International Stroke Trial Research Articles

Associations of chronic heart failure with outcome in acute ischaemic stroke patients who received systemic thrombolysis: analysis from VISTA.

There are concerns that systemic thrombolysis might not achieve clinically important outcome amongst chronic heart failure (CHF) patients with acute ischaemic stroke. Our aim was to investigate the relevance of CHF on the outcome of acute stroke patients who received thrombolysis. A non-randomized cohort analysis was conducted using data obtained from the Virtual International Stroke Trials Archive. The association of outcome amongst CHF patients with thrombolysis treatment was described using the modified Rankin scale (mRS) distribution at day 90, stratified by the presence of atrial fibrillation. Dichotomized outcomes were considered as a secondary end-point. 5677 patients were identified, of whom 2366 (41.7%) received thombolysis. Five hundred and three (8.9%) patients had CHF, of whom 209 (41.6%) received thrombolysis. The presence of CHF was associated with a negative impact on overall stroke outcome [odds ratio (OR) 0.73 (95% confidence interval (CI) 0.62-0.87), P < 0.001]. However, thrombolysis treatment was associated with favourable functional outcome using ordinal mRS, irrespective of CHF status, after adjustment for age and baseline National Institutes of Health Stroke Scale [OR 1.44 (95% CI 1.04-2.01, P = 0.029) for CHF patients versus OR 1.50 (95% CI 1.36-1.66, P < 0.001) for non-CHF patients]. CHF patients had higher mortality at day 90 than non-CHF patients. There was no significant difference for recurrent stroke or symptomatic intracerebral haemorrhage within 7 days of the initial stroke between CHF and thrombolysis groups. Chronic heart failure was associated with a worse outcome with or without thrombolysis. However, acute stroke patients who received thrombolysis had more favourable outcome regardless of CHF status, compared with their untreated peers. Our findings should reassure clinicians considering systemic thrombolysis treatment in hyperacute ischaemic stroke patients with CHF.

Aspirin for acute stroke of unknown etiology in resource-limited settings: a decision analysis.

To analyze the potential impact of aspirin on outcome at hospital discharge after acute stroke in resource-limited settings without access to neuroimaging to distinguish ischemic stroke from intracerebral hemorrhage (ICH). A decision analysis was conducted to evaluate aspirin use in all patients with acute stroke of unknown type for the duration of initial hospitalization. Data were obtained from the International Stroke Trial and Chinese Acute Stroke Trial. Predicted in-hospital mortality and stroke recurrence risk were determined across the worldwide reported range of the proportion of strokes caused by ICH. Sensitivity analyses were performed on aspirin-associated relative risks in patients with ICH. At the highest reported proportion of strokes due to ICH from a large epidemiologic study (34% in sub-Saharan Africa), aspirin initiation after acute stroke of undetermined etiology is predicted to reduce in-hospital mortality (from 85/1,000 without treatment to 81/1,000 with treatment), in-hospital stroke recurrence (58/1,000 to 50/1,000), and combined risk of in-hospital mortality or stroke recurrence (127/1,000 to 114/1,000). Benefits of aspirin therapy remained in sensitivity analyses across a range of plausible parameter estimates for relative risks associated with aspirin initiation after ICH. Aspirin treatment for the period of initial hospitalization after acute stroke of undetermined etiology is predicted to decrease acute stroke-related mortality and in-hospital stroke recurrence even at the highest reported proportion of acute strokes due to ICH. In the absence of clinical trials to test this approach empirically, clinical decisions require patient-specific evaluation of risks and benefits of aspirin in this context.

The THRIVE score predicts symptomatic intracerebral hemorrhage after intravenous tPA administration in SITS-MOST.

The Totaled Health Risks in Vascular Events (THRIVE) score is a clinical prediction score that predicts ischemic stroke outcomes in patients receiving intravenous tissue plasminogen activator, endovascular stroke treatment, or no acute therapy. We have previously found an association between THRIVE and risk of post-tissue plasminogen activator symptomatic intracranial hemorrhage in the National Institute of Neurological Disorders and Stroke (NINDS) tissue plasminogen activator trial and risk of radiographic hemorrhage in Virtual International Stroke Trials Archive. The study aims to validate the relationship between THRIVE and symptomatic intracranial hemorrhage among tissue plasminogen activator-treated patients in the large Safe Implementation of Thrombolysis in Stroke - Monitoring Study (SITS-MOST). This is a retrospective analysis of the prospective SITS-MOST to examine the relationship between THRIVE and symptomatic intracranial hemorrhage after tissue plasminogen activator treatment. Symptomatic intracranial hemorrhage after tissue plasminogen activator was defined according to each of three standard definitions: the NINDS, European Cooperative Acute Stroke Study (ECASS), and Safe Implementation of Thrombolysis in Stroke (SITS) criteria. Multivariable logistic regression was used to confirm the relationship of THRIVE and individual THRIVE components with the risk of symptomatic intracranial hemorrhage and to examine the relationship of THRIVE, symptomatic intracranial hemorrhage, and functional outcome. The odds ratio for symptomatic intracranial hemorrhage at each increased level of THRIVE score is 1·34 (95% CI 1·27 to 1·41, P < 0·001) for symptomatic intracranial hemorrhage by NINDS criteria, 1·36 (95% CI 1·27 to 1·46, P < 0·001) for symptomatic intracranial hemorrhage by ECASS criteria, and 1·21 (95% CI 1·09 to 1·36, P < 0·001) for symptomatic intracranial hemorrhage by SITS criteria. In receiver-operator characteristics analysis, the C-statistic for THRIVE prediction of symptomatic intracranial hemorrhage was 0·65 (95% CI 0·62 to 0·67) for symptomatic intracranial hemorrhage by NINDS criteria, 0·66 (95% CI 0·63 to 0·69) for symptomatic intracranial hemorrhage by ECASS criteria, and 0·61 (95% CI 0·56 to 0·66) for symptomatic intracranial hemorrhage by SITS criteria. Each component of the THRIVE score predicts the risk of symptomatic intracranial hemorrhage, with independent impact of each component in multivariable analysis. The THRIVE score predicts the risk of symptomatic intracranial hemorrhage after intravenous tissue plasminogen activator administration. This external validation of the relationship between THRIVE and symptomatic intracranial hemorrhage in a prospective study further strengthens the role of the THRIVE score in the prediction of poststroke outcomes.

Imaging perfusion deficits, arterial patency and thrombolysis safety and efficacy in acute ischaemic stroke. Anobservational study of the effect of advanced imaging methods in The Third International Stroke Trial (IST-3), arandomised controlled trial

BackgroundIntravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) improves outcome after an ischaemic stroke but increases the risk of intracranial haemorrhage. Restricting rt-PA to patients with salvageable tissue, or arterial occlusion, might reduce risk, increase benefit and enable treatment at late time windows.ObjectivesTo determine if computed tomography (CT) or magnetic resonance (MR) perfusion or angiography (CTP/CTA; MRP/MRA) imaging provide important information to guide the use of rt-PA up to 6 hours after a stroke.DesignProspective, multicentre, randomised, open, blinded, end-point trial of rt-PA.SettingForty-eight centres (eight countries) performed CTP/CTA; 37 centres (11 countries) performed MRP/MRA.ParticipantsPatients aged over 18 years in whom brain scanning excluded intracranial haemorrhage, with known time of stroke onset and no clear indication for or contraindication to rt-PA, in whom treatment can start within 6 hours of a stroke.Interventionsrt-PA (0.9 mg/kg, maximum dose 90 mg) intravenously (10% bolus, the rest infused over 1 hour) compared with best medical care.Main outcome measuresPrimary – alive and independent (Oxford Handicap Score 0–2) at 6 months; secondary – symptomatic and fatal intracranial haemorrhage, early and late death. All imaging assessed centrally, blind to other data. Perfusion lesion sizes [cerebral blood volume (CBV); cerebral blood flow; mean transit time (MTT); time to maximum flow], angiographic occlusion, associations with plain scan findings, clinical baseline and outcomes, and the interaction with rt-PA were assessed with dichotomous and ordinal analyses.ResultsBaseline characteristics of patients in the Third International Stroke Trial (IST-3) with perfusion and angiography imaging did not differ from those without (95% did not meet the prevailing licence criteria for rt-PA): 151 patients had perfusion imaging and 423 had angiography (141 and 307 obtained at randomisation respectively). Most randomisation imaging was with CT (n = 125/141, 89% perfusion;n = 277/307, 90% angiography) with little MR (n = 16/141, 11% perfusion;n = 39/307, 10% angiography). The median patient age was 81 (interquartile range 71–86) years; perfusion imaging or angiography imaging was performed at median of 3.9 hours after stroke. Perfusion lesion size differed significantly between parameters (MTT lesions largest, CBV lesions smallest;p &lt; 0.0000; 46% had mismatch). Patients scanned earlier, who were older, or with more severe stroke, had larger perfusion lesions. Larger perfusion lesions were associated with poor outcome. Neither perfusion lesion size nor mismatch modified rt-PA effect on haemorrhage or 6-month outcome. Randomisation CTA (n = 253) showed arterial stenosis/occlusion in 42% (95% confidence interval 34% to 47%). Abnormal plain CT and plain CT + CTA were equally associated with worse baseline stroke severity, imaging and functional outcomes. rt-PA accelerated dissolution of arterial thrombus and reduced thrombus extension, but rt-PA effects did not differ between patients with angiographic occlusion compared with those without.ConclusionLarger perfusion lesions and arterial occlusion are associated with severe stroke and worse outcomes. However, patients with perfusion lesions, mismatch or angiographic occlusion had similar benefit and no worse hazard from rt-PA compared with those without. Visual assessment is an effective classification method. Perfusion or angiography imaging may improve diagnostic confidence in acute stroke but this does not improve prediction of prognosis or identify patients who respond differently to rt-PA. Although this trial is larger than others, the conclusion regarding perfusion imaging is limited by the sample size.Trial registrationCurrent Controlled Trials ISRCTN25765518.FundingThis project was funded by the NIHR Efficacy and Mechanism Evaluation programme and the Medical Research Council, and will be published in full inEfficacy and Mechanism Evaluation; Vol. 1, No. 1. See the NIHR Journals Library website for further project information.

NEW DIAGNOSTIC AND THERAPEUTIC STRATEGIES FOR VASCULAR COGNITIVE IMPAIRMENT (VCI): LEARNING FROM BIOMARKERS AND MULTI-PART APPROACHES IN STROKE

The term vascular cognitive impairment (VCI) is used to describe individuals with significant cognitive impairments produced by cerebrovascular disease (CVD). Risk factors for VCI are the same as traditional risk factors for CVD. Early identification of subjects at higher risk of VCI is important for the development of effective preventive strategies. Circulating biomarkers have emerged as potential tools for early diagnosis, as they could provide in vivo measures of the underlying pathophysiology. New interventions should be tested in large multicenter pre-clinical and clinical trials to speed-up the translation process. The Barcelona-AsIA (Asymptomatic Intracranial Atherosclerosis) study and ISSYS (Investigating Silent Strokes in hYpertensives) study are two excellent examples of large cohorts to explore biological predictors of VCI. Hypertension, intracranial atherosclerosis, and silent cerebrovascular lesions (SCL) detected by brain magnetic resonance imaging (MRI) are associated with an increased risk of cognitive decline. In that prospective observational study in 1000 hypertensive patients, aged 50-70 years, with no prior history of stroke or dementia, we studied the presence of mild cognitive impairment (MCI) and the relationship between SCL, an array of blood biomarkers, and cognition. MULTI-PART (Multicentre Preclinical Animal Research Team) is an international collaborative approach to overcoming the translational roadblock in neuroprotection and neuroregeneration research with the key objective to establish and implement a platform for international multicenter preclinical stroke trials using the repertoire of randomized clinical trial design and the complexities of a multicenter, multimodel paradigm. We will show examples of blood biomarkers that add predictive value to clinical and radiological models to anticipate the appearance of VCI. We are developing and implementing international, multicenter ‘phase III’-type preclinical trials of promising, novel ischemic stroke therapies to inform the possible transition from animal modeling to clinical trial. In addition, demonstrating neuroprotection and/or neurorepair in this prototypical acute CNS disorder would have vast implications for the development of treatments in many other chronic neurological and neuropsychiatric diseases such as VCI. Combining prediction of VCI through novel biomarkers and a new trial paradigm (MULTI-PART) could serve as a novel strategy to push translation of cellular/molecular mechanistic VCI studies.

Effect of IV rtPA in Mild Strokes in the Third International Stroke Trial (IST3) (S35.003)

Effect of IV rtPA in Mild Strokes in the Third International Stroke Trial (IST3) (S35.003)

Targeting Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke Based on Risk of Intracranial Hemorrhage or Poor Functional Outcome

Background and Purpose— Intravenous recombinant tissue-type plasminogen activator (r-tPA), despite a risk of early symptomatic intracranial hemorrhage (sICH), is of net clinical benefit to acute stroke patients. We tested if predictive models could identify patients least likely to be harmed by sICH or those who gained no net benefit. Methods— We used the Third International Stroke Trial (IST-3) trial data set, an international, multicenter, open treatment randomized trial of 0.9 mg/kg r-tPA versus control in 3035 patients with acute ischemic stroke. We compared the discrimination and calibration of previously developed predictive models for ICH and poststroke poor outcome and developed a new model using variables selected by systematic review. We calculated the absolute and relative risk reduction of death or dependency with r-tPA in patients at a low, medium, or high predicted risk of sICH or poor functional outcome. Results— Prediction models for sICH or poor outcome (Hemorrhage After Thrombolysis [HAT]; Sugar, Early Infarct Signs, Dense Artery, Age, National Institutes of Health (NIH) Stroke Score (SEDAN); Glucose Race Age Sex Pressure Stroke Severity [GRASPS]; Stroke Thrombolytic Predictive Instrument; Dense Artery, Rankin Score, Age, Glucose, Onset to Treatment Time, NIHSS [DRAGON]; Totaled Health Risks in Vascular Events [THRIVE]; our new model; and a model with National Institutes of Health Stroke Scale and age) had similar area under receiver operator characteristic curves (AUROCC) to predict sICH ( P for difference &gt;0.05). The simplest model (with covariates National Institutes of Health Stroke Scale and age) predicted both sICH (AUROCC, 0.63; 95% CI, 0.58–0.68) and poststroke poor functional outcome (AUROCC, 0.80; 95% CI, 0.77–0.82) similarly to complex models. There was no evidence that the effect of r-tPA in patients at high predicted risk of sICH or poor functional outcome after stroke was less than in those at lower risk. Conclusions— There is a clinically relevant net positive effect of r-tPA in patients with acute stroke at a high predicted risk of sICH or poor functional outcome. Clinical Trial Registration— URL: http://www.controlled-trials.com . Unique identifier: ISRCTN25765518.

CP-037 Thrombolysis performed within three hours following stroke reduces disability and costs: an economic model to estimate savings

BackgroundStroke is the second leading cause of death and the leading cause of disability worldwide. In Italy, there are approximately 200,000 new cases each year, of which about 80% are...

The 4.5-Hour Time Window for Intravenous Thrombolysis With Intravenous Tissue-Type Plasminogen Activator Is Not Firmly Established

Most stroke neurologists would likely choose to treat this patient with intravenous tissue-type plasminogen activator (IV tPA) assuming the treatment could be initiated within 4.5 hours from stroke onset. In fact, the American Heart Association and European Stroke Organization guidelines both recommend treatment of selected patients in the 3- to 4.5-hour time window. IV tPA is approved in this time window in 15 countries in Europe and several other countries around the world. In the United States, however, the Food and Drug Administration declined an application by Genentech to extend the time window for treatment beyond 3 hours. The evidence supporting the benefit of treatment in the 3- to 4.5-hour time window includes the results of European Cooperative Acute Stroke Study (ECASS) III,1 a randomized controlled trial enrolling 821 patients. Three prior randomized controlled trials (ECASS, ECASS II, Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke [ATLANTIS]) and 1 subsequent trial (Third International Stroke Trial [IST-3]) attempting to extend the time window for IV tPA beyond 3 hours failed to show significant benefit. In addition, an updated meta-analysis of 7012 patients in 12 IV tPA trials found that the major benefit occurred in patients treated within 3 hours with no significant effect of IV tPA in almost 5000 patients treated 3 to 6 hours after stroke onset (odds ratio, 1.07; 95% confidence interval, …

Third International Stroke Trial 3

The third International Stroke Trial (IST-3) was a randomized controlled trial of thrombolysis with intravenous recombinant tissue plasminogen activator in patients with acute ischemic stroke within 6 h of onset. It sought to determine whether a wider variety of patients might benefit from treatment than were eligible under the prevailing European Union approval for the drug, especially among those aged over 80 years. The entry criteria were broad, and there was no upper age limit for inclusion; over half the 3035 patients were aged over 80 years. For the types of patient recruited in IST-3, despite the early hazards (chiefly of fatal intracerebral hemorrhage), thrombolysis within 6 h did not affect longer-term survival and improved functional outcome. Benefit was greatest among patients treated within 3 h, and benefit did not appear to be diminished among elderly patients or those with severe stroke. These results should, therefore, encourage clinicians to: consider thrombolytic treatment for a wider variety of patients (particularly those aged over 80 years); treat those with more severe strokes; reinforce their efforts to increase the proportion of ischemic strokes treated within 3 h; and, have greater confidence that mortality is not increased by treatment. http://links.lww.com/CONR/A23.

Abstract 6: Response to Thrombolysis Treatment in Ischemic Stroke Patients With and Without Arterial Occlusion on Computed Tomographic Angiography: The Third International Stroke Trial

Background: The Third International Stroke Trial (IST-3) is a multicenter, randomised open label blinded outcome assessment controlled trial (RCT) testing i.v. thrombolysis (rt-PA) given within 6 hours of ischemic stroke: 3035 patients in whom indications for rt-PA were uncertain were randomised to rt-PA 0.9mg/kg or control after plain brain imaging. We also collected CT angiography (CTA) scans from centers where this was routinely performed. We tested whether the presence or absence of arterial occlusion on CTA influenced the effect of rt-PA on 6-month Oxford Handicap Score (OHS). Methods: We included all IST-3 patients with pre-randomisation CTA. One observer analysed all CTAs blind to follow-up imaging and all clinical data. We tested the association between CTA-identified arterial occlusion and 6-month OHS, with and without rt-PA, in an ordinal regression model with age, National Institutes of Health Stroke Scale (NIHSS) and time from onset as covariates. Odds ratios (OR) for the effect of rt-PA on OHS in those with vs without CTA arterial occlusion were compared. Results: Pre-randomisation CTA was performed in 272/3035 patients (44.5% male, median age 81 years, IQR 71-86). CTA showed arterial occlusion in 42% (115/272). CTA-demonstrated arterial occlusion at randomisation reduced the odds of good outcome (OR 0.43, 95%CI 0.25-0.76, p=0.003). The effect of rt-PA on good outcome did not differ significantly between patients with (OR 1.60, 0.71-3.63, p=0.260) vs. without (OR 0.89, 0.50-1.57, p=0.684) CTA occlusion (p-value for difference 0.249) although the direction of effect differed. Conclusion: Patients with arterial occlusion on CTA had worse 6-month outcome but we did not find a significant rt-PA-occlusion interaction in these patients. However the sample size limits detection of a modest interaction. The suggestion that patients with occlusion might benefit more could be tested in individual meta-analysis to achieve a larger sample size.

Abstract T MP21: Effect of IV rtPA in Mild Strokes in the Third International Stroke Trial (IST3): A Post Hoc Analysis

BACKGROUND: A relatively small number of patients with mild ischemic stroke (NIHSS 0-5) had been included in randomized trials of IV tPA up to 2012, and debate continues about the balance of risk and benefit from thrombolysis in this group. In the recent IST3 trial, among patients with NIHSS 0-5, 221/304 (72.7%) tPA vs. 232/308 (75.3%) control subjects were alive and independent (OHS 0-2) at 6 months, a nonsignificantly adverse effect. To determine whether a further trial in mild stroke patients was justified, we examined the effect of tPA in a more restricted subset of IST3 patients with NIHSS 0-5 who met NINDS tPA Study criteria. METHODS: The IST3 trial was a pragmatic, international, randomized-controlled, open-treatment trial with broad entry criteria comparing IV tPA with control within 6 hours of onset in 3035 subjects conducted in 12 countries outside the USA. We restricted analysis to subjects with NIHSS 0-5 who were treated within three hours, had pretreatment BP&lt;185/110, and met all other NINDS tPA Study criteria. No age restriction was applied. The primary outcome was the proportion alive and independent (OHS 0-2) at 6 months; key secondary analyses were an ordinal analysis of OHS and the proportion alive and with ‘favorable outcome’ (OHS 0-1). (Details at www.ist3.com). RESULTS: 612 of 3035 (20.2%) subjects enrolled in the IST3 trial had an NIHSS of 0-5. 106 of 612 (17.6%) were recruited within 3 hours, had pretreatment BP&lt;185/110, and met all NINDS tPA Study criteria. In this subset, tPA was associated with a significant increase in the proportion alive and independent, and a favorable shift in distribution of OHS grades. There was no significant effect on ‘favorable outcome’. See Table. CONCLUSIONS: This post-hoc analysis in a highly selected sample of the IST3 trial supports the rationale of the PRISMS trial, a randomised placebo-controlled Phase III, 950-subject, 75-center, North American study to evaluate the efficacy and safety of IV tPA in mild ischemic strokes.

Abstract 135: Antiplatelet Therapy Following Ischemic Stroke - Continue or Change Pre-existing Therapy?

Introduction: Antiplatelet therapy is routinely prescribed early after ischemic stroke. Many patients will already be taking antiplatelet therapy and it is unknown whether these patients should continue the same antiplatelet treatment or switch to a different regimen. We compared outcomes in patients who continued the same regimen after ischemic stroke to those who changed. Methods: Data from 10304 subjects were extracted from the Virtual International Stroke Trials Archive. 8550 subjects were excluded (12 incomplete data, 4823 no antiplatelet therapy recorded pre-stroke, 3715 no recorded antiplatelets post-stroke). Propensity score matching was employed to create a matched sample for comparison of those who continued the same regimen to those who changed. The nature of change in antiplatelet regimen was not explored. We compared the rate of recurrent stroke (primary endpoint), bleeding complications (defined as intracranial haemorrhage not including haemorrhagic transformation or any major bleed) and day-90 outcomes (using the modified Rankin and National Institutes of Health Stroke Scales). We used logistic regression analysis and adjusted for important clinical factors. Patients who suffered an outcome event prior to resuming antiplatelet therapy were not included in the analysis. Results: 963 subjects changed antiplatelet regimen post stroke and 791 continued the same regimen. In the propensity matched sample (n=791 per group), a recurrent ischemic event occurred in 3.7% of subjects who changed regimen and 3.8% who continued unchanged (OR=1.078; 95% CI 0.62-1.88, p=0.790). The odds of better functional outcome were higher in the change group according to both day-90 mRS (OR=1.31; 95% CI 1.07-1.59, p=0.008) and NIHSS. The rate of intracranial bleeding and major bleeding within the first 90 days was similar in both groups (1.2% vs. 1.2% (p=0.939) and 2.4% vs. 3.2% (p=0.409) respectively). Conclusion: In patients who suffer ischemic stroke whilst taking antiplatelets, a change in antiplatelet regimen was not associated with reduced recurrent stroke rate or bleeding. Day 90 functional outcome was better in the change group but this may be due to a confounding variable.

Response to Letter Regarding Article, “Clot Length Distribution and Predictors in Anterior Circulation Stroke: Implications for Intra-Arterial Therapy”

We thank Wanklyn et al1 for their comments. We agree wholeheartedly that even in the setting of long clots (eg, ≥8 mm), intravenous recombinant tissue-type plasminogen activator (tPA) should be administered rapidly to eligible acute ischemic stroke patients. Although the probability of early intravenous tPA recanalization of such clots is low, it is not zero, as demonstrated by the cases provided. Indeed, in a nonrandomized Virtual International Stroke Trials Archive (VISTA) study, intravenous tPA benefit extended to patients with severe neurological deficits, up to National Institutes of Health Stroke Scale score of 24.2 We know that many of these patients with severe stroke harbor proximal occlusions and long clots. One argument against intravenous tPA use for long …

Interdependence of Stroke Outcome Scales: Reliable Estimates from the Virtual International Stroke Trials Archive (VISTA)

Clinical deficits from stroke are diverse, prompting measurement in trials by a range of outcome scales. Statistical and clinical advantage can be gained by combining scales into a global outcome provided combinations are chosen with limited correlations. We aimed to clarify the interdependence of outcome scales by systematic review of published data and by novel analysis of data from completed acute trials. We systematically searched ScienceDirect and PubMed to summarize published data on correlations between stroke outcome scales. We generated new data on correlations among salient scales at 90 days poststroke in patients from the Virtual International Stroke Trials Archive (VISTA). We calculated Pearson and Spearman-Rank correlation coefficients for continuous and ordinal measures, respectively. We also assessed partial correlations, adjusted for baseline National Institute of Health Stroke Scale (NIHSS), and age. Published estimates of interdependence were limited to small single-trial cohorts and gave divergent results. From the more extensive VISTA dataset, we found that the modified Rankin Scale at 90 days poststroke explained 80.8% of the National Institute of Health Stroke Scale at 90 days poststroke and 86.5% of the European Stroke Scale. National Institute of Health Stroke Scale explained 75.9% of the Barthel Index and 81.2% of the Scandinavian Stroke Scale. After adjustment, modified Rankin Scale explained 56.6% of National Institute of Health Stroke Scale, 75.2% of Barthel Index. National Institute of Health Stroke Scale explained 60.2% of Barthel Index. Correlations and partial correlations among stroke outcome scales in trial datasets are higher than previously reported. The new estimates are more reliable for trial planning due to the sample size and diversity.

Aphasia and Dysarthria in Acute Stroke: Recovery and Functional Outcome.

Background Aphasia and dysarthria have major implications for activities of daily living and social participation following stroke. Few studies describe recovery in the acute stroke setting. We described the evolution of aphasia and dysarthria by three-months poststroke. Methods We conducted a retrospective analysis of pooled clinical trial data from the Virtual International Stroke Trials Archive. We defined aphasia and dysarthria at baseline as a score of ≥1 on the Best Language (Item 9) and Dysarthria (Item 10) domains of the National Institutes of Health Stroke Scale, respectively. We described recovery from these impairments by three-months. Covariate adjusted analyses described the associations between aphasia, dysarthria, and functional outcome using the modified Rankin Scale at three-months following stroke. Results At baseline, 4039/8904 (45·4%) people presented with aphasia and 6192 (69·5%) with dysarthria; 2639 (29·6%) had both impairments. By three-months, aphasia and dysarthria had resolved in 1292/7219 (17·9%) and 2892/7219 (40·1%) survivors, respectively, but persisted in 1713/7219 (23·7%) and 1940/7219 (27%), respectively. Age and severity of initial stroke were associated with poor recovery, whereas thrombolysis was associated with improved recovery. Aphasia at baseline [ P = 0·049, odds ratio = 0·89, 95% confidence interval (0·79,1·00)] and persistent aphasia at three-months [ P < 0·0001, odds ratio = 0·31, 95% confidence interval (0·27, 0·35)] were each associated with poorer modified Rankin Scale scores at three-months. Conclusion Aphasia or dysarthria persisted in at least a quarter of people in our dataset at three-months following stroke. The association between persistent aphasia at three-months and poor modified Rankin Scale renders this impairment a major therapeutic target for recovery and restitution.

A novel measure of treatment benefit for an ordinal scale: a case study of the IST-1 and the IST-3 stroke trials

Background Relative measures quantify the effect of an intervention but are difficult to translate into practice. Clinicians prefer absolute measures like the number needed to treat (NNT). We demonstrate a novel approach for reporting treatment effect across an ordered outcome where higher scores indicate worse functional outcome. We used the first and the third International Stroke Trials (IST-1 and IST-3) as case studies.

Body Mass Index and Acute Ischemic Stroke Outcomes.

Background The impact of body mass index on acute ischemic stroke outcomes is unclear. Aims and/or hypothesis We sought to determine the effect of body mass index on short-term (90 days) acute ischemic stroke outcomes. Methods Data were extracted for patients with acute ischemic stroke and records of body mass index at baseline from the Virtual International Stroke Trials Archive database. Multivariate logistic regression and Cox proportional hazard analysis were used to analyze effect of body mass index on poor functional outcome (modified Rankin Scale >2) and mortality, respectively, within 90 days of stroke's onset. Results Of the 4811 patients (mean age 68·8 ± 12·2 years) included in the study, 2002 (41·6%) were overweight, and 1095 (22·8%) were obese. Overweight (body mass index 25-29·9 kg/m2) was associated with decreased mortality (hazard ratios 0·59; 95% confidence interval 0·51-0·68; P < 0·01) and decrease in poor functional outcome (odds ratio 0·74; 95% confidence interval 0·64-0·85; P < 0·01) following acute ischemic stroke. The association of body mass index with stroke outcomes was dependent on age, gender, and use of thrombolytic therapy. Conclusions Being overweight or obese is associated with a better functional outcome and reduced mortality in patients of acute ischemic stroke. However, the definition of an 'optimal' body mass index, in relation to stroke outcomes, may be affected by age, gender, and use of thrombolytic therapy.

Pre-Stroke CHADS2 and CHA2DS2-VASc Scores Are Useful in Stratifying Three-Month Outcomes in Patients with and without Atrial Fibrillation

Background: CHADS₂ and CHA₂DS₂-VASc scores are validated tools for assessing stroke risk in patients with atrial fibrillation (AF). We investigated whether these scores are associated with 3-month stroke outcomes and evaluated the utility of these scores in stratifying 3-month stroke outcomes in both patients with and without AF. Methods: We analysed 6,612 acute ischaemic stroke patients from the Virtual International Stroke Trials Archive who received either placebo or ineffective active treatments not associated with significant cardiac complications. Outcomes included 3-month mortality, good functional outcomes defined as modified Rankin Scale score ≤1 and serious cardiac adverse events (SCAEs) defined as one of acute coronary syndrome, symptomatic heart failure, cardiopulmonary arrest, life-threatening arrhythmia and cardiac death. The association between the pre-stroke CHADS₂ and CHA₂DS₂-VASc scores and 3-month stroke outcomes was assessed using binary logistic regression. The utility of the two scores in estimating 3-month stroke outcomes was assessed using area under the receiver operator characteristic curves (AUC) and compared using the χ² test. Results: In this cohort, 26.5% had AF, 35.3% received IV tissue plasminogen activator (tPA), 17.7% died, 25.1% achieved good functional outcomes and 9.5% had ≥1 SCAE at 3 months. High-risk (≥2) pre-stroke CHADS₂ and CHA₂DS₂-VASc scores are both associated with 3-month mortality (CHADS₂: odds ratio, OR, 2.33, 95% confidence interval 1.81-3.00; CHA₂DS₂-VASc: OR 3.01, 2.00-4.80), good functional outcomes (CHADS₂: OR 0.47, 0.39-0.57; CHA₂DS₂-VASc: OR 0.55, 0.42-0.71) and SCAEs (CHADS₂: OR 1.76, 1.28-2.42; CHA₂DS₂-VASc: OR 2.69, 1.53-4.73) after adjusting for baseline differences in neurological impairment, tPA use and AF. The pre-stroke CHA₂DS₂-VASc score is better than the CHADS₂ score in estimating 3-month stroke outcomes in both patients with and without AF (p ≤ 0.005 in all AUC comparisons). High-risk pre-stroke CHA₂DS₂-VASc score has high sensitivity for mortality (AF: 0.96, 0.94-0.98; no AF: 0.88, 0.86-0.91) and negative predictive value for SCAE (AF: 0.93, 0.87-0.96; no AF: 0.96, 0.95-0.97) within 3 months. Low risk pre-stroke CHA₂DS₂-VASc score has high specificity for good functional outcome (AF: 0.99, 0.98-0.994; no AF: 0.94, 0.93-0.95) at 3 months. Conclusions: The pre-stroke CHA₂DS₂-VASc score appears to be a simple tool for identifying patients at lower risk of poor outcomes and serious cardiac complications within 3 months following ischaemic stroke in patients with and without AF.

Prestroke Alcohol Consumption and Smoking Are Not Associated with Stroke Severity, Disability at Discharge, and Case Fatality

Heavy alcohol consumption and smoking are known risk factors for stroke, but their influence on stroke severity and outcome may also be important. We tested if alcohol consumption and smoking relate to initial stroke severity, disability at discharge from hospital, and outcome at 30days and at 1year in 1049 patients of the Mures-Uzhgorod-Debrecen database. Initial stroke severity was scored by the National Institutes of Health Stroke Scale. Case fatality and the modified outcome scale of the First International Stroke Trial were used to assess outcome. We used multiple regression analysis. Before their stroke, 24.5% were smokers and 24.7% admitted regular alcohol consumption. Neither smoking nor alcohol consumption status was associated with initial stroke severity. Case fatalities at discharge, at 30days, and at 1year were 12.2%, 16.9%, and 28.3%, respectively. Initial stroke severity, hemorrhagic subtype, and age in men over 60years were strong predictors of outcome. We did not find significant difference among alcohol consumers and nonconsumers in 30-day and in 1-year case fatality in all stroke patients and in ischemic stroke patients. In hemorrhagic stroke, there was a nonsignificant tendency for higher case fatality among alcohol consumers (39.5% versus 26.4%, P>.2, at 30days and 48.8% versus 35.8%, P>.2, at 1year). Smoking did not influence significantly the outcome at 30 days and at 1 year. Despite being risk factors, prestroke smoking and alcohol consumption do not have a significant influence on stroke severity and on short- and long-term outcome.