent stroke risk was 9.2% resulting in a RR of 0.53 (95% CI 0.36-0.79, p=0.001). In the clopidogrel treated patients the RR was 0.89(95% CI 0.36-2.20); 7.9% of 63 clopidogrel patients who discontinued due to headache within 90 days of randomization had stroke vs. 8.9% in all other patients. In ESPS 2, 129 patients taking aspirin plus DP discontinued treatment due to headache in the first 90 days. Their rate of recurrent stroke was 6.2%. In patients who did not discontinue aspirin plus DP due to headache in the first 90 days, the recurrent stroke rate was 9.8% resulting in a RR of 0.63 (95% CI 0.31-1.26, p=0.18). Conclusions In PROFESS patients who developed headache on aspirin plus DP for secondary stroke prevention had a reduced risk of stroke recurrence in comparison with those who did not or were treated with clopidogrel. These results are directionally supported by similar but non-significant findings on treatment discontinuation of aspirin plus DP in ESPS 2. Headache in clopidogrel treated patients did not demonstrate any protective effects, suggesting specificity. These results suggest that DP-induced headache may be a marker for more reactive vessel walls in cerebral arteries.

Raised blood pressure is common in acute stroke, and is associated with an increased risk of poor outcomes. We aimed to examine whether careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure.Participants in this randomised, placebo-controlled, double-blind trial were recruited from 146 centres in nine north European countries. Patients older than 18 years with acute stroke (ischaemic or haemorrhagic) and systolic blood pressure of 140 mm Hg or higher were included within 30 h of symptom onset. Patients were randomly allocated to candesartan or placebo (1:1) for 7 days, with doses increasing from 4 mg on day 1 to 16 mg on days 3 to 7. Randomisation was stratified by centre, with blocks of six packs of candesartan or placebo. Patients and investigators were masked to treatment allocation. There were two co-primary effect variables: the composite endpoint of vascular death, myocardial infarction, or stroke during the first 6 months; and functional outcome at 6 months, as measured by the modified Rankin Scale. Analyses were by intention to treat. The study is registered, number NCT00120003 (ClinicalTrials.gov), and ISRCTN13643354.2029 patients were randomly allocated to treatment groups (1017 candesartan, 1012 placebo), and data for status at 6 months were available for 2004 patients (99%; 1000 candesartan, 1004 placebo). During the 7-day treatment period, blood pressures were significantly lower in patients allocated candesartan than in those on placebo (mean 147/82 mm Hg [SD 23/14] in the candesartan group on day 7 vs 152/84 mm Hg [22/14] in the placebo group; p0·0001). During 6 months' follow-up, the risk of the composite vascular endpoint did not differ between treatment groups (candesartan, 120 events, vs placebo, 111 events; adjusted hazard ratio 1·09, 95% CI 0·84-1·41; p=0·52). Analysis of functional outcome suggested a higher risk of poor outcome in the candesartan group (adjusted common odds ratio 1·17, 95% CI 1·00-1·38; p=0·048 [not significant at p≤0·025 level]). The observed effects were similar for all prespecified secondary endpoints (including death from any cause, vascular death, ischaemic stroke, haemorrhagic stroke, myocardial infarction, stroke progression, symptomatic hypotension, and renal failure) and outcomes (Scandinavian Stroke Scale score at 7 days and Barthel index at 6 months), and there was no evidence of a differential effect in any of the prespecified subgroups. During follow-up, nine (1%) patients on candesartan and five (1%) on placebo had symptomatic hypotension, and renal failure was reported for 18 (2%) patients taking candesartan and 13 (1%) allocated placebo.There was no indication that careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure. If anything, the evidence suggested a harmful effect.South-Eastern Norway Regional Health Authority; Oslo University Hospital Ullevål; AstraZeneca; Takeda.

SummaryBackgroundEpidemiological studies suggest that raised plasma concentrations of total homocysteine might be a risk factor for major vascular events. Whether lowering total homocysteine with B vitamins prevents major vascular events in patients with previous stroke or transient ischaemic attack is unknown. We aimed to assess whether the addition of once-daily supplements of B vitamins to usual medical care would lower total homocysteine and reduce the combined incidence of non-fatal stroke, non-fatal myocardial infarction, and death attributable to vascular causes in patients with recent stroke or transient ischaemic attack of the brain or eye.MethodsIn this randomised, double-blind, parallel, placebo-controlled trial, we assigned patients with recent stroke or transient ischaemic attack (within the past 7 months) from 123 medical centres in 20 countries to receive one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B6, and 0·5 mg vitamin B12). Patients were randomly allocated by means of a central 24-h telephone service or an interactive website, and allocation was by use of random permuted blocks stratified by hospital. Participants, clinicians, carers, and investigators who assessed outcomes were masked to the assigned intervention. The primary endpoint was the composite of stroke, myocardial infarction, or vascular death. All patients randomly allocated to a group were included in the analysis of the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT00097669, and Current Controlled Trials, ISRCTN74743444.FindingsBetween Nov 19, 1998, and Dec 31, 2008, 8164 patients were randomly assigned to receive B vitamins (n=4089) or placebo (n=4075). Patients were followed up for a median duration of 3·4 years (IQR 2·0–5·5). 616 (15%) patients assigned to B vitamins and 678 (17%) assigned to placebo reached the primary endpoint (risk ratio [RR] 0·91, 95% CI 0·82 to 1·00, p=0·05; absolute risk reduction 1·56%, −0·01 to 3·16). There were no unexpected serious adverse reactions and no significant differences in common adverse effects between the treatment groups.InterpretationDaily administration of folic acid, vitamin B6, and vitamin B12 to patients with recent stroke or transient ischaemic attack was safe but did not seem to be more effective than placebo in reducing the incidence of major vascular events. These results do not support the use of B vitamins to prevent recurrent stroke. The results of ongoing trials and an individual patient data meta-analysis will add statistical power and precision to present estimates of the effect of B vitamins.FundingAustralia National Health and Medical Research Council, UK Medical Research Council, Singapore Biomedical Research Council, Singapore National Medical Research Council, Australia National Heart Foundation, Royal Perth Hospital Medical Research Foundation, and Health Department of Western Australia.

Background Poststroke complications such as pulmonary embolism, deep vein thrombosis and pneumonia can impact outcome by causing deterioration in general health, delaying or preventing rehabilitation. While stroke carries a direct risk of complications, some events may be unrelated to index stroke severity and could confound outcome. We examined whether the presence of complications ‘unrelated’ to index stroke at later time-points could confound outcome, and if this could be minimised through altering study end-points. Methods We analysed 531 placebo-treated patients from the Virtual International Stroke Trials Archive who had experienced an acute ischaemic stroke and at least one poststroke complication during the 90-day follow-up period. We categorised complications into those deemed ‘related’ or ‘unrelated’ to index stroke severity. We examined modified Rankin Scale at 30 and 90 days, stratified by type of complication and assessed the impact of eliminating ‘unrelated’ complications on functional outcome (modified Rankin Scale) at 30 and 90 days using logistic regression (accounting for age and baseline National Institutes of Health Stroke Scale). Results The majority of complications in the early acute period after index stroke were ‘stroke related’ (30·2%). Patients did not have a better modified Rankin Scale profile at 30 days when compared with 90 days, regardless of the type of complications experienced. The absence of ‘stroke unrelated’ complications was associated with a worse outcome at 30 days [ P = 0·04, adjusted odds ratio for good functional outcome = 0·54, 95% confidence interval (0·3, 0·96)], and had no significant effect on outcome at 90 days. Conclusions We identified complications, which we deemed not to have occurred as a direct consequence of index stroke, but found that the absence of these events did not beneficially alter outcome at either short-term (30 days) or long-term (90 days) follow-up periods. Our analyses did not support the shortening of trial follow-up periods with the aim of minimising the risk of stroke-unrelated complications.

High blood pressure (BP) is common in acute stroke and is independently associated with a poor outcome. Many patients with acute stroke are taking antihypertensive medications. To test the safety and efficacy of 7 days of transdermal glyceryl trinitrate (GTN, 5 mg/day) vs. no GTN in patients with acute stroke; patients taking antihypertensive therapy immediately before their stroke are also randomised to continue vs. stop this temporarily. ENOS is a prospective international multicentre single-blind randomised-controlled trial in 5000 patients with acute (< 48 h of onset) ischaemic or haemorrhagic stroke. The primary outcome is combined death and dependency (modified Rankin scale > 2) at 90 days measured by blinded central telephone follow-up. Secondary outcomes include: BP over the 7 days of treatment; death, impairment (Scandinavian stroke scale), recurrence, and neuroimaging at 7 days; discharge disposition, disability (Barthel index), cognition (mini-mental status examination) and quality of life (EuroQoL). The sample size will allow an absolute difference in death/dependency of 5% to be detected with 90% power at 5% significance for GTN versus no GTN. Randomisation and data collection are performed over a secure Internet site with real-time data validation. Neuroimaging and serious adverse events are adjudicated blinded to treatment.

The paper draws on a number of Grid projects, particularly on the experience of NeuroGrid, a UK project in the Neurosciences tasked with developing a Grid-based collaborative research environment to support the sharing of digital images and patient data across multiple distributed sites. It outlines recurrent socio-technical issues, highlighting the challenges of scaling up technological networks in advance of the regulatory networks which normally regulate their use in practice.

The ISH statement on the management of blood pressure in acute stroke was finalized after presentation and discussion at the World Health Organization and International Society of Hypertension (WHO-ISH) Meeting on Stroke and Blood Pressure, held in Melbourne, Australia, 5-7 December 2002. The meeting was conducted under the auspices of the Austin Hospital Medical Research Foundation, Melbourne.

1. Antiplatelet drugs have been demonstrated to reduce the incidence of recurrent events in patients with symptomatic vascular disease. However, there is no experimental data indicating the effects of these agents when given together on platelets and leukocytes. We investigated the ability of aspirin (an inhibitor of cyclo-oxygenase), dipyridamole (an inhibitor of phospodiesterases and adenosine uptake) and AR-C69931 (a direct acting P(2T) antagonist with effects similar to those of clopidogrel which can be used in vitro) when used alone or in combination to inhibit platelet and leukocyte function. 2. Measurements of platelet and leukocyte function were performed in blood taken from normal volunteers, and the inhibitory effects of aspirin (100 micromol l(-1)), dipyridamole (10 micromol l(-1)) and AR-C66931 (100 nmol l(-1)) were determined. Platelet aggregation was induced by stirring blood with and without adenosine diphosphate (ADP) or platelet activating factor (PAF) and measured by platelet counting. Platelet P-selectin expression, platelet-leukocyte conjugate formation, and leukocyte activation were determined by flow cytometry. 3. Dipyridamole, AR-C69931, dipyridamole and AR-C69931, dipyridamole and aspirin, AR-C69931 and aspirin, and all three agents together inhibited platelet aggregation induced by stirring, ADP and PAF (P0.01). However, it was only the combination of all three agents inhibited P-selectin expression (P0.01). Similarly, it was the combination of all three antiplatelet agents that most consistently inhibited platelet-monocyte and platelet-neutrophil conjugate formation and monocyte and neutrophil activation. 4. Since both platelets and leukocytes are thought to contribute to arterial thrombosis and atherosclerosis, it is possible that combinations of different antiplatelet agents with different mechanisms of action may afford better protection than individual or pairs of agents used on their own.