Mortality After Total Anterior Circulation Stroke: A 25-Year Observational Study.

BACKGROUND: Mortality remains a substantial problem after acute ischemic stroke, despite advances in acute stroke treatment over the past three decades. Mortality is particularly high among patients with Total Anterior Circulation Stroke (TACS), generally representing patients with middle cerebral artery occlusions. Notably however, these patients also stand to benefit most from new therapies including endovascular thrombectomy (EVT). In this study, we aimed to examine temporal trends in, and factors associated with, 30-day in-hospital mortality after TACS. METHODS: Information on all patients with community-onset TACS from 1994 through 2019 was extracted from a prospective acute stroke registry. Multivariate analysis was performed on the primary outcome of 30-day in-hospital mortality, as well as secondary functional outcomes. RESULTS: We studied 1106 patients hospitalized for community-onset TACS, 456 (41%) of whom experienced 30-day in-hospital mortality. Over the 25 years of observation, 30-day in-hospital mortality rose and then fell. Increased odds of mortality was associated with age and stroke severity. Decreased odds of mortality was associated with alteplase therapy and EVT, as well as presentation to hospital more than 12 hours after stroke onset. Treatment with alteplase, EVT, or both was associated with higher odds of functional independence and discharge home, and shorter lengths of stay in acute care. CONCLUSIONS: Patients receiving alteplase, EVT, or both had lower 30-day in-hospital mortality and better functional outcomes than those who were untreated. These observational data demonstrate the benefits of recanalization therapy in routine clinical practice.

Endovascular Thrombectomy for Stroke Effectiveness Study-An Audit From a Small Tertiary Care Center.

PURPOSE: Endovascular thrombectomy (EVT) treatment for acute ischemic stroke is now recommended as a standard of care. However, implementing EVT in routine clinical practice poses many challenges, even in countries with advanced health-care systems. The aim of the current study is to delineate if EVT at our institution is an effective treatment for acute ischemic stroke. METHODS: All patients who underwent EVT at our institution between December 2011 and July 2017 were retrospectively assessed from our prospective registry. Clinical and imaging (including the Alberta Stroke Program Early CT [ASPECT] score, single-phase computed tomography angiography, and computed tomography perfusion) criteria were utilized to determine EVT suitability. Primary outcomes included modified Rankin score (mRS) at 90 days and recanalization determined by the modified Treatment in Cerebral Infarction score. Effectiveness was assessed by comparing our cohort with patients receiving EVT in the ESCAPE (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke) trial. RESULTS: Eighty-eight patients presented to our hospital after a median of 87 minutes last seen normal. Of these, median ASPECT score was 9. A majority (72%) also received intravenous alteplase. Successful recanalization (≥TICI 2b) was achieved in 79%. At 90 days, 48% (36/75) were functionally independent (mRS score of 0-2) and 28% (21/75) were disabled (mRS score of 3-5); 24% (18/75) died (mRS of 6) within 90 days. CONCLUSIONS: An audit of our initial experience with EVT for the treatment of acute ischemic stroke in a small tertiary care center yielded similar results compared to the ESCAPE trial, which is encouraging for implementing this treatment in routine clinical practice.

Case-Control Study of Endovascular Thrombectomy in a Canadian Stroke Center.

BACKGROUND: Although the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke caused by intracranial anterior circulation large vessel occlusion (LVO) is proven, demonstration of local effectiveness is critical for health system planning and resource allocation because of the complexity and cost of this treatment. METHODS: Using our prospective registry, we identified all patients who underwent EVT for out-of-hospital LVO stroke from February 1, 2013 through January 31, 2017 (n = 44), and matched them 1:1 in a hierarchical fashion with control patients not treated with EVT based on age (±5 years), prehospital functional status, stroke syndrome, severity, and thrombolysis administration. Demographics, in-hospital mortality, discharge disposition from acute care, length of hospitalization, and functional status at discharge from acute care and at follow-up were compared between cases and controls. RESULTS: For EVT-treated patients (median age 66, 50% women), the median onset-to-recanalization interval was 247 min, and successful recanalization was achieved in 30/44 (91%). Alteplase was administered in 75% of cases and 57% of controls (p = 0.07). In-hospital mortality was 11% among the cases and 36% in the control group (p = 0.006); this survival benefit persisted during follow-up (p = 0.014). More EVT patients were discharged home from acute care (50% vs. 18%, p = 0.002). Among survivors, there were nonsignificant trends in favor of EVT for median length of hospitalization (14 vs. 41 days, p = 0.11) and functional independence at follow-up (51% vs. 32%, p = 0.079). CONCLUSION: EVT improved survival and decreased disability. This demonstration of single-center effectiveness may help facilitate expansion of EVT services in similar health-care jurisdictions.

Étude cas-témoin portant sur la thrombectomie endovasculaire dans un centre canadien de prise en charge des AVC. Contexte : Bien qu'on ait prouvé l'efficacité de la thrombectomie endovasculaire dans le cas d'accidents ischémiques cérébraux aigus causés par l'occlusion de grosses artères affectant la circulation antérieure intracrânienne, la démonstration de son efficacité sur le terrain est essentielle à la planification du réseau la santé et à l'allocation des ressources en raison de la complexité de ce traitement et des coûts qui y sont associés. Méthodes : À l'aide d'un registre prospectif, nous avons identifié tous les patients ayant bénéficié (n = 44), du 1er février 2013 au 31 janvier 2017, d'une thrombectomie endovasculaire à la suite d'un AVC survenu en dehors d'un établissement de la santé, AVC causé par l'occlusion de grosses artères. De manière hiérarchique, nous avons fait correspondre nos patients dans un rapport de 1 à 1 à nos témoins non traités par thrombectomie endovasculaire, et ce, en nous basant sur leur âge (± 5 ans), sur leur situation fonctionnelle avant d'être admis, sur les signes cliniques et la gravité de leur AVC, et sur l'administration d'un traitement thrombolytique. Nous avons également comparé leurs caractéristiques démographiques, leur taux de mortalité hospitalière, les modalités d'obtention d'un congé des soins intensifs, la durée de leur hospitalisation et leur situation fonctionnelle au moment de quitter les soins intensifs et à l'occasion d'un suivi. Résultats : Dans le cas de nos patients traités par thrombectomie endovasculaire (âge médian : 66 ans ; 50 % de femmes), l'intervalle médian entre les premiers signes d'un AVC et la recanalisation a été de 247 minutes. Fait à souligner, une recanalisation réussie a été accomplie dans 30 cas sur 44 (91 %). L'altéplase a été administré dans 75 % des cas et chez 57 % des témoins (p = 0,07). En ce qui concerne le taux de mortalité hospitalière, il a été de 11 % parmi tous nos cas et de 36 % chez nos témoins (p = 0,006) ; À noter que cet avantage en termes de survie a persisté au moment des suivis (p = 0,014). Plus de patients traités par thrombectomie endovasculaire ont obtenu leur congé des soins intensifs et sont revenus à la maison (50 % contre 18 % ; p = 0,002). Parmi les survivants à ces AVC, on a noté des tendances non significatives en faveur des patients traités par thrombectomie endovasculaire pour ce qui est de la durée médiane d'hospitalisation (14 jours contre 41 jours ; p = 0,11) et de l'autonomie fonctionnelle au moment des suivis (51 % contre 32 % ; p = 0,079). Conclusion : En somme, la thrombectomie endovasculaire a permis d'améliorer le taux de survie des patients ainsi que leur niveau d'autonomie fonctionnelle. Effectuée dans un seul établissement hospitalier, cette démonstration de l'efficacité de ce traitement pourrait contribuer à faciliter l'essor des traitements de thrombectomie endovasculaire dans d'autres systèmes de santé similaires.

A Cost-Utility Analysis of Endovascular Thrombectomy in a Real-World Setting.

OBJECTIVE: Endovascular thrombectomy (EVT) is efficacious for ischemic stroke caused by proximal intracranial large-vessel occlusion involving the anterior cerebral circulation. However, evidence of its cost-effectiveness, especially in a real-world setting, is limited. We assessed whether EVT ± tissue plasminogen activator (tPA) was cost-effective when compared with standard care ± tPA at our center. METHOD: We identified patients treated with EVT ± tPA after the Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing computed tomography to recanalization times trial from our prospective stroke registry from February 1, 2013 to January 31, 2017. Patients admitted before February 2013 and treated with standard care ± tPA constitute the controls. The sample size was 88. Cost-effectiveness was assessed using the net monetary benefit (NMB). Differences in average costs and quality-adjusted life years (QALYs) were estimated using the augmented inverse probability weighted estimator. We accounted for sampling and methodological uncertainty in sensitivity analyses. RESULTS: Patients treated with EVT ± tPA had a net gain of 2.89 [95% confidence interval (CI): 0.93-4.99] QALYs at an additional cost of $22,200 (95% CI: -28,902-78,244) per patient compared with the standard care ± tPA group. The NMB was $122,300 (95% CI: -4777-253,133) with a 0.85 probability of being cost-effective. The expected savings to the healthcare system would amount to $321,334 per year. CONCLUSION: EVT ± tPA had higher costs and higher QALYs compared with the control, and is likely to be cost-effective at a willingness-to-pay threshold of $50,000 per QALY.

Analyse coût-efficacité de la thrombectomie endovasculaire dans un contexte réel. Objectif : La thrombectomie endovasculaire (TE) est efficace dans le cas d'accidents ischémiques cérébraux (AIC) causés par une occlusion proximale de l'artère cérébrale antérieure. Toutefois, les preuves d'un bon rapport coût-efficacité, particulièrement dans le cadre d'une pratique réelle, demeurent limitées. Nous avons ainsi évalué au sein de notre établissement dans quelle mesure la thrombectomie endovasculaire jumelée à un traitement au moyen d'un activateur tissulaire du plasminogène (t-PA) étaient davantage rentables en comparaison avec des soins usuels également jumelés à un traitement de t-PA. Méthodes : En consultant nos registres prospectifs, nous avons identifié des patients traités par une thrombectomie endovasculaire jumelée à un traitement de t-PA après avoir subi, du 1er février 2013 au 31 janvier 2017, un traitement endovasculaire destiné à un petit AVC central et ischémique à occlusion proximale avec un accent mis sur la minimisation du temps de recanalisation par tomodensitométrie. Les patients hospitalisés avant février 2013 et auxquels des soins usuels avaient été prodigués de concert avec l'administration d'un t-PA ont fait partie de notre groupe témoin. Au total, notre échantillon était formé de 88 patients. Nous avons évalué le rapport coût-efficacité au moyen du concept d'avantage monétaire net (AMN). Nous avons également estimé les différences en ce qui concerne les coûts moyens et l'indicateur QALY (quality-adjusted life years) en faisant appel à un estimateur pondéré par l'inverse de la probabilité inverse (augmented inverse probability weighted estimator). Enfin, nous avons tenu compte de l'incertitude de notre échantillonnage et de nos choix méthodologiques dans nos analyses de sensibilité. Résultats : Les patients traités par thrombectomie endovasculaire et l'administration d'un t-PA ont donné à voir un gain net de 2,89 années selon l'indicateur QALY (IC 95 % : 0,93 ­ 4,99) pour un coût additionnel de 22 200 $ (IC 95 % : −28,902 ­ 78,244) par patient si on les compare à notre groupe témoin. L'AMN s'est quant à lui élevé à 122 300 $ (IC 95 % : −4 777 ­ 253 133), sa probabilité d'être rentable atteignant 0,85. À cet égard, les économies annuelles pour le système de soins de santé pourraient atteindre les 321 334 $. Conclusion : Il appert que la thrombectomie endovasculaire jumelée à un traitement de t-PA entraînent des coûts plus élevés et un meilleur indicateur QALY en comparaison avec notre groupe témoin. Il est probable qu'une telle approche soit rentable en vertu d'un seuil de disposition à payer (willingness-to-pay threshold) avoisinant les 50 000 $ par année selon le QALY.

Clock Drawing Test in acute stroke and its relationship with long-term functional and cognitive outcomes.

Objective: The Clock Drawing Test (CDT) is commonly used as a screening tool for the assessment of dementia. The association between the CDT in acute stroke and long-term functional and cognitive outcomes in this population is unknown. The present prospective study is the first to examine if CDT scores in the acute stage after stroke are related to long-term outcomes and to compare the predictive ability of two scoring systems in a large sample of stroke patients. Method: A total of 340 patients admitted to an acute stroke unit were included in the present study. Separate stepwise multiple linear regression analyses were performed with eight independent variables (demographic/pre-stroke variables - age, sex, premorbid functioning; stroke-related variables - stroke severity, localization; cognitive variables - Orientation Test, CDT [2 scoring systems]), and four dependent variables administered one year post-stroke (Barthel Index, modified Rankin Scale, Reintegration to Normal Living index, Global Deterioration Scale). Results: Although both CDT scoring methods were related to all long-term outcome measures, the more comprehensive scoring system was the only baseline variable that significantly explained the variance in outcome measures in all four multiple regression models. Conclusion: Performance on the CDT in acute stroke is related to long-term outcomes including patients' degree of independence in performing activities of daily living, the degree to which they achieved reintegration into daily occupations, and the degree of cognitive decline observed one-year post-stroke. Future studies are needed to clarify the nature of the relationship between different CDT scoring systems and post-stroke outcomes.

Differences in wake-up and unknown onset stroke examined in a stroke registry.

INTRODUCTION: Debate exists as to whether wake-up stroke (WUS) (i.e. symptoms first noted on waking) differs from stroke developing while awake [awake onset stroke (AOS)]. Unknown onset stroke (UOS) with unclear symptom onset time is infrequently studied. AIMS: This study aimed to examine differences in stroke characteristics and outcomes in these three groups. METHODS: The stroke registry database from Halifax Infirmary, Canada, was interrogated for hospitalised stroke patients between 1999-2011. Information was available on demographics, stroke characteristics, and functional status at discharge and six months (modified Rankin score [mRS]). RESULTS: Of 3890 patients, 65% had AOS, 21% WUS and 14% UOS. UOS patients were significantly older, more commonly female and living alone than AOS patients, with no difference between AOS and WUS. UOS rates increased from 10 to 16% of patients during the study period (P < 0.0001). UOS but not WUS had a higher stroke severity than AOS. Intracerebral hemorrhage was less common (9 vs. 13%) and lacunar stroke more common (23 vs. 19%) in WUS compared to AOS. In UOS left hemisphere location was more likely, and lacunar stroke less common. Excellent outcomes were slightly lower for WUS. UOS had significantly higher rates of in-hospital mortality (23 vs. 16%, P < 0.0001) and poorer functional outcome six months after stroke (mRS < 3 in 26% of UOS and 46% of AOS, P = 0.02). CONCLUSION: WUS has lower rates of ICH but similar stroke severity and outcomes to AOS. UOS prevalence appears to be increasing, with higher stroke severity and worse prognosis.

Fatigue impact scale demonstrates greater fatigue in younger stroke survivors.

BACKGROUND: Fatigue affects 33-77% of stroke survivors. There is no consensus concerning risk factors for fatigue post-stroke, perhaps reflecting the multifaceted nature of fatigue. We characterized post-stroke fatigue using the Fatigue Impact Scale (FIS), a validated questionnaire capturing physical, cognitive, and psychosocial aspects of fatigue. METHODS: The Stroke Outcomes Study (SOS) prospectively enrolled ischemic stroke patients from 2001-2002. Measures collected included basic demographics, pre-morbid function (Oxford Handicap Scale, OHS), stroke severity (Stroke Severity Scale, SSS), stroke subtype (Oxfordshire Community Stroke Project Classification, OCSP), and discharge function (OHS; Barthel Index, BI). An interview was performed at 12 months evaluating function (BI; Modified Rankin Score, mRS), quality of life (Reintegration into Normal living Scale, RNL), depression (Geriatric Depression Scale, GDS), and fatigue (FIS). RESULTS: We enrolled 522 ischemic stroke patients and 228 (57.6%) survivors completed one-year follow-up. In total, 36.8% endorsed fatigue (59.5% rated one of worst post-stroke symptoms). Linear regression demonstrated younger age was associated with increased fatigue frequency (ß=-0.20;p=0.01), duration (ß=-0.22;p<0.01), and disability (ß=-0.24;p<0.01). Younger patients were more likely to describe fatigue as one of the worst symptoms post-stroke (ß=-0.24;p=0.001). Younger patients experienced greater impact on cognitive (ß=-0.27;p<0.05) and psychosocial (ß=-0.27;p<0.05) function due to fatigue. Fatigue was correlated with depressive symptoms and diminished quality of life. Fatigue occurred without depression as 49.0% of respondents with fatigue as one of their worst symptoms did not have an elevated GDS. CONCLUSIONS: Age was the only consistent predictor of fatigue severity at one year. Younger participants experienced increased cognitive and psychosocial fatigue.

Developing predictive models of excellent and devastating outcome after stroke.

BACKGROUND: models to predict functional status post-stroke have utility in balancing groups in randomised trials, for outcome comparison between stroke centres and may assist in outcome prediction. This study aimed to develop models of both excellent [modified Rankin score (mRS) 0-1] and devastating outcomes (mRS of 5-6). METHODS: patients admitted with ischaemic or haemorrhagic stroke in 2001-02 to the Halifax Infirmary, Canada, were enrolled. Sixteen clinical variables from the first neurological assessment and six radiological variables from the acute CT scan were used to the model outcome at 6 months. RESULTS: five hundred and thirty-eight stroke patients were enrolled. Thirty per cent had an excellent outcome and 30% had a devastating outcome. Three models of the excellent outcome were developed [area under the receiver operator curve (AUC) 0.866-882] including the variables age, pre-stroke functional status, stroke severity, ability to lift both arms, walk independently, normal verbal Glasgow Coma Scale and leukoaraiosis. Predictive models of the devastating outcome (AUC of 0.859-0.874) included additional variables living alone pre-stroke and total anterior circulation stroke. The simplest models of both outcomes were externally validated (AUC of 0.856-0.885). CONCLUSION: this study demonstrates new externally validated predictive models of both excellent and devastating outcomes. Leukoaraiosis was the only independent radiological predictor of both outcomes. Living alone pre-stroke predicted devastating outcome post-stroke.

Predicting functional outcome after stroke by modelling baseline clinical and CT variables.

BACKGROUND: we aimed to assess whether the performance of stroke outcome models comprising simple clinical variables could be improved by the addition of more complex clinical variables and information from the first computed tomography (CT) scan. METHODS: 538 consecutive acute ischaemic and haemorrhagic stroke patients were enrolled in a Stroke Outcome Study between 2001 and 2002. Independent survival (modified Rankin scale

Gender differences in stroke examined in a 10-year cohort of patients admitted to a Canadian teaching hospital.

BACKGROUND AND PURPOSE: Studies suggest that women with stroke are investigated less aggressively and receive tissue plasminogen activator less frequently than men. We tested whether gender differences in the investigation, treatment, and outcome of stroke are due to confounding factors. METHODS: Gender differences in the use of investigations, trial enrollment, treatment with intravenous tissue plasminogen activator, and in-hospital outcomes were examined in data from our prospective registry using multivariate analysis to adjust for age, prestroke functional status, stroke subtype and severity, and atrial fibrillation. RESULTS: Of 2725 consecutive hospitalized patients (1996 to 2006), 88% had ischemic stroke and 48% were women. Women were older (median age, 77 versus 70 years), had more severe strokes, and were less likely to be independent prestroke (78% versus 87%) compared with men (all P<0.001). The proportion of women, but not men, aged >or=80 years, increased significantly between 1996 to 1997 and 2005 to 2006. After adjustment for confounding, women were less likely to have infratentorial strokes (OR, 0.78; 95% CI, 0.62 to 0.97), be able to walk unaided on admission (OR, 0.69; 95% CI, 0.54 to 0.87), be treated with tissue plasminogen activator (OR, 0.51; 95% CI, 0.35 to 0.72), experience pneumonia (OR, 0.38; 95% CI, 0.26 to 0.55), achieve a discharge Barthel Index of >or=95 (OR, 0.75; 95% CI, 0.61 to 0.94, and were more likely to experience a urinary tract infection (OR, 2.06; 95% CI, 1.61 to 2.64). There was no gender difference in adjusted use of investigations. CONCLUSIONS: The majority of the gender differences in stroke were explained by confounding. More research is required to understand gender differences in stroke pathophysiology and the utilization of thrombolytic therapy.

Transforming growth factor-beta receptor inhibition enhances adenoviral infectability of carcinoma cells via up-regulation of Coxsackie and Adenovirus Receptor in conjunction with reversal of epithelial-mesenchymal transition.

Expression of the Coxsackie and Adenovirus Receptor (CAR) is frequently reduced in carcinomas, resulting in decreased susceptibility of such tumors to infection with therapeutic adenoviruses. Because CAR participates physiologically in the formation of tight-junction protein complexes, we examined whether molecular mechanisms known to down-regulate cell-cell adhesions cause loss of CAR expression. Transforming growth factor-beta (TGF-beta)-mediated epithelial-mesenchymal transition (EMT) is a phenomenon associated with tumor progression that is characterized by loss of epithelial-type cell-cell adhesion molecules (including E-cadherin and the tight junction protein ZO-1), gain of mesenchymal biochemical markers, such as fibronectin, and acquisition of a spindle cell phenotype. CAR expression is reduced in tumor cells that have undergone EMT in response to TGF-beta. This down-regulation results from repression of CAR gene transcription, whereas altered RNA stability and increased proteasomal protein degradation play no role. Loss of CAR expression in response to TGF-beta is accompanied by reduced susceptibility to adenovirus infection. Indeed, treatment of carcinoma cells with LY2109761, a specific pharmacologic inhibitor of TGF-beta receptor types I and II kinases, resulted in increased CAR RNA and protein levels as well as improved infectability with adenovirus. This was observed in cells induced to undergo EMT by addition of exogenous TGF-beta and in those that were transformed by endogenous autocrine/paracrine TGF-beta. These findings show down-regulation of CAR in the context of EMT and suggest that combination of therapeutic adenoviruses and TGF-beta receptor inhibitors could be an efficient anticancer strategy.

Inhibition of the Raf/MEK/ERK pathway up-regulates expression of the coxsackievirus and adenovirus receptor in cancer cells.

Recombinant adenoviruses are presently being tested clinically as a new strategy for the treatment of cancer. An important determining factor for the successful entry of such adenoviruses into target cells is expression of the coxsackievirus and adenovirus receptor (CAR) at the cell surface. Recent observations suggest that expression of this receptor, which physiologically participates in formation of cell-cell adhesions, is frequently reduced in highly malignant cancer cells. This raises the possibility that those tumors representing the greatest therapeutic challenge might be the least susceptible to infection with therapeutic adenoviruses. We explored the role of the Raf-MEK-ERK pathway on CAR expression in a panel of cancer cells because this pathway is frequently up-regulated in cancer cells and is known to down-regulate cell-cell adhesion molecules. We found that disruption of signaling through the Raf-MEK-ERK pathway by inhibition of MEK up-regulated CAR expression, which was accompanied by increased representation of the protein at the cell surface. After Raf-MEK-ERK inhibition, adenovirus entry into cells was increased and cell killing by replication competent adenoviruses was enhanced in a CAR-dependent manner. Conversely, induction of Raf-1 resulted in reduction and disruption of CAR expression at the cell surface. We conclude that loss of CAR expression in cancer cells is, at least in part, mediated through the Raf-MEK-ERK signal transduction pathway and that pharmacological restoration of CAR at the cell surface could improve adenovirus-based treatments of cancer.