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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.

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: 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 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.

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 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.

No abstract available.