Comparison of functional and safety outcomes between the extended versus early time window after intravenous thrombolysis and endovascular thrombectomy.

INTRODUCTION: Based on recent trials regarding the early time window, omitting intravenous thrombolysis (IVT) before endovascular thrombectomy (EVT) in eligible patients seems unjustified. Whether this also concerns the extended time window, 4.5 to 9 h from last seen well, is yet unclear. PATIENTS AND METHODS: All consecutive patients treated with IVT, EVT, or IVT plus EVT in the extended time window at Helsinki University Hospital (HUS) between 1/2021 and 12/2022 were compared with matched controls treated in the early time window between 1/2016 and 12/2020. Regression analysis was applied on functional outcome at 90 days, evaluated on modified Rankin Scale (mRS), and on the occurrence of symptomatic intracerebral hemorrhage (sICH), adjusted for potential confounders. RESULTS: Altogether 134 patients and 134 matching controls were included. Functional outcomes did not significantly differ between the extended versus early time window. Among patients with IVT plus EVT, the adjusted odds ratio (aOR) for a favorable outcome shift on mRS was 1.15, 95% confidence interval (CI) 0.54-2.43. Although sICH occurred more frequently (2.2% versus 3.0%) in the extended time window, regression analysis did not show a significant difference, aOR 0.96, 95% CI 0.14-6.87. DISCUSSION AND CONCLUSION: We found no significant differences in the functional or safety outcomes between the extended versus early time window among patients with either IVT, EVT, or IVT plus EVT. There were no signals indicating, that IVT or EVT should be avoided in eligible patients in the extended time window which aligns with the current clinical treatment guidelines of HUS.

Safety and clinical outcomes of endovascular therapy versus medical management in late presentation of large ischemic stroke.

INTRODUCTION: The benefit of endovascular therapy (EVT) among stroke patients with large ischemic core (ASPECTS 0-5) in the extended time window outside of trial settings remains unclear. We analyzed the effect of EVT among these stroke patients in real-world settings. PATIENTS AND METHODS: The CT for Late Endovascular Reperfusion (CLEAR) study recruited patients from 66 centers in 10 countries between 01/2014 and 05/2022. The extended time-window was defined as 6-24 h from last-seen-well to treatment. The primary outcome was shift of the 3-month modified Rankin scale (mRS) score. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and mortality. Outcomes were analyzed with ordinal and logistic regressions. RESULTS: Among 5098 screened patients, 2451 were included in the analysis (median age 73, 55% women). Of patients with ASPECTS 0-5 (n = 310), receiving EVT (n = 209/310) was associated with lower 3-month mRS when compared to medical management (median 4 IQR 3-6 vs 6 IQR 4-6; aOR 0.4, 95% CI 0.2-0.7). Patients undergoing EVT had higher sICH (11.2% vs 4.0%; aOR 4.1, 95% CI 1.2-18.8) and lower mortality (31.6% vs 58.4%, aOR 0.4; 95% CI 0.2-0.9) compared to medically managed patients. The relative benefit of EVT was comparable between patients with ASPECTS 0 and 5 and 6-10 in the extended time window (interaction aOR 0.9; 95% CI 0.5-1.7). CONCLUSION: In the extended time window, patients with ASPECTS 0-5 may have preserved relative treatment benefit of EVT compared to patients with ASPECTS 6-10. These findings are in line with recent trials showing benefit of EVT among real-world patients with large ischemic core in the extended time window. TRIAL REGISTRATION NUMBER: clinicaltrials.gov; Unique identifier: NCT04096248.

Tenecteplase for the treatment of acute ischemic stroke in the extended time window: a systematic review and meta-analysis.

Background: Outcome data regarding the administration of tenecteplase (TNK) to acute ischemic stroke (AIS) patients presenting in the extended time window are limited. Objectives: We aimed to assess the current evidence regarding the efficacy and safety of TNK at a dose of 0.25 mg/kg for AIS treatment in the extended time window. Design: A systematic review and meta-analysis was conducted including all available randomized-controlled clinical trials (RCTs) that compared TNK 0.25 mg/kg versus no thrombolysis in AIS patients presenting in the extended time window (>4.5 h after last-seen-well or witnessed onset). Data sources and methods: Eligible studies were identified by searching Medline, Scopus, and international conference abstracts. The predefined efficacy outcomes of interest were 3-month excellent functional outcome [defined as the modified Rankin Scale (mRS) score ⩽1; primary outcome], 3-month good functional outcome (mRS ⩽ 2), 3-month reduced disability (⩾1-point reduction across all mRS scores). We determined symptomatic intracranial hemorrhage (sICH), any ICH and 3-month mortality as safety endpoints. A random-effects model was used to calculate risk ratios (RRs) and common odds ratios (cORs) with corresponding 95% confidence intervals (CIs). Results: Three RCTs were included comprising 556 patients treated with TNK versus 560 controls. TNK 0.25 mg/kg was associated with a higher likelihood of 3-month excellent functional outcome compared to controls (RR = 1.17; 95% CI = 1.01-1.36; I2 = 0%), whereas there was no difference regarding good functional outcome (RR = 1.05; 95% CI = 0.94-1.17; I2 = 0%) and reduced disability (adjusted cOR = 1.14; 95% CI = 0.92-1.40; I2 = 0%) at 3 months. The risks of sICH (RR = 1.67; 95% CI = 0.70-4.00; I2 = 0%), any ICH (RR = 1.08; 95% CI = 0.90-1.29; I2 = 0%) and 3-month mortality (RR = 1.10; 95% CI = 0.81-1.49; I2 = 0%) were similar between the groups. Conclusion: Based on data from three RCTs showing increased efficacy and a favorable safety profile of TNK in the treatment of AIS in the extended time window, continuing efforts of ongoing RCTs in the field are clearly supported. Trial registration: PROSPERO registration ID: CRD42023448707.

Noncontrast versus perfusion CT to select endovascular therapy in an extended time window: Systematic review/meta-analysis.

BACKGROUND AND PURPOSE: The effect of noncontrast CT (NCCT) on the eligibility for endovascular therapy (EVT) in an extended time window remains to be elucidated. We sought to assess the efficacy and safety of NCCT in comparison with CT perfusion (CTP) in selecting patients with acute ischemic stroke (AIS) for EVT 6-24 hours after onset. METHODS: PubMed, Embase, and Cochrane libraries were searched from inception to August 31, 2022, to identify all studies reporting 90-day outcomes of EVT in patients with AIS in an extended time window. A meta-analysis was performed for the pooled risk ratio (RR) with 95% confidence interval (CI) using a random-effects model. The primary outcome used to assess efficacy was good functional independence, defined as a modified Rankin Scale score of 0-2 at 90 days. Secondary outcomes included successful reperfusion, symptomatic intracranial hemorrhage (sICH), and mortality at 90 days. RESULTS: We included four nonrandomized studies with a total of 2685 patients. The outcomes of good functional independence at 90 days (RR = 0.98; 95% CI: 0.88-1.07; I2  = 0%; p = .62), successful reperfusion (RR = 0.98; 95% CI: 0.93-1.03; I2  = 50.5%; p = .11), sICH (RR = 1.11; 95% CI: 0.55-2.21; I2  = 49.4%; p = .12), or mortality at 90 days (RR = 1.18; 95% CI: 0.99-1.40; I2  = 0%; p = .42) did not differ significantly between the two groups. CONCLUSIONS: These findings suggest that NCCT is as effective as CTP in selecting patients for EVT in an extended time window.

Low-dose vs. standard-dose intravenous alteplase for acute ischemic stroke with unknown time of onset.

Background: Standard-dose intravenous alteplase for acute ischemic stroke (AIS) in the unknown or extended time window beyond 4.5 h after symptom onset is both effective and safe for certain patients who were selected based on multimodal neuroimaging. However, uncertainty exists regarding the potential benefit of using low-dose alteplase among the Asian population outside the 4.5-h time window. Methods: Consecutive AIS patients who received intravenous alteplase between 4.5 and 9 h after symptom onset or with an unknown time of onset guided by multimodal computed tomography (CT) imaging were identified from our prospectively maintained database. The primary outcome was excellent functional recovery, defined as having a modified Rankin scale (mRS) score of 0-1 at 90 days. Secondary outcomes included functional independence (an mRS score of 0-2 at 90 days), early major neurologic improvement (ENI), early neurologic deterioration (END), any intracranial hemorrhage (ICH), symptomatic ICH (sICH), and 90-day mortality. Propensity score matching (PSM) and multivariable logistic regression models were used to adjust for confounding factors and compare the clinical outcomes between the low- and standard-dose groups. Results: From June 2019 to June 2022, a total of 206 patients were included in the final analysis, of which 143 were treated with low-dose alteplase and 63 were treated with standard-dose alteplase. After accounting for confounding factors, we observed that there were no statistically significant differences between the standard- and low-dose groups with respect to excellent functional recovery [adjusted odds ratio = 1.22 (aOR), 95% confidence interval (CI): 0.62-2.39; adjusted rate difference (aRD) = 4.6%, and 95% CI: -11.2 to 20.3%]. Patients of both groups had similar rates of functional independence, ENI, END, any ICH, sICH, and 90-day mortality. In the subgroup analysis, patients aged ≥70 years were more likely to achieve excellent functional recovery when receiving standard-dose rather than low-dose alteplase. Conclusion: The effectiveness of low-dose alteplase might be comparable to that of standard-dose alteplase in AIS patients aged <70 years with favorable perfusion-imaging profiles in the unknown or extended time window but not in those aged ≥70 years. Furthermore, low-dose alteplase did not significantly reduce the risk of sICH compared to standard-dose alteplase.

European Stroke Organisation (ESO) expedited recommendation on tenecteplase for acute ischaemic stroke.

Within the last year, four randomised-controlled clinical trials (RCTs) have been published comparing intravenous thrombolysis (IVT) with tenecteplase and alteplase in acute ischaemic stroke (AIS) patients with a non-inferiority design for three of them. An expedited recommendation process was initiated by the European Stroke Organisation (ESO) and conducted according to ESO standard operating procedure based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. We identified three relevant Population, Intervention, Comparator, Outcome (PICO) questions, performed systematic reviews of the literature and meta-analyses, assessed the quality of the available evidence, and wrote evidence-based recommendations. Expert consensus statements were provided if insufficient evidence was available to provide recommendations based on the GRADE approach. For patients with AIS of <4.5 h duration who are eligible for IVT, tenecteplase 0.25 mg/kg can be used as a safe and effective alternative to alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS of <4.5 h duration who are eligible for IVT, we recommend against using tenecteplase at a dose of 0.40 mg/kg (low evidence, strong recommendation). For patients with AIS of <4.5 h duration with prehospital management with a mobile stroke unit who are eligible for IVT, we suggest tenecteplase 0.25 mg/kg over alteplase 0.90 mg/kg (low evidence, weak recommendation). For patients with large vessel occlusion (LVO) AIS of <4.5 h duration who are eligible for IVT, we recommend tenecteplase 0.25 mg/kg over alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS on awakening from sleep or AIS of unknown onset who are selected with non-contrast CT, we recommend against IVT with tenecteplase 0.25 mg/kg (low evidence, strong recommendation). Expert consensus statements are also provided. Tenecteplase 0.25 mg/kg may be favoured over alteplase 0.9 mg/kg for patients with AIS of <4.5 h duration in view of comparable safety and efficacy data and easier administration. For patients with LVO AIS of <4.5 h duration who are IVT-eligible, IVT with tenecteplase 0.25 mg/kg is preferable over skipping IVT before MT, even in the setting of a direct admission to a thrombectomy-capable centre. IVT with tenecteplase 0.25 mg/kg may be a reasonable alternative to alteplase 0.9 mg/kg for patients with AIS on awakening from sleep or AIS of unknown onset and who are IVT-eligible after selection with advanced imaging.

Evaluation of Collateral Circulation in Patients with Acute Ischemic Stroke.

The cerebral collateral circulation is an increasingly important consideration in the management of acute ischemic stroke and is a key determinant of outcomes. Growing evidence has demonstrated that better collaterals can predict the rate of infarct progression, degree of recanalization, the likelihood of hemorrhagic transformation and various therapeutic opportunities. Collaterals can also identify those unlikely to respond to reperfusion therapies, helping to optimize resources. More randomized trials are needed to evaluate the risks and benefits of endovascular reperfusion with consideration of collateral status. This reviews our current understanding of the pathophysiologic mechanisms, effect on outcomes and strategies for improvement of the collateral system.

Early Response to Endovascular Thrombectomy after Stroke: Early, Late, and Very Late Time Windows.

BACKGROUND AND PURPOSE: Endovascular thrombectomy (EVT) has benefits in selected patients 6-24 h after stroke onset. However, the response to EVT >24 h after stroke onset is still unclear. We compared the early response to EVT in patients with different time windows. METHODS: Patients who underwent EVT in an emergency setting were enrolled and categorized according to when EVT was performed: within 6 (early), 6-24 (late), and >24 h (very late) after stroke onset. Early neurological improvement (ENI) and deterioration (END) were defined as improvement and worsening, respectively, of National Institutes of Health Stroke Scale (NIHSS) score by ≥4 points after EVT. The three groups' clinical characteristics and response to EVT were compared. We also investigated factors associated with ENI and END. RESULTS: During study period, 274 patients underwent EVT (109 early, 104 late, and 61 very late). Patients who underwent EVT very late were younger (p = 0.007), had smaller ischemic cores, and had lower initial NIHSS scores (8 ± 5) than those who underwent EVT early (14 ± 6) and late (13 ± 7; p < 0.001). Stroke mechanisms also differed according to the time window (p < 0.001): cardioembolism was more common after early EVT, whereas large-artery atherosclerosis was more prevalent among patients who underwent EVT very late. ENI was significantly more common after early (60.6%) and late EVT (51.0%) than after very late EVT (29.5%; p = 0.001); however, rates of END did not differ (11.0%, 13.5%, and 4.9%, respectively). ENI was independently associated with male, higher NIHSS score, and early and late EVT. END was associated with failure of recanalization. CONCLUSIONS: ENI was more observed and associated with early and late EVT. Highly selected patients receiving very late EVT may not benefit from ENI but may still have a chance to prevent END. The occurrence of END was associated not with time window but with failure of recanalization.

Extended Time Window (>6 Hour) Mechanical Thrombectomy; Good Clinical Outcome in the Younger Age Population in Thrombectomy Cases: Relationship between Age and Prognosis.

BACKGROUND: Mechanical thrombectomy (MT) has become increasingly common in recent years, as studies have shown that it can be an effective treatment for acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). However, the efficacy of MT in the extended time window (6 to 24 h) is still uncertain. Our study aims to evaluate the outcomes of MT in the extended time window for AIS patients. METHODS: We reviewed data on AIS patients who received MT beyond six hours of stroke onset from 2015 to 2022. The patients' occlusions were in the internal carotid artery (ICA), middle cerebral artery (MCA), or posterior circulation. Our evaluation included the modified Rankin scale (mRS) and 90-day mortality rates, as well as complications, such as symptomatic intracranial hemorrhage (sICH). RESULTS: Thirty-one patients were included in this study, with a mean age of 75.6 ± 15.1 years, of whom 54.8% were male. The median NIHSS score at presentation was 17. Successful recanalization (TICI 2b to 3) was achieved in 90.3% of patients and the rate of sICH was 6.4%. No difference was observed between the two age groups. The younger age group (<80 years old) showed a better clinical outcome (mRS 0-2; p < 0.05, Fisher's exact test) compared with the older age group. The overall mortality rate was 6.4%. CONCLUSION: Our study shows that (MT) can be performed effectively and safely within an extended time window, resulting in satisfactory functional outcomes, particularly in the younger age group.

[Neurothrombectomy 2022-Extension of indications and technical innovations]. / Neurothrombektomie 2022 ­ Indikationserweiterung und technische Innovationen.

For advanced territorial ischemia numerous retrospective and prospective studies have shown a positive effect of mechanical thrombectomy (MT) compared to best medicinal treatment alone. For patients with minor stroke (NIHSS < 6) there is currently a lack of evidence for MT. Appropriate study protocols must differentiate between patients with large vessel occlusion with disproportionately mild symptoms and more distal vascular occlusion and therefore correspondingly fewer clinical symptoms. The role of intravenous lysis treatment before MT as bridging lysis also currently retains its general recommendation, as large studies could not show a uniform noninferiority of MT alone. In addition, the use of intra-arterial lysis after successful MT offers a promising approach, which still needs to be evaluated. Novel aspiration catheters and stent-retrievers as well as competing thrombectomy techniques can be compared by the first pass effect, the successful recanalization with only one attempt at thrombectomy. Contact aspiration and stent-retriever thrombectomy under aspiration are equivalent and established thrombectomy procedures. For the latter, several detailed maneuver tactics are described for improvement of thrombectomy success. Also, in retrospective studies the combination with a balloon-guided catheter promises a further improvement of recanalization results. In the case of failure of supra-aortic vessel probing with inguinal access, radial access and direct carotid puncture are alternative access routes. Recent studies on ICA stenting with tandem occlusions showed a benefit of stents without an increased risk for symptomatic intracranial hemorrhage. The retrograde approach, to first treat the intracranial vessel occlusion and then the carotid stenosis, seems to be advantageous.

Endovascular Thrombectomy Eligibility in the 0-24-Hour Time Window at a Large Academic Center in India.

Background: The data regarding patients eligible for endovascular thrombectomy (EVT), especially in the developing world is lacking. Objective: To determine the proportion of patients with acute ischemic stroke (AIS) who are eligible for EVT in the 0-24-h time window. Materials and Methods: We performed a retrospective cohort study using prospectively collected AIS data between July 2017 and September 2019. Demographic, clinical, and management information were analyzed. EVT eligibility was explored using the following criteria: National Institutes of Health Stroke Scale (NIHSS) score ≥6, presence of anterior circulation large-vessel occlusion (ACLVO), Alberta stroke program early Computerized Tomography score (ASPECTS) ≥6, baseline modified Rankin Scale (mRS) score 0-2, and within 24 h of time last seen well (TLSW). EVT-eligible patients were further evaluated for in-hospital course and outcomes. Results: In the study period of 27 months, there were 221 patients with AIS who presented within 24 h. The mean age of the patients was 54.4 (16.0) years and 66.1% (146) were males. A majority (61.5% [136/221]) arrived within 6 h of TLSW. Of these, 81.6% (111/136) presented in the time window for thrombolysis (0-4.5 h). The patients with NIHSS ≥6 and ACLVO constituted 41.2% (91/221) of the patients. AIS eligible for EVT constituted 19.5% (43/221) of the patients. Conclusion: In our study, the proportion of AIS eligible for endovascular thrombectomy was comparable to the developed world. These data predict a large potential for the late-window EVT in India.

Research progress of acute reperfusion therapies for acute ischemic stroke in extended time window / 中华神经科杂志

The reperfusion therapies for acute ischemic stroke (AIS) patients in the past have set strict limits on time window. However, with the imaging assessment algorithms for "tissue window" becoming more mature, the time window for reperfusion therapies has been continuously extended. Nowadays the time window of intravenous thrombolysis has been extended to 9 hours after onset of stroke and is expected to be further broadened to 24 hours. At the same time, clinical studies of mechanical thrombectomy for posterior circulation large vessel occlusion (LVO), LVO with large ischemic cores and distal and medium vessel occlusion are all in hot progress. This article summarized diverse imaging assessment algorithms for "tissue window" and the latest advances of clinical research related to different fibrinolytic drugs for intravenous thrombolysis, mechanical thrombectomy for various vascular occlusion and bridging therapy of AIS in the extended time window. The objective of this review was to provide some references for the clinical diagnosis and therapy of stroke beyond time window.

IV-Thrombolysis in Ischemic Stroke With Unknown Time of Onset-Safety and Outcomes in Posterior vs. Anterior Circulation Stroke.

Background: rt-PA for ischemic stroke in the unknown or extended time window beyond the first 4. 5 h after symptom onset is safe and effective for certain patients after selection by multimodal neuroimaging. However, the evidence for this approach comes mainly from patients with anterior circulation stroke (ACS), while the data on posterior circulation stroke (PCS) are scarce. Methods: Ischemic stroke patients treated with IV-thrombolysis in the unknown or extended time window between January 2011 and May 2019 were identified from an institutional registry. The patients were categorized into PCS or ACS based on clinico-radiological findings. We analyzed the hemorrhagic complications, clinical and imaging efficacy outcomes, and mortality rates by comparing the PCS and ACS patient groups. Adjusted outcome analyses were performed after propensity score matching for the relevant factors. Results: Of the 182 patients included, 38 (20.9%) had PCS and 144 (79.1%) had ACS. Symptomatic acute large vessel occlusion (LVO) was present in 123 patients on admission [27 (22.0%) PCS and 96 (78.0%) ACS]. The score on the National Institutes of Health Stroke Scale (NIHSS), the time from last seen normal, and the door-to-needle times were similar in PCS and ACS. In patients with LVO, the NIHSS score was lower [8 (5-15) vs. 14 (9-18), p = 0.005], and infarction visible on follow-up imaging was less common [70.4 vs. 87.5%; aRD, -18.9% (-39.8 to -2.2%)] in the PCS patient group. There was a trend toward a lower risk for intracranial hemorrhage (ICH) following intravenous thrombolysis in PCS vs. ACS, without reaching a statistical significance [5.3 vs. 16.9%; aRD, -10.4% (-20.4 to 4.0%)]. The incidence of symptomatic ICH [according to the ECASS III criteria: 2.6 vs. 3.5%; aRD, -2.9% (-10.3 to 9.2%)], efficacy outcomes, and mortality rates were similar in PCS and ACS patients. Conclusions: In this real-world clinical cohort, the safety and the efficacy of rt-PA for ischemic stroke in the unknown or extended time window did not show relevant differences between PCS and ACS, with a trend toward less hemorrhagic complications in PCS. The findings reconfirm the clinician in the usage of rt-PA beyond the first 4.5 h also in selected patients with PCS.

Adapting Clinical Practice of Thrombolysis for Acute Ischemic Stroke Beyond 4.5 Hours: A Review of the Literature.

Several clinical trials have demonstrated that advanced neuroimaging can select patients for recanalization therapy in an extended time window. The favorable functional outcomes and safety profile of these studies have led to the incorporation of neuroimaging in endovascular treatment guidelines, and most recently, also extended to decision making on thrombolysis. Two randomized clinical trials have demonstrated that patients who are not amenable to endovascular thrombectomy within 4.5 hours from symptoms discovery or beyond 4.5 hours from the last-known-well time may also be safely treated with intravenous thrombolysis and have a clinical benefit above the risk of safety concerns. With the growing aging population, increased stroke incidence in the young, and the impact of evolving medical practice, healthcare and stroke systems of care need to adapt continuously to provide evidence-based care efficiently. Therefore, understanding and incorporating appropriate screening strategies is critical for the prompt recognition of potentially eligible patients for extended-window intravenous thrombolysis. Here we review the clinical trial evidence for thrombolysis for acute ischemic stroke in the extended time window and provide a review of new enrolling clinical trials that include thrombolysis intervention beyond the 4.5 hour window.

Comparing extended versus standard time window for thrombectomy: caseload, patient characteristics, treatment rates and outcomes-a prospective single-centre study.

PURPOSE: New guidelines recommend thrombectomy up to 24 h in selected patients; however, the workload and benefit of extending time window are not known. We conducted a prospective single-centre study to determine the caseload, imaging and interventional need of extended time window. METHODS: All consecutive ischemic stroke patients within 24 h from onset in an 11-month period were included. Thrombectomy eligibility in the 0-6 h time window was based on current guidelines; in the 6-24 h time window, it was based on a combination of DEFUSE 3 and DAWN study criteria using MRI to identify target mismatch. Clinical outcome in treated patients was assessed at 3 months. RESULTS: Within 24 h of onset, 437 patients were admitted. In the 0-6 h time window, 238 patients (54.5%) arrived of whom 221 (92.9%) underwent CTA or MRA, 82 (34.5%) had large vessel occlusion (LVO), 30 (12.6%) had thrombectomy and 11 (36.6%) became independent (mRS ≤ 2). In the extended 6-24 h time window, 199 patients (45.5%) arrived of whom 127 (63.8%) underwent CTA or MRA, 44 (22.1%) had LVO, 8 (4%) had thrombectomy and 4 (50%) became independent. CONCLUSION: Extending the time window from 6 to 24 h results in a 26.7% increase in patients receiving thrombectomy and a 36.4% increase of independent clinical outcome in treated patients at the price of a significantly increased burden of clinical and imaging screening due to the similar caseload but a smaller proportion of treatment eligible patients in the extended as compared with the standard time window.

The Relationship Between Penumbral Tissue and Blood-Brain Barrier Disruption in Acute Stroke Patients Presenting in an Extended Time Window.

Background: Penumbral brain tissue identified with multimodal imaging can be salvaged with reperfusion in an extended time window. The risk of severe hemorrhagic complications after reperfusion therapy increases with worsening disruption of the blood-brain barrier (BBB). The relationship between penumbral tissue and BBB disruption has not been previously studied. Methods: Stroke patients presenting in an extended time window without a large vessel occlusion who underwent diffusion-perfusion MRI within 24 h of last-seen-normal were included. The volume of penumbral tissue was calculated using mismatch on MRI. Mean permeability derangement (MPD) of the BBB was measured within the ischemic lesion. A target profile (TP) for treatment was defined based on the EXTEND trial. Results: 222 patients were included with a median age of 73 and 55% women. The median NIHSS was 6, the mean core volume was 14 ml, the mean ischemic volume was 47 mL and the mean mismatch volume was 33 mL. Higher MPD was significantly associated with less mismatch volume (p = 0.001). A target profile was associated with lower MPD (OR 0.97; CI 0.96:0.99; p < 0.001). Of the 105 patients who had a TP, 31 (30%) had a MPD > 20% suggesting an increased risk of hemorrhage. Thus, 33% (74/222) of patients had a favorable profile for benefit and safety. Conclusions: Patients presenting in an extended time window with a favorable penumbral profile for treatment have less severe BBB disruption. Up to a third of patients who currently go untreated could be considered for enrollment in a clinical trial of thrombolysis in an extended time window.

Frequency of thrombolytic targets in stroke patients presenting in an extended time window.

OBJECTIVE: The objective of this study was to determine the proportion of stroke patients presenting in an extended time window who have a thrombolytic treatment target. BACKGROUND: Patients presenting up to 24 h after stroke onset have been found to have penumbral tissue on multimodal imaging. Stroke patients presenting in this extended time window without a large vessel occlusion (LVO) may benefit from reperfusion therapy using thrombolysis. METHODS: Patients seen at our institutions from 2011 through 2015 were reviewed to identify those who presented >4 h and <24 h from last seen normal (LSN) and did not receive acute treatment. Magnetic resonance imaging (MRI) scans were used to dichotomize patients using a diffusion-perfusion mismatch ratio of 1.2. RESULTS: During the study period, 3469 patients were evaluated by our stroke service, with 893 seen 4-24 h from LSN who were not treated. MRI was performed with diffusion and perfusion imaging in 439 patients, of whom 26 were excluded due to hemorrhage and 37 were excluded due to LVO. This left 376 patients who potentially could have been treated with thrombolysis in an extended time window and were included in the analysis. Of these, 156 (42%) demonstrated a mismatch ratio >1.2. Patients with a mismatch presented earlier (P = 0.012), were more likely to be female (P = 0.03), and had higher National Institutes of Health Stroke Scale (P < 0.001). CONCLUSIONS: Almost half of the patients presenting 4-24 h from LSN had a target for thrombolysis in our study. Multimodal imaging may be able to expand the population of treatable stroke patients given the results of recent clinical trials.

Hyperacute Management of Ischemic Strokes: JACC Focus Seminar.

Acute ischemic stroke is the leading cause of disability and among the leading causes of mortality worldwide. Intravenous tissue plasminogen activator has been a cornerstone for treatment of acute ischemic stroke for more than 20 years; however, its use is limited due to a narrow therapeutic window, several contraindications, and low efficacy to recanalize the artery in large vessel occlusion. Recently, the addition of endovascular mechanical thrombectomy of large artery occlusion has revolutionized the stroke treatment for most disabling strokes. The paper reviews updates to the thrombolytic treatment as well as catheter-based treatment, and results from recent trials in the selection of patients in an extended time window using perfusion imaging.