Virtual International Stroke Trials Archive Research Articles

Cerebral Small Vessel Disease and Infarct Growth in Acute Ischemic Stroke Treated with Intravenous Thrombolysis.

We investigated relations between cerebral small vessel disease (cSVD) markers and evolution of the ischemic tissue from ischemic core to final infarct in people with acute ischemic stroke treated with intravenous thrombolysis. Data from the Stroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA) were used. Any pre-existing lacunar infarcts and white matter hyperintensities (WMH) were assessed on magnetic resonance (MR) before thrombolytic therapy. Acute ischemic core and final infarct volume were then assessed by two independent radiologists. The relationship among baseline markers of cSVD, acute ischemic core volume, final infarct volume, infarct growth (IG = final infarct - ischemic core), and infarct growth ratio (IGR = final infarct/ischemic core) was then assessed using linear and ordinal regression adjusted for age, sex, onset-to-treatment time, and stroke severity. We included 165 patients, mean (± SD) age 69.5 (± 15.7) years, 74 (45%) males, mean (± SD) ischemic core volume 25.48 (± 42.22) ml, final infarct volume 52.06 (± 72.88) ml, IG 26.58 (± 51.02) ml, IGR 8.23 (± 38.12). Seventy (42%) patients had large vessel occlusion, 20 (12%) acute small subcortical infarct. WMHs were present in 131 (79%) and lacunar infarcts in 61 (37%) patients. Final infarct volumes were 53.8ml and 45.2ml (WMHs/no WMHs), p = 0.139, and 24.6ml and 25.9ml (lacunar infarcts/no lacunar infarcts), p = 0.842. In linear and ordinal regression analyses, presence of lacunar infarcts was associated with smaller IG (β = - 0.17; p = 0.024; cOR = 0.52; 95%CI = 0.28-0.96, respectively) and WMHs were associated with smaller IGR (β = - 0.30; p = 0.004; cOR = 0.27; 95%CI = 0.11-0.69, respectively). In people with acute ischemic stroke treated with intravenous thrombolysis, cSVD features were associated with smaller growth of the acute ischemic area, suggesting less salvageable tissue at time of reperfusion therapy.

Bayesian modeling framework for optimizing pre-hospital stroke triage decisions

Ischemic stroke is responsible for significant morbidity and mortality in the United States and worldwide. Stroke treatment optimization requires emergency medical personnel to make rapid triage decisions concerning destination hospitals that may differ in their ability to provide highly time-sensitive pharmaceutical and surgical interventions. These decisions are particularly crucial in rural areas, where transport decisions can have a large impact on treatment times – often involving a trade-off between delay in pharmaceutical therapy or a delay in endovascular thrombectomy. In this work, we explore a Bayesian modeling framework to address this decision-making process, showing how these techniques may be used to fully account for diagnostic and therapeutic uncertainty. We demonstrate how these techniques can contextualize triage decision at a fine-grained spatial scale. We further show the application of this modeling approach in the US State of Iowa, using data from the Virtual International Stroke Trials Archive (VISTA), and describe potential next steps for improved triage. ABBREVIATION LVO: large vessel occlusion; non-LVO, non-large vessel occlusion; IVT: intravenous tissue plasminogen activator; EVT: endovascular thrombectomy; CSC: comprehensive stroke centers; PSC: primary stroke centers; DS: drip and ship; MS, mothership; EMS: Emergency Medical Service; BGLM: Bayesian Generalized Linear Model; BGAM: Bayesian Generalized Additive Model; BART: Bayesian Additive Regression Trees; VISTA: Virtual International Stroke Trials Archive; NIHSS: National Institute of Health Stroke Severity Scale; ASPECTS: Alberta Stroke Programme Early CT Score; mRS, modified Rankin score; ROCAUC: Area under the receiver operating characteristic curve; ELPD: Expected Log pointwise Predictive Density; SE: Standard Error; ICA: Internal Carotid Artery; M1: Middle Cerebral Artery segment 1; M2: Middle Cerebral Artery segment 2; TIA: Transient Ischemic Attack; Cr-I: Credible Intervals; LKW: Last Known Well

Abstract TMP95: Context Matters: Geographic Decision-Making Could Improve Prehospital Stroke Triage

Introduction: Emergency medical services (EMS) play a key role in stroke outcomes, as triage decisions made under diagnostic uncertainty impact availability of time sensitive treatments. Quantifying both time varying effects and uncertainty allows for optimized algorithms to improve destination decisions for stroke patients. We developed a Bayesian model of neurological outcomes and an algorithm for hospital triage based on clinical trials data. Methods: We used data from Virtual International Stroke Trials Archive (VISTA), RACECAT, and FAST-MAG. To model prehospital diagnosis, we included patients with any stroke-like illness (ischemic/hemorrhagic stroke, and mimics). Primary outcome was 90-day modified Rankin scale (mRS). Due to variability in reported measures from each trial, model-based Bayesian imputation was used. Our model accepts time-from symptoms, location, and capability of all local hospitals as inputs. Results: We included 9048 participants with 8600 (95%) ischemic strokes, 1801 (20%) had large vessel occlusion, and 4064 (45%) had a 90-day mRS of 0-2 (good neurologic outcome). We evaluated the impact of our algorithm using 1,320 stroke events from RACECAT. The estimated median absolute difference in chance of good mRS score between bypass and non local hospital bypass was 2.3% (ranging from 0 to 7.4%) among 1,320 stroke events in the RACECAT data set; covariate-adjusted patient scenarios predicted a preference for local hospital bypass of -2.9% to 7.4%. Destination maps for Catalonia show important patterns of bypass optimality. Conclusion: We found that no uniform destination selection approach is likely to be optimal under all circumstances. This finding is important, because it suggests that a personalized approach considering diagnostic uncertainty, patient characteristics, and geospatial factors could outperform simpler approaches. Predicted time-to-treatment targets may be insufficient for appropriate system optimization.

Validation of general pain scores from multidomain assessment tools in stroke

PurposeWe describe how well general pain reported in multidomain assessment tools correlated with pain-specific assessment tools; associations between general pain, activities of daily living and independence after stroke.Materials and methodsAnalyses of individual participant data (IPD) from the Virtual International Stroke Trials Archive (VISTA) described correlation coefficients examining (i) direct comparisons of assessments from pain-specific and multidomain assessment tools that included pain, (ii) indirect comparisons of pain assessments with the Barthel Index (BI) and modified Rankin Scale (mRS), and (iii) whether pain identification could be enhanced by accounting for reported usual activities, self-care, mobility and anxiety/depression; factors associated with pain.ResultsEuropean Quality of Life 3- and 5-Level (EQ-5D-3L and EQ-5D-5L), RAND 36 Item Health Survey 1.0 (SF-36) or the 0–10 Numeric Pain Rating Scale (NPRS) were available from 10/94 studies (IPD = 10,002). The 0–10 NPRS was the only available pain-specific assessment tool and was a reference for comparison with other tools. Pearson correlation coefficients between the 0–10 NPRS and (A) the EQ-5D-3L and (B) EQ5D-5 L were r = 0.572 (n = 436) and r = 0.305 (n = 1,134), respectively. mRS was better aligned with pain by EQ-5D-3L (n = 8,966; r = 0.340) than by SF-36 (n = 623; r = 0.318). BI aligned better with pain by SF-36 (n = 623; r = −0.320). Creating a composite score using the EQ-5D 3 L and 5 L comprising pain, mobility, usual-activities, self-care and anxiety/depression did not improve correlation with the 0–10 NPRS.DiscussionThe EQ-5D-3L pain domain aligned better than the EQ-5D-5L with the 0–10 NPRS and may inform general pain description where resources and assessment burden hinder use of additional, pain-specific assessments.

Effect of alteplase, benzodiazepines and beta-blocker on post-stroke pneumonia: Exploration of VISTA-Acute.

Post-stroke pneumonia is a frequent complication of stroke and is associated with high mortality. Investigators have described its associations with beta-blocker. However, there has been no evaluation of the role of recombinant tissue plasminogen activator (RTPA). We postulate that RTPA may modify the effect of stroke on pneumonia by reducing stroke disability. We explore this using data from neuroprotection trials in Virtual International Stroke Trials Archive (VISTA)-Acute. We evaluated the impact of RTPA and other medications in random forest model. Random forest is a type of supervised ensemble tree-based machine learning method. We used the standard approach for performing random forest and partitioned the data into training (70%) and validation (30%) sets. This action enabled to the model developed on training data to be evaluated in the validation data. We borrowed idea from Coalition Game Theory on fair distribution of marginal profit (Shapley value) to determine proportional contribution of a covariate to the model. Consistent with other analysis using the VISTA-Acute data, the diagnosis of post-stroke pneumonia was based on reports of serious adverse events. The overall frequency of pneumonia was 10.9% (614/5652). It was present in 11.5% of the RTPA (270/2358) and 10.4% (344/3295) of the no RTPA groups. There was significant (p<0.05) imbalance in covariates (age, baseline National Institutes of Health Stroke Scale (NIHSS), diabetes, and sex). The AUC for training data was 0.70 (95% CI 0.65-0.76), validation data was 0.67 (95% CI 0.62-0.73). The Shapley value shows that baseline NIHSS (≥10) and age (≥80) made the largest contribution to the model of pneumonia while absence of benzodiazepine may protect against pneumonia. RTPA and beta-blocker had very low effect on frequency of pneumonia. In this cohort pneumonia was strongly associated with stroke severity and age whereas RTPA had a much lower effect. An intriguing finding is a possible association between benzodiazepine and pneumonia but this requires further evaluation.

RCT versus real-world cohorts: Differences in patient characteristics drive associations with outcome after EVT.

The selection of patients with large-vessel occlusion (LVO) stroke for endovascular treatment (EVT) depends on patient characteristics and procedural metrics. The relation of these variables to functional outcome after EVT has been assessed in numerous datasets from both randomized controlled trials (RCT) and real-world registries, but whether differences in their case mix modulate outcome prediction is unknown. We leveraged data from individual patients with anterior LVO stroke treated with EVT from completed RCTs from the Virtual International Stroke Trials Archive (N = 479) and from the German Stroke Registry (N = 4079). Cohorts were compared regarding (i) patient characteristics and procedural pre-EVT metrics, (ii) these variables' relation to functional outcome, and (iii) the performance of derived outcome prediction models. Relation to outcome (functional dependence defined by a modified Rankin Scale score of 3-6 at 90 days) was analyzed by logistic regression models and a machine learning algorithm. Ten out of 11 analyzed baseline variables differed between the RCT and real-world cohort: RCT patients were younger, had higher admission NIHSS scores, and received thrombolysis more often (all p < 0.0001). Largest differences at the level of individual outcome predictors were observed for age (RCT: adjusted odds ratio (aOR), 1.29 (95% CI, 1.10-1.53) vs real-world aOR, 1.65 (95% CI, 1.54-1.78) per 10-year increments, p < 0.001). Treatment with intravenous thrombolysis was not significantly associated with functional outcome in the RCT cohort (aOR, 1.64 (95 % CI, 0.91-3.00)), but in the real-world cohort (aOR, 0.81 (95% CI, 0.69-0.96); p for cohort heterogeneity = 0.056). Outcome prediction was more accurate when constructing and testing the model using real-world data compared to construction with RCT data and testing on real-world data (area under the curve, 0.82 (95% CI, 0.79-0.85) vs 0.79 (95% CI, 0.77-0.80), p = 0.004). RCT and real-world cohorts considerably differ in patient characteristics, individual outcome predictor strength, and overall outcome prediction model performance.

Stroke Outcome Related to Initial Volume Status and Diuretic Use.

Background We hypothesized that stroke outcome is related to multiple baseline hydration-related factors including volume contracted state (VCS) and diuretic use. Methods and Results We analyzed a prospective cohort of subjects with ischemic stroke <24 hours of onset enrolled in acute treatment trials within VISTA (Virtual International Stroke Trials Archive). A VCS was defined based on blood urea nitrogen-to-creatinine ratio. The primary end point was modified Rankin Scale score at 90 days. Primary analysis used generalized ordinal logistic regression over the mRS range, adjusted for Totaled Health Risks in Vascular Events score, onset-to-enrollment time, and thrombolytic use. Of 5971 eligible patients with stroke, 42% were taking diuretics at the time of hospitalization, and 44% were in a VCS. Patients in a VCS were older, had more vascular risk factors, were more likely taking diuretics, and had more severe strokes. Diuretic use was associated with both reduced chance of achieving a good functional outcome (odds ratio [OR], 0.57 [95% CI, 0.52-0.63]) and increased mortality at 90 days (OR, 2.30 [95% CI, 2.04-2.61]). VCS was associated with greater mortality 90 days after stroke (OR, 1.53 [95% CI, 1.33-1.76]). There was no evidence of effect modification among the 3 exposures of VCS, diuretic use, or hypokalemia in relation to outcome. Conclusions A VCS at the time of hospitalization was associated with more severe stroke and odds of death but not associated with worse functional outcome when accounting for relevant characteristics. Diuretic use and low serum potassium at the time of stroke onset were associated with worse outcome and may be worthy of further investigation.

Validation and comparison of multiple risk scores for prediction of symptomatic intracerebral hemorrhage after intravenous thrombolysis in VISTA.

Prediction models/scores may help to identify patients at high risk of symptomatic intracerebral hemorrhage (sICH) after intravenous thrombolysis. We aimed to validate and compare the performance of different prediction models for sICH after thrombolysis using direct model estimation in the Virtual International Stroke Trials Archive (VISTA). We searched PubMed for potentially eligible prediction models from inception to 1 June 2019. Simple and practical models/scores were validated in VISTA. The primary outcome was sICH based on two criteria (National Institute of Neurological Diseases and Stroke, NINDS; Safe Implementation of Thrombolysis in Stroke-Monitoring Study, SITS-MOST) and the secondary outcome was parenchymal hematoma (PH). The discrimination performance of each model was evaluated using area under the curve (AUC) and calibration was evaluated by Hosmer-Lemeshow goodness-of-fit tests. We found 13 prediction models and five models (HAT, MSS, SPAN-100, GRASPS and THRIVE) were finally validated in VISTA. A total of 1884 participants were eligible for our study, of whom the proportion with sICH was 4.6% (87/1884) per NINDS and 3.9% (73/1884) per SITS-MOST, and with PH was 11.3% (213/1884). MSS and GRASPS had the greatest predictive ability for sICH (NINDS criteria: MSS AUC 0.7, 95% CI 0.63-0.77, p < 0.001; GRASPS AUC 0.69, 95% CI 0.63-0.76, p < 0.001; SITS-MOST criteria: MSS, AUC 0.76, 95% CI 0.68-0.85, p < 0.001; GRASPS, AUC 0.79, 95% CI 0.71-0.87, p < 0.001). Similar results were found for PH (MSS AUC 0.68, 95% CI 0.64-0.73, p = 0.017; GRASPS AUC 0.68, 95% CI 0.63-0.72, p = 0.017). The calibration of each model was almost good. MSS and GRASPS had good discrimination and calibration for sICH and PH after thrombolysis as assessed in VISTA. These two models could be used in clinical practice and clinical trials to identity individuals with high risk of sICH.

Outcome prediction in large vessel occlusion ischemic stroke with or without endovascular stroke treatment: THRIVE-EVT.

The THRIVE score and the THRIVE-c calculation are validated ischemic stroke outcome prediction tools based on patient variables that are readily available at initial presentation. Randomized controlled trials (RCTs) have demonstrated the benefit of endovascular treatment (EVT) for many patients with large vessel occlusion (LVO), and pooled data from these trials allow for adaptation of the THRIVE-c calculation for use in shared clinical decision making regarding EVT. To extend THRIVE-c for use in the context of EVT, we extracted data from the Virtual International Stroke Trials Archive (VISTA) from 7 RCTs of EVT. Models were built in a randomly selected development cohort using logistic regression that included the predictors from THRIVE-c: age, NIH Stroke Scale (NIHSS) score, presence of hypertension, diabetes mellitus, and/or atrial fibrillation, as well as randomization to EVT and, where available, the Alberta Stroke Program Early CT Score (ASPECTS). Good outcome was achieved in 366/787 (46.5%) of subjects randomized to EVT and in 236/795 (29.7%) of subjects randomized to control (P < 0.001), and the improvement in outcome with EVT was seen across age, NIHSS, and THRIVE-c good outcome prediction. Models to predict outcome using THRIVE elements (age, NIHSS, and comorbidities) together with EVT, with or without ASPECTS, had similar performance by ROC analysis in the development and validation cohorts (THRIVE-EVT ROC area under the curve (AUC) = 0.716 in development, 0.727 in validation, P = 0.30; THRIVE-EVT + ASPECTS ROC AUC = 0.718 in development, 0.735 in validation, P = 0.12). THRIVE-EVT may be used alongside the original THRIVE-c calculation to improve outcome probability estimation for patients with acute ischemic stroke, including patients with or without LVO, and to model the potential improvement in outcomes with EVT for an individual patient based on variables that are available at initial presentation. Online calculators for THRIVE-c estimation are available at www.thrivescore.org and www.mdcalc.com/thrive-score-for-stroke-outcome.

Machine learning prediction of symptomatic intracerebral hemorrhage after stroke thrombolysis: a cross-cultural validation in Caucasian and Han Chinese cohort.

Background:Previous studies found that Asians seemed to have higher risk of HT after thrombolysis than Caucasians due to its race differences in genetic polymorphism. Whether the model developed by Caucasians could predict risk of symptomatic intracerebral hemorrhage (sICH) in Asians was unknown.Objectives:To develop a machine learning–based model for predicting sICH after stroke thrombolysis in Caucasians and externally validate it in an independent Han Chinese cohort.Design:The derivation Caucasian sample included 1738 ischemic stroke (IS) patients from the Virtual International Stroke Trials Archive (VISTA) data set, and the external validation Han Chinese cohort included 296 IS patients who were treated with intravenous thrombolysis.Methods:Twenty-eight variables were collected across both samples. According to their properties, we classified them into six distinct clusters (ie, demographic variables, medical history, previous medication, baseline blood biomarkers, neuroimaging markers on initial CT scan and clinical characteristics). A support vector machine (SVM) model, which consisted of data processing, model training, testing and a 10-fold cross-validation, was developed to predict the risk of sICH after stroke thrombolysis. The receiving operating characteristic (ROC) was used to assess the prediction performance of the SVM model. A domain contribution analysis was then performed to test which cluster had the highest influence on the performance of the model.Results:In total, 85 (4.9%) patients developed sICH in the Caucasians, and 29 (9.8%) patients developed sICH in the Han Chinese cohort. Eight features including age, NIHSS score, SBP (systolic blood pressure), DBP (diastolic blood pressure), ALP (alkaline phosphatase), ALT (alanine transaminase), glucose, and creatine level were included in the final model, all of which were from demographic, clinical characteristics, and blood biomarkers clusters, respectively. The SVM model showed a good predictive performance in both Caucasians (AUC = 0.87) and Han Chinese patients (AUC = 0.74). Domain contribution analysis showed that inclusion/exclusion of clinical characteristic cluster (NIHSS score, SBP, and DBP), had the highest influence on the performance of predicting sICH in both Caucasian and Han Chinese cohorts.Conclusion:The established SVM model is feasible for predicting the risk of sICH after thrombolysis quickly and efficiently in both Caucasian and Han Chinese cohort.

Temporal Profile of Pneumonia After Stroke.

The occurrence of pneumonia after stroke is associated with a higher risk of poor outcome or death. We assessed the temporal profile of pneumonia after stroke and its association with poor outcome at several time points to identify the most optimal period for testing pneumonia prevention strategies. We analyzed individual patient data stored in the VISTA (Virtual International Stroke Trials Archive) from randomized acute stroke trials with an inclusion window up to 24 hours after stroke onset and assessed the occurrence of pneumonia in the first 90 days after stroke. Adjusted odds ratios and hazard ratios were calculated for the association between pneumonia and poor outcome and death by means of logistic and Cox proportional hazard regression, respectively, at different times of follow-up. Of 10 821 patients, 1017 (9.4%) had a total of 1076 pneumonias. Six hundred eighty-nine (64.0%) pneumonias occurred in the first week after stroke. The peak incidence was on the third day and the median time of onset was 4.0 days after stroke (interquartile range, 2-12). The presence of a pneumonia was associated with an increased risk of poor outcome (adjusted odds ratio, 4.8 [95% CI, 3.8-6.1]) or death (adjusted hazard ratio, 4.1 [95% CI, 3.7-4.6]). These associations were present throughout the 90 days of follow-up. Two out of 3 pneumonias in the first 3 months after stroke occur in the first week, with a peak incidence on the third day. The most optimal period to assess pneumonia prevention strategies is the first 4 days after stroke. However, pneumonia occurring later was also associated with poor functional outcome or death.

Acute Blood Pressure and Outcome After Intracerebral Hemorrhage: The VISTA-ICH Cohort

BackgroundRecent clinical trials suggest that it is safe to acutely lower systolic blood pressure (BP) to 140 mm Hg after ICH, but uncertainty remains regarding optimal management. We sought to better define the link between BP and outcome in ICH patients using data from the Virtual International Stroke Trials Archive (VISTA). MethodsWe performed a retrospective analysis of patients of the VISTA-ICH trials. We measured the strength of association between systolic and diastolic BP various components at different timepoints with unfavorable 3 month-outcome, defined as death or moderate-to-severe disability at 3 months (mRS of 4-6), after adjustment for known confounders. We also dichotomized BP values obtained at 24 h at different thresholds to better define an optimal treatment target. The association of BP with hematoma expansion (HE) was also analyzed. ResultsA total of 384 patients were included. Higher BP at 24 hours was associated with unfavorable outcome for systolic BP (OR 1.16, 95% C.I. 1.07–1.25), pulse pressure (OR 1.13, 95% C.I. 1.03–1.24), and diastolic BP (OR 1.11, 95% C.I. 1.01–1.23) per 10 mm Hg increment. The association between higher BP at 24 h and unfavorable outcome remained significant down to >140 mm Hg. Elevated systolic BP at 24 h was also associated with HE (OR 1.11, 95% C.I. 1.02–1.21 per 10 mm Hg increment). ConclusionElevated BP after ICH at 24 h is associated with poor outcome. Our results support the practice of targeting a systolic BP of 140 mm Hg.

Missing outcome data management in acute stroke trials testing iv thrombolytics. Is there risk of bias?

Missing outcome data may undermine interpretation of randomised clinical trials by weakening power and limiting apparent effect size. We assessed bias and inefficiency of two imputation methods commonly used in stroke trials evaluating the efficacy of iv thrombolysis. We searched the virtual international stroke trials archive (VISTA)-acute for ischaemic stroke patients with 90-day modified Rankin scale as an outcome, and known thrombolysis status. We excluded any with missing 30-day modified Rankin scale. We planned two analyses; first, we calculated odds ratios for outcome in thrombolysed versus not thrombolysed from imputed-only data, (a) among patients with missing modified Rankin scale 90 and (b) among matched patients with intact data (using propensity score methods and relevant covariates). Imputation approaches were last observation carried forward (LOCF) or multiple imputation. Outcome comparisons used dichotomisation and shift analysis. Thereafter, we calculated whole-population odds ratios using LOCF and multiple imputation (also through dichotomisation and shift analysis); first with the original 1.5% missing outcome data, and then artificially increasing the burden (5%; 10%; 20%; 30%). We considered 9657 patients from eight of the studies included in VISTA, 3034 (31%) thrombolysed. Missing data replacement by LOCF with analysis by dichotomisation gave the highest estimate of thrombolysis influence. Imputing while increasing the burden of missing data progressively raised the odds ratios estimates, though thresholds for overestimation were 10% for LOCF; 20% for multiple imputation.Discussion: Replacing missing outcome data tended to overestimate differences of thrombolysed versus non-thrombolysed patients, but had minimal impact below a 10% burden of missing data.Conclusion: In the specific context of acute stroke trials testing iv thrombolytics, replacing missing data by carrying forward the last observation tended to overestimate treatment odds ratios more than multiple imputation.

Abstract TMP87: Stroke Outcomes Related to Initial Volume Status, Diuretic Use, and Potassium Levels

Background and Purpose: The relationship between stroke outcome and initial presentation in a volume contracted state (VCS) has not been well established, and may intersect with concomitant diuretic use and serum potassium (K) levels. We hypothesized that stroke outcome is a function of multiple volume related factors. Methods: We analyzed a prospective cohort of subjects with ischemic stroke &lt;24 hours of onset, enrolled in acute treatment trials within the Virtual International Stroke Trials Archive. VCS was defined as a BUN-to-creatinine ratio&gt;20 and hypokalemia as &lt;3.5 mEq/L. The primary endpoint was modified Rankin Scale (mRS) at 90 days. Primary analysis employed generalized ordinal logistic regression over the full mRS range, with adjustment for THRIVE score, onset-to-enrollment time, and intravenous rtPA usage. Secondary analyses dichotomized the mRS. Results: Of 5971 eligible patients, 44% were in a VCS and 56% were euvolemic. Patients with VCS were older, had more vascular risk factors, more severe strokes, and were more likely taking diuretics. VCS was not significantly associated with mRS scores after adjustment (Table). Post hoc sensitivity analysis using BUN-to-creatinine ratio&gt;30 yielded similar results. Diuretic use was associated with worse outcomes (Table), mainly driven by non-K sparing diuretics, while K-sparing diuretics tended to have the opposite effect. Hypokalemia had discordant associations with mRS, depending on the analytic approach (Table). There was no evidence of effect modification among the three exposures of VCS, diuretic use, or hypokalemia in relation to outcome (all p&gt;0.30). Conclusions: A VCS at the time of hospitalization was associated with more severe stroke but not associated with worse functional outcome when accounting for key measurable baseline characteristics. However, diuretic use and low serum potassium at the time of stroke onset were associated with worse outcome and may be worthy of further investigation.

Liver Fibrosis Indices and Outcomes After Primary Intracerebral Hemorrhage.

Background and Purpose- Cirrhosis-clinically overt, advanced liver disease-is associated with an increased risk of hemorrhagic stroke and poor stroke outcomes. We sought to investigate whether subclinical liver disease, specifically liver fibrosis, is associated with clinical and radiological outcomes in patients with primary intracerebral hemorrhage. Methods- We performed a retrospective cohort study using data from the Virtual International Stroke Trials Archive-Intracerebral Hemorrhage. We included adult patients with primary intracerebral hemorrhage presenting within 6 hours of symptom onset. We calculated 3 validated fibrosis indices-Aspartate Aminotransferase-Platelet Ratio Index, Fibrosis-4 score, and Nonalcoholic Fatty Liver Disease Fibrosis Score-and modeled them as continuous exposure variables. Primary outcomes were admission hematoma volume and hematoma expansion. Secondary outcomes were mortality, and the composite of major disability or death, at 90 days. We used linear and logistic regression models adjusted for previously established risk factors. Results- Among 432 patients with intracerebral hemorrhage, the mean Aspartate Aminotransferase-Platelet Ratio Index, Fibrosis-4, and Nonalcoholic Fatty Liver Disease Fibrosis Score values on admission reflected intermediate probabilities of fibrosis, whereas standard hepatic assays and coagulation parameters were largely normal. After adjusting for potential confounders, Aspartate Aminotransferase-Platelet Ratio Index was associated with hematoma volume (β, 0.20 [95% CI, 0.04-0.36]), hematoma expansion (odds ratio, 1.6 [95% CI, 1.1-2.3]), and mortality (odds ratio, 1.8 [95% CI, 1.1-2.7]). Fibrosis-4 was also associated with hematoma volume (β, 0.27 [95% CI, 0.07-0.47]), hematoma expansion (odds ratio, 1.9 [95% CI, 1.2-3.0]), and mortality (odds ratio, 2.0 [95% CI, 1.1-3.6]). Nonalcoholic Fatty Liver Disease Fibrosis Score was not associated with any outcome. Indices were not associated with the composite of major disability or death. Conclusions- In patients with largely normal liver chemistries, 2 liver fibrosis indices were associated with admission hematoma volume, hematoma expansion, and mortality after intracerebral hemorrhage.

Early in-hospital exposure to statins and outcome after intracerebral haemorrhage - Results from the Virtual International Stroke Trials Archive.

Recent data suggest that statin use after intracerebral haemorrhage might be beneficial. However, data on the effects of early in-hospital statin exposure are lacking. Therefore, we sought to assess whether (1) early statin exposure during the acute phase after intracerebral haemorrhage and (2) early continuation of prevalent statin use are associated with favourable functional outcome. Data were obtained from the Virtual International Stroke Trials Archive. Patients were categorised according to use patterns of statins during this early in-hospital phase (continuation, discontinuation or new initiation of statins). Univariate and multivariable analyses were conducted to explore the association between early statin exposure and functional outcome. A total of 919 patients were included in the analysis. Early in-hospital statin exposure (n = 89, 9.7%) was associated with better functional outcome (modified Rankin Scale ≤ 3) compared with 790 patients without statin exposure before or early after the event (66% versus 47%, adjusted OR 2.1, 95% confidence interval 1.3-3.6). Compared with patients without exposure to statins before and early after the event, early continuation of statin therapy (n = 57) was associated with favourable functional outcome (adjusted odds ratio 2.6, 95% confidence interval 1.3-5.2). The association between early continuation of statins and outcome remained robust in sensitivity analyses restricted to patients able to take oral medication within 72 h and one-week survivors. It is possible that part of the observed associations are not due to a protective effect of statins but are confounded by indication bias. Statin exposure and continuation of prevalent statin therapy early after intracerebral haemorrhage are associated with favourable functional outcome after 90 days.

Expanding Eligibility in Stroke Prevention Trials to Patients with Early Disability

Background and Purpose: Early disability after stroke is common, though many patients improve. Stroke secondary prevention trials often prohibit the recruitment of nonambulatory patients, limiting their access to potential treatment options and impeding trial enrollment. We aimed to determine outcomes after early dependence around the time of transition from acute care to recovery. Methods: Data were obtained from a composite of patients enrolled in acute stroke clinical trials within the Virtual International Stroke Trials Archive (VISTA-Acute). Early disability was defined by the modified Rankin Scale (mRS) of 4 or 5 between days 3-10 after onset, representing the time of discharge or transition to a rehabilitation-focused care setting. We developed multivariable models to identify factors associated with recovery to independent ambulatory function and recurrent stroke during the 90 days after stroke. Results: 4965 patients were included, with 2905 (59%) having early disability. Patients with early dependence were older, more likely to be women, had higher baseline NIHSS scores, and had more atrial fibrillation and diabetes mellitus, compared with those who were initially ambulatory. Recovery to ambulatory function occurred in 58% with early mRS = 4, compared to only 16% with early mRS = 5. Of those with early mRS = 4, return to independent ambulatory status by 90 days was associated in multivariable analysis with age, diabetes, prior stroke, NIH motor and gaze subscores, and thrombolysis. Recurrent ischemic stroke through day 90 was reported in 126 of 2905 (4.3%) subjects with early dependence compared to 63 of 2060 (3.1%), which was not different after adjustment for age, sex, and risk factors (odds ratio 1.27; 95% confidence interval 0.92-1.73). Conclusions: Favorable outcomes are common among ischemic stroke patients previously enrolled in acute clinical trials despite early dependence (mRS = 4) after initial acute hospital care. Further, their risk of recurrent stroke is high in the short term. These patients likely benefit from aggressive poststroke care and should be actively recruited into secondary prevention trials.

Cortical thickness, white matter hyperintensities, and cognition after stroke.

A thinner cerebral cortex is associated with higher white matter hyperintensity burden and cognitive impairment in community-dwelling and dementia cohorts. It is important to assess these associations in people with ischemic stroke because their cerebrovascular disease profiles are different to these cohorts. We aimed to determine whether cortical thickness was related to white matter hyperintensity burden and cognition after ischemic stroke. We measured cortical thickness using advanced normalization tools' "KellyKapowski" function in 244 patients with ischemic stroke or transient ischemic attack from the Virtual International Stroke Trials Archive. We measured white matter hyperintensity burden via quantitative volumes and Fazekas score. We extracted data on vascular risk factors at baseline and Mini Mental State Examination scores at one year. We assessed associations between imaging and clinical data using correlation and multiple linear regression. Pairwise correlation showed that higher white matter hyperintensity Fazekas score was associated with a thinner cortex (rho = -0.284, P < 0.0001). White matter hyperintensities were generally distributed adjacent to and above the lateral ventricles. Voxel-wise analyses showed statistically significant negative associations between cortical thickness and white matter hyperintensities across fronto-temporal and inferior parietal cortical regions. Mean cortical thickness was positively related to Mini Mental State Examination in pair-wise correlation (r = 0.167, P = 0.0088) but there was no independent association after adjustment for age and white matter hyperintensities (beta = 0.016, P = 0.7874). Cortical thickness was not an independent predictor of cognition after ischemic stroke. Further work is required to understand how white matter hyperintensities are associated with a thinner cortex in temporal regions but less so in more superior regions where white matter hyperintensities are generally found in people with stroke.

Antibiotic Class and Outcome in Post-stroke Infections: An Individual Participant Data Pooled Analysis of VISTA-Acute.

Introduction: Antibiotics used to treat post-stroke infections have differing antimicrobial and anti-inflammatory effects. Our aim was to investigate whether antibiotic class was associated with outcome after post-stroke infection.Methods: We analyzed pooled individual participant data from the Virtual International Stroke Trials Archive (VISTA)-Acute. Patients with ischemic stroke and with an infection treated with systemic antibiotic therapy during the first 2 weeks after stroke onset were eligible. Antibiotics were grouped into eight classes, according to antimicrobial mechanism and prevalence. The primary analysis investigated whether antibiotic class for any infection, or for pneumonia, was independently associated with a shift in 90 day modified Rankin Scale (mRS) using ordinal logistic regression.Results: 2,708 patients were eligible (median age [IQR] = 74 [65 to 80] y; 51% female; median [IQR] NIHSS score = 15 [11 to 19]). Pneumonia occurred in 35%. Treatment with macrolides (5% of any infections; 9% of pneumonias) was independently associated with more favorable mRS distribution for any infection [OR (95% CI) = 0.59 (0.42 to 0.83), p = 0.004] and for pneumonia [OR (95% CI) = 0.46 (0.29 to 0.73), p = 0.001]. Unfavorable mRS distribution was independently associated with treatment of any infection either with carbapenems, cephalosporins or monobactams [OR (95% CI) = 1.62 (1.33 to 1.97), p < 0.001], penicillin plus β-lactamase inhibitors [OR (95% CI) = 1.26 (1.03 to 1.54), p = 0.025] or with aminoglycosides [OR (95% CI) = 1.73 (1.22 to 2.46), p = 0.002].Conclusion: This retrospective study has several limitations including effect modification and confounding by indication. Macrolides may have favorable immune-modulatory effects in stroke-associated infections. Prospective evaluation of the impact of antibiotic class on treatment of post-stroke infections is warranted.

Stroke aetiological classification reliability and effect on trial sample size: systematic review, meta-analysis and statistical modelling

BackgroundInter-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.MethodsWe 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.ResultsFrom 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.ConclusionsStroke aetiological classification systems suffer from inter-observer variability, and the resulting misclassification may limit trial power.Trial registrationProtocol available at reviewregistry540.