Impact of Strategy on Clinical Outcome in Large Vessel Occlusion Stroke Successfully Reperfused: ETIS Registry Results.

BACKGROUND AND PURPOSE: Approximately half of the patients with acute ischemic stroke due to anterior circulation large vessel occlusion do not achieve functional independence despite successful reperfusion. We aimed to determine influence of reperfusion strategy (bridging therapy, intravenous thrombolysis alone, or mechanical thrombectomy alone) on clinical outcomes in this population. METHODS: From ongoing, prospective, multicenter, observational Endovascular Treatment in Ischemic Stroke registry in France, all patients with anterior circulation large vessel occlusion who achieved successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b-3) following reperfusion therapy were included. Primary end point was favorable outcome, defined as 90-day modified Rankin Scale score ≤2. Patient groups were compared using those treated with bridging therapy as reference. Differences in baseline characteristics were reduced after propensity score-matching, with a maximum absolute standardized difference of 14% for occlusion site. RESULTS: Among 1872 patients included, 970 (51.8%) received bridging therapy, 128 (6.8%) received intravenous thrombolysis alone, and the remaining 774 (41.4%) received MT alone. The rate of favorable outcome was comparable between groups. Excellent outcome (90-day modified Rankin Scale score 0-1) was achieved more frequently in the bridging therapy group compared with the MT alone (odds ratio after propensity score-matching, 0.70 [95% CI, 0.50-0.96]). Regarding safety outcomes, hemorrhagic complications were similar between the groups, but 90-day mortality was significantly higher in the MT alone group compared with the bridging therapy group (odds ratio, 1.60 [95% CI, 1.09-2.37]). CONCLUSIONS: This real-world observational study of patients with anterior circulation large vessel occlusion demonstrated a similar rate of favorable outcome following successful reperfusion with different therapeutic strategies. However, our results suggest that bridging therapy compared with MT alone is significantly associated with excellent clinical outcome and lower mortality. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03776877.

Does Src Kinase Mediated Vasoconstriction Impair Penumbral Reperfusion?

Despite successful recanalization, a significant number of patients with ischemic stroke experience impaired local brain tissue reperfusion with adverse clinical outcome. The cause and mechanism of this multifactorial complication are yet to be understood. At the current moment, major attention is given to dysfunction in blood-brain barrier and capillary blood flow but contribution of exaggerated constriction of cerebral arterioles has also been suggested. In the brain, arterioles significantly contribute to vascular resistance and thus control of perfusion. Accordingly, pathological changes in arteriolar wall function can, therefore, limit sufficient reperfusion in ischemic stroke, but this has not yet received sufficient attention. Although an increased vascular tone after reperfusion has been demonstrated in several studies, the mechanism behind it remains to be characterized. Importantly, the majority of conventional mechanisms controlling vascular contraction failed to explain elevated cerebrovascular tone after reperfusion. We propose here that the Na,K-ATPase-dependent Src kinase activation are the key mechanisms responsible for elevation of cerebrovascular tone after reperfusion. The Na,K-ATPase, which is essential to control intracellular ion homeostasis, also executes numerous signaling functions. Under hypoxic conditions, the Na,K-ATPase is endocytosed from the membrane of vascular smooth muscle cells. This initiates the Src kinase signaling pathway that sensitizes the contractile machinery to intracellular Ca2+ resulting in hypercontractility of vascular smooth muscle cells and, thus, elevated cerebrovascular tone that can contribute to impaired reperfusion after stroke. This mechanism integrates with cerebral edema that was suggested to underlie impaired reperfusion and is further supported by several studies, which are discussed in this article. However, final demonstration of the molecular mechanism behind Src kinase-associated arteriolar hypercontractility in stroke remains to be done.

Filling the gaps on stroke research: Focus on inflammation and immunity.

For the last two decades, researchers have placed hopes in a new era in which a combination of reperfusion and neuroprotection would revolutionize the treatment of stroke. Nevertheless, despite the thousands of papers available in the literature showing positive results in preclinical stroke models, randomized clinical trials have failed to show efficacy. It seems clear now that the existing data obtained in preclinical research have depicted an incomplete picture of stroke pathophysiology. In order to ameliorate bench-to-bed translation, in this review we first describe the main actors on stroke inflammatory and immune responses based on the available preclinical data, highlighting the fact that the link between leukocyte infiltration, lesion volume and neurological outcome remains unclear. We then describe what is known on neuroinflammation and immune responses in stroke patients, and summarize the results of the clinical trials on immunomodulatory drugs. In order to understand the gap between clinical trials and preclinical results on stroke, we discuss in detail the experimental results that served as the basis for the summarized clinical trials on immunomodulatory drugs, focusing on (i) experimental stroke models, (ii) the timing and selection of outcome measuring, (iii) alternative entry routes for leukocytes into the ischemic region, and (iv) factors affecting stroke outcome such as gender differences, ageing, comorbidities like hypertension and diabetes, obesity, tobacco, alcohol consumption and previous infections like Covid-19. We can do better for stroke treatment, especially when targeting inflammation following stroke. We need to re-think the design of stroke experimental setups, notably by (i) using clinically relevant models of stroke, (ii) including both radiological and neurological outcomes, (iii) performing long-term follow-up studies, (iv) conducting large-scale preclinical stroke trials, and (v) including stroke comorbidities in preclinical research.

Reperfusion therapies and poststroke seizures.

Seizures are not only a frequent complication of stroke but have been associated with an unfavorable functional and vital outcome of patients who have had stroke. Facing a new paradigm of acute standard stroke care, acute symptomatic seizures in this clinical setting deserve to be rethought. Reperfusion therapies, the gold standard treatment for acute ischemic stroke, improve long-term survival and outcome of patients who have had stroke and have been associated both with clinical seizures and the occurrence of epileptiform activity in the electroencephalogram (EEG). This narrative review describes the different physiopathological mechanisms underlying the possible association between reperfusion therapies and seizures, both acute symptomatic seizures and unprovoked seizures, and the current evidence regarding the risk of poststroke seizures in treated patients. It also identifies the gaps in our knowledge to foster future studies in this field. By different mechanisms, reperfusions therapies may have opposing effects on the risk of poststroke seizures. There is a need for a better definition of the specific physiopathology of seizures in clinical practice, as many factors can be recognized. Additionally, most of the current clinical evidence refers to acute symptomatic seizures and not to unprovoked seizures or poststroke epilepsy, and our analysis does not support the existence of a strong association between thrombolysis and poststroke seizures. So far, the impact of reperfusion therapies on the frequency of poststroke seizures is unclear. To study this effect, many clinical challenges must be overcome, including a better and clear operational definition of seizures and stroke characteristics, the standard of stroke and epilepsy care and EEG monitoring, and the degree of reperfusion success. Prospective, high quality, larger, and longer follow-up multicentric studies are urgently needed. Additionally, stroke registries can also prove useful in better elucidate whether there is an association between reperfusion therapies and seizures. This article is part of the Special Issue "Seizures & Stroke".

Incidence of early poststroke seizures during reperfusion therapies in patients with acute ischemic stroke: An observational prospective study: (TESI study: "Trombolisi/Trombectomia e crisi Epilettiche precoci nello Stroke Ischemico").

INTRODUCTION: The aim of this study was to prospectively investigate the occurrence of early poststroke seizures (within 7 days of stroke) in patients undergoing reperfusion therapies (intravenous rtPA [recombinant tissue plasminogen activator] and/or endovascular thrombectomy) in comparison to those not undergoing these procedures. METHODS: Patients aged ≥18 years with acute ischemic stroke admitted in five Italian centers were prospectively recruited. Clinical data, details on stroke type and etiology, stroke treatment, and radiological data were collected. The frequency of early poststroke seizures was assessed, and predictive factors for their occurrence were evaluated. RESULTS: Five hundred and sixteen patients (262 in the reperfusion therapies group) were included. Stroke severity on admission and at discharge was higher among patients undergoing reperfusion therapies. Ten patients (3.8%) undergoing reperfusion therapies and 6 (2.3%) of those not receiving these treatments experienced early poststroke seizures (p = 0.45). There were no differences in any of the baseline characteristics between patients experiencing and those not experiencing early seizures. CONCLUSION: The incidence of early poststroke seizures was overall rare, and no significant differences emerged between patients receiving and those not receiving reperfusion therapies. This article is part of the Special Issue "Seizures and Stroke".

Exploring Reperfusion Following Endovascular Thrombectomy.

Background and Purpose- Cerebral perfusion in acute ischemic stroke patients is often assessed before endovascular thrombectomy (EVT), but rarely after. Perfusion data obtained following EVT may provide additional prognostic information. We developed a tool to quantitatively derive perfusion measurements from digital subtraction angiography (DSA) data and examined perfusion in patients following EVT. Methods- Source DSA images from acute anterior circulation stroke patients undergoing EVT were retrospectively assessed. Following deconvolution, maps of mean transit time (MTT) were generated from post-EVT DSA source data. Thrombolysis in Cerebral Infarction grades and MTT in patients with and without hemorrhagic transformation (HT) at 24 hours were compared. Receiver operating characteristic modeling was used to classify the presence/absence of HT at 24 hours by MTT. Results- Perfusion maps were generated in 50 patients using DSA acquisitions that were a median (interquartile range) of 9 (8-10) seconds in duration. The median post-EVT MTT within the affected territory was 2.6 (2.2-3.3) seconds. HT was observed on follow-up computed tomography in 16 (32%) patients. Thrombolysis in Cerebral Infarction grades did not differ in patients with HT from those without (P=0.575). Post-EVT MTT maps demonstrated focal areas of hyperperfusion (n=8) or persisting hypoperfusion (n=3) corresponding to the regions where HT later developed. The relationship between MTT and HT was U-shaped; HT occurred in patients at both the lowest and highest extremes of MTT. An MTT threshold <2 or >4 seconds was 81% sensitive and 94% specific for classifying the presence of HT at follow-up. Conclusions- Perfusion measurements can be obtained using DSA perfusion with minimal changes to current stroke protocols. Perfusion imaging post-recanalization may have additional clinical utility beyond visual assessment of source angiographic images alone.

Rates and Quality of Preinterventional Reperfusion in Patients With Direct Access to Endovascular Treatment.

Background and Purpose- Preinterventional reperfusion before endovascular treatment (ET) is a benefit of bridging with intravenous tPA (tissue-type plasminogen activator). However, detailed data on reperfusion quality and rates of obviating ET in a cohort of patients with immediate access to ET is lacking. Purpose of this analysis was to evaluate prevalence and quality of preinterventional reperfusion in mothership patients. Methods- All mothership patients (n=627) from a prospective registry subjected to angiography with an intention to perform ET were reviewed. Preinterventional change of occlusion site (COS) was categorized into COS with Thrombolysis in Cerebral Infarction (TICI) 0/1, COS with TICI ≥2a, COS with TICI ≥2b, and COS with perfusion worsening. Predictors and clinical relevance were evaluated using multivariable logistic regression and results are displayed as adjusted odds ratios (aOR) and corresponding 95% confidence intervals (95% CI). Results- Prevalence of COS in all patients was 10.7% (95% CI, 8.3%-13.1%), subdividing into 2.7% COS with TICI 0/1, 6.2% COS with ≥TICI 2a (including 2.9% with TICI ≥2b), and 1.8% COS with perfusion worsening. Factors related to COS with ≥TICI 2a were intravenous tPA (aOR, 11.98; 95% CI, 4.5-31.6), cardiogenic thrombus origin (aOR, 2.3; 95% CI, 1.1-4.6), and thrombus length (aOR per 1 mm increase 0.926; 95% CI, 0.87-0.99). Additional ET was performed despite COS with ≥TICI 2a in 51.3%. COS with ≥TICI 2a showed a tendency for favorable outcomes (modified Rankin Scale, ≤2; aOR, 2.65; 95% CI, 0.98-7.17). Rates of COS with ≥TICI 2a were particularly low in internal carotid artery and proximal M1 occlusions (2.2%; 95% CI, 0.9%-5%), where intravenous tPA was associated with perfusion worsening (aOR, 4.33; 95% CI, 1.12-16.80). Conclusions- Prevalence of preinterventional reperfusion is non-negligible in patients with direct access to ET and is clearly favored by intravenous tPA treatment. However, it is often incomplete and often requires additional ET. Preinterventional reperfusion of internal carotid artery and proximal M1 occlusions is rare and usually of low quality, where intravenous tPA may also promote perfusion worsening.

Ischemic core thresholds change with time to reperfusion: A case control study.

INTRODUCTION: We aimed to identify whether acute ischemic stroke patients with known complete reperfusion after thrombectomy had the same baseline computed tomography perfusion (CTP) ischemic core threshold to predict infarction as thrombolysis patients with complete reperfusion. METHODS: Patients who underwent thrombectomy were matched by age, clinical severity, occlusion location, and baseline perfusion lesion volume to patients who were treated with intravenous alteplase alone from the International Stroke Perfusion Imaging Registry. A pixel-based analysis of coregistered pretreatment CTP and 24-hour diffusion-weighted imaging (DWI) was then undertaken to define the optimum CTP thresholds for the ischemic core. RESULTS: There were 132 eligible thrombectomy patients and 132 matched controls treated with alteplase alone. Baseline National Institutes of Health Stroke Scale (median, 15; interquartile range [IQR], 11-19), age (median, 65; IQR, 59-80), and time to intravenous treatment (median, 153 minutes; IQR, 82-315) were well matched (all p > 0.05). Despite similar baseline CTP ischemic core volumes using the previously validated measure (relative cerebral blood flow [rCBF], <30%), thrombectomy patients had a smaller median 24-hour infarct core of 17.3ml (IQR, 11.3-32.8) versus 24.3ml (IQR, 16.7-42.2; p = 0.011) in alteplase-treated controls. As a result, the optimal threshold to define the ischemic core in thrombectomy patients was rCBF <20% (area under the curve [AUC], 0.89; 95% CI, 0.84, 0.94), whereas in alteplase controls the optimal ischemic core threshold remained rCBF <30% (AUC, 0.83; 95% CI, 0.77, 0.85). INTERPRETATION: Thrombectomy salvaged tissue with lower CBF, likely attributed to earlier reperfusion. For patients who achieve rapid reperfusion, a stricter rCBF threshold to estimate the ischemic core should be considered. Ann Neurol 2017;82:995-1003.

Early Trajectory of Stroke Severity Predicts Long-Term Functional Outcomes in Ischemic Stroke Subjects: Results From the ESCAPE Trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times).

BACKGROUND AND PURPOSE: The trajectory of neurological improvement after stroke treatment is clinically likely to be an important prognostic signal. We compared the accuracy of early longitudinal National Institutes of Health Stroke Scale (NIHSS) measurement versus other early markers of stroke severity post treatment in predicting subjects' 90-day stroke outcome. METHODS: Data are from the Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times). Stroke severity was assessed at baseline, 1, 2, 5, 30, and 90 days. Subjects' functional outcome was assessed using the modified Rankin Scale at baseline, 30 days, and 90 days. Group-based trajectory model was used to identify distinct subgroups of longitudinal trajectories of NIHSS measured over the first 2, 5, and 30 days. The accuracy of baseline NIHSS, infarct volume, 24-hour change in NIHSS, infarct volume, and disease severity trajectory subgroups in predicting 90-day stroke outcome were assessed using logistic regression analysis. RESULTS: Group-based trajectory model of the 2-day longitudinal NIHSS data revealed 3 distinct subgroups of NIHSS trajectories-large improvement (41.6%), minimal improvement (31.1%), and no improvement (27.3%) subgroups. Individuals in the large improvement group were more likely were more likely to exhibit good outcomes after 90 days than those in the minimal improvement or no improvement subgroup. Among candidate predictors, the 2-day trajectory subgroup variable was the most accurate in predicting 90-day modified Rankin Scale at 84.5%. CONCLUSIONS: Early trajectory of neurological improvement defined by 2-day longitudinal NIHSS data predicts functional outcomes with greater accuracy than other common variables. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01778335.

Regional Pediatric Acute Stroke Protocol: Initial Experience During 3 Years and 13 Recanalization Treatments in Children.

BACKGROUND AND PURPOSE: To evaluate hyperacute management of pediatric arterial ischemic stroke, setting up dedicated management pathways is the first recommended step to prove the feasibility and safety of such treatments. A regional pediatric stroke alert protocol including 2 centers in the Paris-Ile-de-France area, France, was established. METHODS: Consecutive pediatric patients (28 days-18 years) with confirmed arterial ischemic stroke who had acute recanalization treatment (intravenous r-tPA [recombinant tissue-type plasminogen activator], endovascular procedure, or both) according to the regional pediatric stroke alert were retrospectively reviewed during a 40-month period. RESULTS: Thirteen children, aged 3.7 to 16.6 years, had recanalization treatment. Median time from onset to magnetic resonance imaging was 165 minutes (150-300); 9 out of 13 had large-vessel occlusion. Intravenous r-tPA was used in 11 out of 13 patients, with median time from onset to treatment of 240 minutes (178-270). Endovascular procedure was performed in patients time-out for intravenous r-tPA (n=2) or after intravenous r-tPA inefficiency (n=2). No intracranial or peripheral bleeding was reported. One patient died of malignant stroke; outcome was favorable in 11 out of 12 survivors (modified Rankin Scale score 0-2). CONCLUSIONS: Hyperacute recanalization treatment in pediatric stroke, relying on common protocols and adult/pediatric ward collaboration, is feasible. Larger systematic case collection is encouraged.

Impact of Glucose on Outcomes in Patients Treated With Mechanical Thrombectomy: A Post Hoc Analysis of the Solitaire Flow Restoration With the Intention for Thrombectomy Study.

BACKGROUND AND PURPOSE: Sparse data are available regarding the association between hyperglycemia and outcomes in acute ischemic stroke patients receiving mechanical thrombectomy (MT). We investigated whether hyperglycemia affected the outcomes of subjects treated with MT in the Solitaire Flow Restoration With the Intention for Thrombectomy (SWIFT) multicenter randomized trial, overall and according to reperfusion status after MT. METHODS: We analyzed the relationships between the presenting glucose level as a continuous variable and presenting hyperglycemia (>140 mg/dL glucose) as a binary variable and several outcomes of interest. Subjects were stratified according to the completeness of reperfusion (Thrombolysis In Myocardial Ischemia scale 3 versus 0-2) after MT. Excellent outcome at 3 months was defined as a modified Rankin scale score of 0-1. RESULTS: Among all patients undergoing MT, patients with hyperglycemia less frequently exhibited an excellent outcome at 3 months than patients without hyperglycemia, 13% versus 34%; P=0.01. Presenting glucose levels did not differ among patients achieving complete reperfusion and incomplete reperfusion. Among patients with incomplete reperfusion, after adjustment for covariates, higher glucose levels were independently associated with worse outcome at 3 months (per 10 mg/dL increase in glucose: odds ratio for modified Rankin scale score 0-1 at 3 months 0.58, 95% confidence interval 0.34-0.99; P=0.047). In contrast, among patients with complete reperfusion, differences in presenting glucose levels by final outcome did not reach statistical significance. CONCLUSIONS: In patients treated with MT, hyperglycemia was independently associated with worse outcome at 3 months, and the negative effects of hyperglycemia may have been exacerbated in patients with incomplete reperfusion after MT. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01054560.

Large Volumes of Critically Hypoperfused Penumbral Tissue Do Not Preclude Good Outcomes After Complete Endovascular Reperfusion: Redefining Malignant Profile.

BACKGROUND AND PURPOSE: Acute ischemic stroke patients with large volumes of severe hypoperfusion (Tmax>10 s>100 mL) on magnetic resonance imaging have a higher likelihood of intracranial hemorrhage and poor outcomes after reperfusion. We aim to evaluate the impact of the extent of Tmax>10 s CTP lesions in patients undergoing successful treatment. METHODS: Retrospective database review of endovascular acute ischemic stroke treatment between September 2010 and March 2015 for patients with anterior circulation occlusions with baseline RAPID CTP and full reperfusion (mTICI 3). The primary outcome was the impact of the Tmax>10 s lesion spectrum on infarct growth. Secondary safety and efficacy outcomes included parenchymal hematomas and good clinical outcomes (90-day modified Rankin Scale score, 0-2). RESULTS: Of 684 treated patients, 113 patients fit the inclusion criteria. Tmax>10 s>100 mL patients (n=37) had significantly higher baseline National Institutes of Health Stroke Scale (20.7±3.8 versus 17.0±5.9; P<0.01), more internal carotid artery terminus occlusions (29% versus 9%; P=0.02), and larger baseline (38.6±29.6 versus 11.7±15.8 mL; P<0.01) and final (60.7±60.0 versus 29.4±33.9 mL; P<0.01) infarct volumes when compared with patients without Tmax>10 s>100 mL (n=76); however, the 2 groups were otherwise well balanced. There were no significant differences in infarct growth (22.1±51.6 versus 17.8±32.4 mL; P=0.78), severe intracranial hemorrhage (PH2: 2% versus 4%; P=0.73), good outcomes (90-day mRS score, 0-2: 56% versus 59%; P=0.83), or 90-day mortality (16% versus 7%; P=0.28). On multivariate analysis, only baseline National Institutes of Health Stroke Scale (odds ratio, 1.19; 95% confidence interval, 1.06-1.34; P<0.01) and baseline infarct core volume (odds ratio, 1.05; 95% confidence interval, 1.02-1.08; P<0.01) were independently associated with Tmax>10 s>100 mL. There was no association between Tmax>10 s>100 mL with any PH, good outcome, or infarct growth. CONCLUSIONS: In the setting of limited baseline ischemic cores, large Tmax>10 s lesions on computed tomographic perfusion do not seem to be associated with a higher risk of parenchymal hematomas and do not preclude good outcomes in patients undergoing endovascular reperfusion with contemporary technology.

Reperfusion Beyond 6 Hours Reduces Infarct Probability in Moderately Ischemic Brain Tissue.

BACKGROUND AND PURPOSE: We aimed to examine perfusion changes between 3 and 6 and 6 and 24 hours after stroke onset and their impact on tissue outcome. METHODS: Acute ischemic stroke patients underwent perfusion magnetic resonance imaging at 3, 6, and 24 hours after stroke onset and follow-up fluid-attenuated inversion recovery at 1 month to assess tissue fate. Mean transit time prolongation maps (MTTp=MTT-[median MTT of contralateral hemisphere]) were obtained at 3 (MTTp3 h), 6 (MTTp6 h), and 24 hours (MTTp24 h). Perfusion changes between 3 and 6 hours (ΔMTTp3_6) and 6 and 24 hours (ΔMTTp6_24) were calculated. A 2-step analysis was performed to evaluate the impact of ΔMTTp3_6 and ΔMTTp6_24 on tissue fate. First, a voxel-based multivariable logistic regression was performed for each individual patient with MTTp3 h, ΔMTTp3_6, and ΔMTT6_24 as independent variables and tissue fate as outcome. Second, Wilcoxon signed-rank tests on logistic regression coefficients were performed across patients to evaluate whether ΔMTTp3_6 and ΔMTT6_24 had significant impact on tissue fate for varying severities of baseline perfusion. RESULTS: Perfusion change was common during both time periods: 85% and 81% of patients had perfusion improvement during 3- to 6- and 6- and 24-hour time intervals, respectively. ΔMTT3_6 significantly influenced 1-month infarct probability across a wide range of baseline perfusion (MTTp 0-15 s). ΔMTT6_24 also impacted 1-month infarct probability, but its influence was restricted to tissue with milder baseline ischemia (MTTp 0-10 s). CONCLUSIONS: Brain tissue with mild to moderate ischemia can be salvaged by reperfusion even after 6 hours. Such tissue could be targeted for intervention beyond current treatment windows.

Time to endovascular reperfusion and degree of disability in acute stroke.

OBJECTIVE: Faster time from onset to recanalization (OTR) in acute ischemic stroke using endovascular therapy (ET) has been associated with better outcome. However, previous studies were based on less-effective first-generation devices, and analyzed only dichotomized disability outcomes, which may underestimate the full effect of treatment. METHODS: In the combined databases of the SWIFT and STAR trials, we identified patients treated with the Solitaire stent retriever with achievement of substantial reperfusion (Thrombolysis in Cerebral Infarction [TICI] 2b-3). Ordinal numbers needed to treat values were derived by populating joint outcome tables. RESULTS: Among 202 patients treated with ET with TICI 2b to 3 reperfusion, mean age was 68 (±13), 62% were female, and median National Institutes of Health Stroke Scale (NIHSS) score was 17 (interquartile range [IQR]: 14-20). Day 90 modified Rankin Scale (mRS) outcomes for OTR time intervals ranging from 180 to 480 minutes showed substantial time-related reductions in disability across the entire outcome range. Shorter OTR was associated with improved mean 90-day mRS (1.4 vs. 2.4 vs. 3.3, for OTR groups of 124-240 vs. 241-360 vs. 361-660 minutes; p < 0.001). The number of patients identified as benefitting from therapy with shorter OTR were 3-fold (range, 1.5-4.7) higher on ordinal, compared with dichotomized analysis. For every 15-minute acceleration of OTR, 34 per 1,000 treated patients had improved disability outcome. INTERPRETATION: Analysis of disability over the entire outcome range demonstrates a marked effect of shorter time to reperfusion upon improved clinical outcome, substantially higher than binary metrics. For every 5-minute delay in endovascular reperfusion, 1 of 100 patients has a worse disability outcome.

Poor Collateral Circulation Assessed by Multiphase Computed Tomographic Angiography Predicts Malignant Middle Cerebral Artery Evolution After Reperfusion Therapies.

BACKGROUND AND PURPOSE: Collateral circulation (CC) has been associated with recanalization, infarct volume, and clinical outcome in patients undergoing acute reperfusion therapies. However, its relationship with the development to malignant middle cerebral artery infarction (mMCAi) has not been evaluated. Our aim was to determine the impact of CC using multiphase computed tomographic angiography (during the acute stroke phase in the prediction of mMCAi. METHODS: Patients with consecutive acute stroke with <4.5 hours who were evaluated for reperfusion therapies and presented with an M1-MCA or terminal internal carotid artery occlusion by CTA were included. CC was evaluated on 6 grades by multiphase CTA according to the University of Calgary CC Scale; CC status was defined as poor (grades, 0-3) or good (grades, 4-5). The mMCAi was defined according to clinical and radiological criteria. Recanalization was assessed with transcranial Doppler at 24 hours and final Thrombolysis in Brain Ischemia score≥2b in patients undergoing endovascular reperfusion treatment. RESULTS: Eighty-two patients were included. Mean age was 65.1±13.83 years, median baseline National Institutes of Health Stroke Scale score was 18 (interquartile range, 13-20), and 67.9% M1 and 32.1% terminal internal carotid artery occlusions. Fifty-three patients received endovascular reperfusion treatment. Fifteen patients developed mMCAi. In the univariate analysis, patients with mMCAi had lower CC scores (2.29 versus 3.71; P=0.001). Endovascular reperfusion treatment was associated with lower rate of mMCAi development than only intravenous reperfusion treatment (9.4% versus 29.6%; P=0.028). Patients with poor CC had higher risk of developing mMCAi (13% versus 2%; P=0.001). On the multivariate analysis adjusted by age, vessel occlusion, baseline National Institutes of Health Stroke Scale, and recanalization, the presence of poor CC by multiphase CTA was the only independent predictor of mMCAi (P=0.048; odds ratio, 9.72; 95% confidence interval, 1.387-92.53). CONCLUSIONS: CC assessment by multiphase CTA independently predicts malignant MCA infarction progression. In patients with persistent occlusion after reperfusion therapies, the presence of poor CC may improve the early mMCAi detection and management.

Acute stroke reperfusion therapy trends in the expanded treatment window era.

BACKGROUND: The American Heart Association/American Stroke Association (AHA/ASA) recommended an expansion of the time window for acute ischemic stroke (AIS) reperfusion with intravenous (IV) recombinant tissue plasminogen activator (rt-PA) from 3 to 4.5 hours after symptom onset. We examine rates of IV and intra-arterial (IA) reperfusion before and after the recommendations to track guideline adoption in community practice. METHODS: Patients with AIS in the Paul Coverdell National Acute Stroke Registry spanning years 2007-2012 were identified. Trends in rates of IV rt-PA versus IA therapy were examined. Outcomes included symptomatic intracerebral hemorrhage (sICH), in-hospital mortality, ability to ambulate at discharge, and discharge destination. RESULTS: From 2007 to 2012, there were 182,235 AIS patients (median age, 72 years; 51.5% women) in the database at the time of analysis. AIS patients receiving IV rt-PA increased significantly from 3.7% in 2007 to 5.1% in 2012 in the ≤3 hours time window and from .2% in 2007 to 1.3% in 2012 in the 3-4.5 hours time window (P < .001 for both). There was also a significant increase in the rate of IA therapy between 2007 and 2012 (P < .001). There was a significant decrease in the rate of sICH among patients who received any reperfusion between 2007 and 2012. CONCLUSIONS: There was a trend for increased utilization of IV rt-PA in the 0-3 hours and the 3-4.5 hours time windows, which began around the same time as the publication of AHA/ASA recommendations in 2009. This increase was associated with an increase in IA treatment rates along with a decrease in overall sICH rates for patients receiving any reperfusion.

Smoking-thrombolysis paradox: recanalization and reperfusion rates after intravenous tissue plasminogen activator in smokers with ischemic stroke.

BACKGROUND AND PURPOSE: The so-called smoking-thrombolysis paradox of an improved outcome after thrombolysis was first described in smokers with myocardial infarction. We investigated whether reperfusion rates and clinical outcome differ between smokers and nonsmokers with ischemic stroke after intravenous tissue plasminogen activator. METHODS: Consecutive acute ischemic stroke patients, who had magnetic resonance imaging before and 1 day after thrombolysis, were included for analysis. All of the patients received intravenous tissue plasminogen activator within 4.5 hours. Reperfusion was defined as a 75% reduction in perfusion deficit (mean transit time >6 s) after thrombolysis compared with baseline. Magnetic resonance angiography was used to evaluate arterial stenosis and occlusion. Functional outcome was assessed 3 months after stroke using the modified Rankin Score. RESULTS: Of 148 patients, 21.6% were smokers (n=32). Smokers were younger (median, 61 years [SD, 9.4 years] versus 75 years [SD, 11.6 years]; P<0.001), less often women (28% versus 51%; P=0.03), had lower baseline glucose levels (median, 6.2 mmol/L [interquartile range, 5.7-6.8 mmol/L] versus 6.7 mmol/L [interquartile range, 6.1-8.2 mmol/L]; P<0.01) and higher baseline perfusion deficits (median, 53 mL [interquartile range, 13-141 mL] versus 17 mL [interquartile range, 2-66 mL]; P=0.04). In a backward stepwise regression analysis including age, sex, hypertension, glucose, perfusion deficit, and smoking, smoking had an odds ratio of 4 (95% confidence interval, 1-16; P=0.03) for reperfusion and 6 (95% confidence interval, 1-30; P=0.05) for recanalization (regression analysis for recanalization also included localization of arterial occlusion). Smokers had a better outcome (modified Rankin Score=0-2) than nonsmokers (77% versus 55%; P=0.05). CONCLUSIONS: Smoking is independently associated with recanalization and reperfusion, indicating that thrombolytic therapy acts more effectively in smokers; because of small numbers, these results should be considered preliminary. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique Identifier: NCT00715533.

Trends and outcomes after surgical lower limb revascularization in England.

BACKGROUND: The aim was to analyse contemporary data on the number of surgical revascularization procedures performed each year in England, and their outcome. METHODS: Hospital Episode Statistics and Office for National Statistics data were used to quantify numbers and identify factors associated with outcome after all femoropopliteal and femorodistal bypass procedures performed between 2002 and 2006. Outcome measures were repeat bypass, major amputation, death and a composite measure. Single-level multivariable logistic regression modelling was used to quantify the effect of these variables on outcome. RESULTS: A total of 21,675 femoropopliteal and 3458 femorodistal bypass procedures were performed. Mean in-hospital mortality rates were 6·7 and 8·0 per cent respectively. One-year survival rates were 82·8 and 79·1 per cent; both increased over the study interval. The mean 1-year major amputation rate after femoropopliteal bypass was 10·4 per cent, which decreased significantly over the 5 years (P < 0·001); after distal bypass the rate of 20·8 per cent remained unchanged (P = 0·456). Diabetes mellitus and chronic kidney disease were significant predictors of adverse outcome for both procedures: odds ratio (OR) at 1 year 1·56 (95 per cent confidence interval 1·46 to 1·67; P < 0·001) and 2·15 (1·88 to 2·45; P < 0·001) respectively for femoropopliteal bypass. Previous femoral angioplasty was associated with an increased rate of major amputation 1 year after proximal bypass (OR 1·18, 1·05 to 1·33; P = 0·004). CONCLUSION: Although all mortality rates are improving, the major amputation rate remains high after femorodistal bypass. Adverse events occurred after 37·6 per cent of femoropopliteal and 49·7 per cent of femorodistal bypasses; diabetes and chronic renal failure were the main predictors of poor outcome.