Major Neurological Improvement Research Articles

Isolated insular stroke: topography is the answer with respect to outcome and cardiac involvement.

Isolated insular strokes (IIS) are a rare occurrence due to the frequent concomitant involvement of adjacent territories, supplied by the M2 segment of the middle cerebral artery (MCA), and clinical aspects are sometimes contradictory. We aimed to describe clinical and radiological characteristics of a pure IIS case series, focusing on its functional outcome and cardiac involvement. We identified 15 isolated insular ischemic strokes from a pool of 563 ischemic strokes occurred between January 2020 and December 2021. Data collection consisted of demographic and baseline clinical characteristics, comorbidities, electrocardiograms, echocardiograms, stroke topography and etiology, reperfusive treatments, and outcome measures. Descriptive statistical analysis was carried out. Newly detected cardiovascular alterations were the prevalent atypical presentation. Cardioembolism was the most frequent etiology. Most of patients had major neurological improvement at discharge and good outcome at 3-months follow-up. IIS are extremely rare, representing according to our study about 2.6% ischemic strokes cases per year, and patients have peculiar clinical manifestations, such as dysautonomia and awareness deficits. Our data suggest the possibility for these patients to completely recover after acute ischemic stroke notwithstanding the pivotal role of the insula in cerebral connections and the frequent association with MCA occlusion. Moreover, given the central role of the insula in regulating autonomic functions, newly detected cardiac arrhythmias must be taken into consideration, as well as a full diagnostic work-up for the research of cardioembolic sources. To our knowledge, this is the largest monocentric case series of IIS and it might be useful for future systematic reviews.

Abstract WP31: Real World Comparison of Outcomes of IV Tenecteplase versus IV Alteplase for Acute Ischemic Stroke

Background: Tenecteplase (TNK) has been reported to be non-inferior to alteplase from a clinical outcome and safety standpoint according to recent studies. In our study, we compare the outcomes of IV TNK & IV alteplase for acute ischemic stroke patients. Materials and Methods: We evaluated acute AIS patients treated with IVT between10/2020-03/2023 at theDepartment of Neurology, Hackensack MeridianHealth, JFKMedical Center. All analyses was done using SPSS version 29 software. Results: Among the total 270 patients, 150(55.6%) received IV alteplase and 120(44.4%) received IV TNK. Major neurological improvement (defined as improvement in NIHSS score by 8 or more points at 24hours) was observed with TNK. Any intracranial hemorrhage was higher among patients treated with IV TNK compared to alteplase (25% versus 14.7%, p=0.024). Symptomatic intracranial hemorrhage(sICH) was higher inTNK group (8.3% versus3.3%, p=0.075). The proportion of routine discharge was higher among alteplase patients, while non-routine discharge was higher among TNK patients (51.7% vs. 28%, p<0.001). In the logistic regression analysis, patients treated with IV TNK were at a significantly higher risk of any intracranial hemorrhage(odds ratio[OR], 1.93, 95% confidence interval [CI]1.051-3.57, p=0.034). After adjusting for age, gender, NIHSS, thrombectomy, hypertension, diabetes, hyperlipidemia, CHF, previous TIA and previous stroke, there was anon-significant higher rate of intracranial hemorrhage. A nonsignificant decrease in the odds of symptomatic intracranial hemorrhage (sICH) was seen with TNK. There were significantly higher rates of non-routine discharge (OR, 3.078, 95% CI 1.8-5.19, p<0.001) and death (OR, 4.84, 95% CI1.20-19.66, p=0.002) inpatients treated with IV TNK. After adjusting for the above-mentioned factors, there was a significantly higher rate of non-routine discharge in the TNK group and a higher trend of death in the TNK group. Conclusions: We found that IV TNK was associated with higher rates of intracranial hemorrhage compared to IV alteplase in patients with acute ischemic stroke.

Reteplase versus alteplase for acute ischaemic stroke within 4.5 hours (RAISE): rationale and design of a multicentre, prospective, randomised, open-label, blinded-endpoint, controlled phase 3 non-inferiority trial

Background and purposeReteplase is the third generation of alternative thrombolytic agent. We hypothesis that reteplase will be non-inferior to alteplase in achieving excellent functional outcome at 90 days among eligible...

Safety and efficacy of N-acetylcysteine (NAC) as an adjunct to standard treatment in patients with acute ischemic stroke: a randomized controlled pilot trial (NACTLYS)

There is a pressing clinical need for thrombolytic agents that can effectively disaggregate arterial thrombi in acute ischemic stroke without significantly increasing the risk of bleeding. This pilot study aimed to investigate the safety and efficacy of N-acetylcysteine (NAC) as an adjunctive therapy to intravenous recombinant tissue plasminogen activator (rtPA or alteplase). A randomized, open-label, blinded assessor pilot study was conducted. Patients presenting with an acute ischemic stroke within 4.5 h from onset were randomized into two groups: intravenous NAC and rtPA or rtPA alone. Primary outcomes included intracerebral hemorrhage, symptomatic intracerebral hemorrhage, extracranial bleeding, and adverse reactions. Secondary outcomes comprised major neurological improvement assessed by (National Institute of Health Stroke Scale) NIHSS at 24 h, recanalization on first run of angiography in patients who underwent thrombectomy or on repeat vascular imaging at 24 h, modified Rankin scale, and three-month mortality. Forty patients were enrolled, with 21 receiving only rtPA and 19 receiving NAC with rtPA. Baseline characteristics were comparable among groups. No significant differences were observed in adverse events (p = 0.99), intracranial hemorrhage (p = 0.21), symptomatic intracerebral hemorrhage (p = 0.47), or extracranial bleeding (p = 0.21). Median NIHSS at 24 h was significantly lower in the intervention group (p = 0.03). Functional outcomes and three-month mortality were similar between groups (p = 0.85 and p = 0.99 respectively). The co-administration of N-acetylcysteine with alteplase did not significantly alter safety profiles, morbidity, or mortality at 3 months. While no substantial differences were noted, a slightly improved early neurological outcome was observed in the intervention arm. The study's findings were constrained by a small sample size, emphasizing the necessity for future large-scale trials to comprehensively evaluate the safety and efficacy of N-acetylcysteine as a thrombolytic agent in acute ischemic stroke.Trial Registration Clinical Trials Registry India—CTRI/2019/05/019305.

Intravenous Odatroltide for Acute Ischemic Stroke Within 24 Hours of Onset: A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

Odatroltide (LT3001), a novel small synthetic peptide molecule designed to recanalize occluded blood vessels and reduce reperfusion injury, is safe and efficacious in multiple embolic stroke animal models. This study aimed to investigate the safety and tolerability of intravenous administration of odatroltide in patients with acute ischemic stroke within 24 hours of onset. Patients with National Institutes of Health Stroke Scale (NIHSS 4-30) who were untreated with intravenous thrombolysis or endovascular thrombectomy were randomized (2:1) to receive a single dose of odatroltide (0.025 mg/kg) or placebo within 24 hours of stroke symptom onset. The primary safety outcome was symptomatic intracranial hemorrhage (sICH) occurrence within 36 hours. Twenty-four patients were enrolled and randomized; of these 16 and 8 received intravenous odatroltide infusion and placebo, respectively. sICH did not occur in both groups, and other safety measures were comparable between the groups. The rate of excellent functional outcome (modified Rankin Scale score, 0-1, at 90 days) was 21% and 14% in the odatroltide and placebo groups, respectively. Furthermore, 47% and 14% of patients in the odatroltide and placebo groups, respectively, showed major neurological improvement (NIHSS improvement ≥4 points from baseline to 30 days). Among the 9 odatroltide-treated patients with baseline NIHSS ≥6, 78% showed major neurological improvement. Compared with placebo, treatment with intravenous odatroltide within 24 hours following onset of ischemic stroke appears to be safe and may be associated with better neurological and functional outcomes. However, the efficacy and safety of odatroltide requires further confirmation in the next phase of clinical trials. Clinicaltrials.gov identifier: NCT04091945.

Rationale and design of Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events III (TRACE III): a randomised, phase III, open-label, controlled trial

Background and purposeRecombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) was not inferior to alteplase for ischaemic stroke within 4.5 hours. Our study aimed to investigate the efficacy and safety of...

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

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. 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. 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. 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.

The association between stress hyperglycemia and unfavorable outcomes in patients with anterior circulation stroke after mechanical thrombectomy.

Stress hyperglycemia is common in critical and severe diseases. However, few studies have examined the association between stress hyperglycemia and the functional outcomes of patients with anterior circulation stroke, after mechanical thrombectomy (MT), in different diabetes status. This study therefore aimed to determine the relationship between stress hyperglycemia and the risk of adverse neurological functional outcomes in anterior circulation stroke patients with and without diabetes after MT. Data of 408 patients with acute anterior circulation stroke treated with MT through the green-channel treatment system for emergency stroke at the First Affiliated Hospital of Jinan University between January 2016 and December 2020 were reviewed retrospectively. The stress hyperglycemia ratio (SHR) was calculated as fasting plasma glucose (mmol/L) divided by glycosylated hemoglobin (%). The patients were stratified into four groups by quartiles of SHR (Q1-Q4). The primary outcome was an excellent (nondisabled) functional outcome at 3 months after admission (modified Rankin Scale score of 0-1). The relationship between stress hyperglycemia and neurological outcome after stroke was assessed using multivariate logistic regression. After adjusting for potential confounders, compared with patients in Q1, those in Q4 were less likely to have an excellent outcome at 3 months (odds ratio [OR], 0.32, 95% confidence interval [CI], 0.14-0.66, p = 0.003), a good outcome at 3 months (OR, 0.41, 95% CI, 0.20-0.84, p = 0.020), and major neurological improvement (OR, 0.38, 95% CI, 0.19-0.73, p = 0.004). Severe stress hyperglycemia increased risks of 3-months all-cause mortality (OR, 2.82, 95% CI, 1.09-8.29, p = 0.041) and ICH (OR, 2.54, 95% CI, 1.21-5.50, p = 0.015). Stress hyperglycemia was associated with a reduced rate of excellent neurological outcomes, and increased mortality and ICH risks in patients with anterior circulation stroke after MT regardless of diabetes status.

559: TENECTEPLASE VERSUS ALTEPLASE FOR THE TREATMENT OF ACUTE ISCHEMIC STROKE

Introduction: Since 1995 alteplase has been the preferred thrombolytic for acute ischemic stroke. Recently, data from prospective trials has shown that treatment with tenecteplase, a variant of alteplase with a longer half-life, results in similar rates of excellent functional outcomes (defined as a modified Rankin Scale (mRS) score of 0 or 1) at 90 days, and similar rates of adverse events, including symptomatic intracranial hemorrhage (sICH). The purpose of this study is to evaluate clinical outcomes after transition from alteplase to primarily tenecteplase for treatment of acute ischemic stroke at our institution. The primary objective was to determine if there was a difference in excellent functional outcome at 90 days in patients treated with tenecteplase versus alteplase for AIS. Methods: This single center, retrospective chart review conducted from March 2019 to July 2021 used a pre-test post-test design. Data from two cohorts was collected: the first cohort included patients treated with alteplase for AIS from March 2019 to March 2020, and the second cohort included patients treated with tenecteplase for AIS from July 2020 to July 2021. We collected baseline demographics and assessed outcomes including favorable mRS at 90 days, major neurologic improvement at 36 hours, time to thrombolytics, and sICH rates. Data collected was adjusted for age and presenting NIH scores. Results: We included 136 patients treated with alteplase and 120 patients treated with tenecteplase. Patients were found to have a significant difference in median NIH score at arrival (8 vs 9, p=0.02), as well as a difference in each stroke severity category (p=0.01). There was no statistically significant difference between groups in age (70 vs 74, p=0.07), comorbidities, mean premorbid mRS (0.6±1.1 vs 0.58±1.19, p=0.886), or number of patients with large vessel occlusion (32% vs 42%, p=0.16). We found no difference in favorable mRS at 90 days between groups (59% vs 61%, p=0.89), major neurologic improvement at 36 hours (57% vs 51%, p=0.48), or sICH rates (2% vs 0%, p=0.48). We saw a decrease in time from arrival to thrombolytic administration (28 vs 22 minutes, p< 0.001). Conclusions: Routine use of tenecteplase was found to have similar efficacy and safety to that of alteplase, and a shorter door-to-needle time.

Hyperdense middle cerebral artery sign predicts favorable outcome in patients undergoing mechanical thrombectomy.

Non-contrast computer tomography detects the presence of hyperdense middle cerebral artery sign (HMCAS). Studies on the prognostic value of HMCAS among patients undergoing mechanical thrombectomy (MT) are conflicting. A retrospective analysis of consecutive patients with acute ischemic stroke due to middle cerebral artery occlusion, presenting with or without HMCAS, who underwent MT, was performed. We enrolled 191 patients (HMCAS +, n = 140; HMCAS -, n = 51). Prevalence of successful recanalization was significantly higher in patients with HMCAS than in those without HMCAS (92.1% versus 74.5%, p = 0.001). Patients with HMCAS had a better clinical outcome than those HMCAS - (54.3% versus 37.3%, p = 0.037, for three-month favorable outcome; 62.9% versus 39.3%, p = 0.004, for major neurological improvement at discharge; 8.6% versus 19.6%, p = 0.035, for in-hospital mortality; 14.3% versus 27.5%, p = 0.035, for intracranial hemorrhage; 2.9% versus 17.6%, p = 0.001, for symptomatic intracranial hemorrhage). Multivariate analyses confirmed that HMCAS represents an independent predictor of three-month favorable outcome (OR 2.48, 95% CI 1.10-5.58, p = 0.028), major neurological improvement at discharge (OR 2.40, 95% CI 1.09-5.20, p = 0.030), in-hospital mortality (OR 0.29, 95% CI 0.010-0.81, p = 0.018), presence of ICH (OR 0.49, 95% CI 0.25-0.97, p = 0.042) and presence of SICH (OR 0.16, 95% CI 0.04-0.63, p = 0.009). HMCAS presence predicts favorable outcome in patients undergoing MT. This result may indicate that hyperdense clots are more likely to respond to MT than isodense ones. This effect is mediated by reduction in hemorrhagic transformation.

Association of the 24‐Hour National Institutes of Health Stroke Scale After Mechanical Thrombectomy With Early and Long‐Term Survival

Background The National Institutes of Health Stroke Scale (NIHSS) obtained 24 hours after ischemic stroke is a good indicator for functional outcome and early mortality, but the correlation with long‐term survival is less clear. We analyzed the correlation of the NIHSS after 24 hours (24h NIHSS) and early clinical neurological development after mechanical thrombectomy with early and long‐term survival as well as its predictive power on survival. Methods We reviewed a prospective observational registry for all patients undergoing mechanical thrombectomy between January 2010 and December 2018. Vital status was extracted from the Swiss Population Registry. Adjusted hazard ratio (aHR) and crude hazard ratios were calculated using Cox regression. To assess predictive power of the 24h NIHSS, different Random Survival Forest models were evaluated. Results We included 957 patients (median follow‐up 1376 days). Patients with lower 24h NIHSS and major early neurological improvement had substantially better survival rates. We observed significantly higher aHR for death in patients with 24h NIHSS 12 to 15 (aHR, 1.78; 95% CI, 1.1–2.89), with 24h NIHSS 16 to 21 (aHR, 2.54, 95% CI, 1.59–4.06), and with 24h NIHSS &gt;21 (aHR, 5.74; 95% CI, 3.47–9.5). The 24h NIHSS showed the best performance predicting mortality (receiver operating characteristic area under the curve at 3 months [0.85±0.034], at 1 year [0.82±0.029], at 2 years [0.82±0.031], and at 5 years [0.83±0.035]), followed by NIHSS change. Conclusions Patients with acute ischemic stroke achieving a low 24h NIHSS or major early neurological improvement after mechanical thrombectomy had markedly lower long‐term mortality. Furthermore, 24h NIHSS had the best predictive power for early and long‐term survival in our machine learning–based prediction.

Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-II (TRACE II): rationale and design

Background and purposeTenecteplase (TNK) is a promising agent for treatment of acute ischaemic stroke (AIS). We hypothesised that recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) is non-inferior to rt-PA in...

Short-Term Efficacy Outcomes of Tenecteplase versus Alteplase for Acute Ischemic Stroke: A Meta-Analysis of 5 Randomized Trials.

Tenecteplase (TNK) has been shown to be noninferior to Alteplase (ALT) for long term efficacy and safety outcomes. Whether this also applies to short term efficacy outcomes such as early clinical improvement and recanalization is unknown. To compare TNK and ALT regarding the short term efficacy outcomes: early neurological improvement and recanalization. The PRISMA was used to conduct a meta analysis, adapted to noninferiority analysis. The primary outcome was early (24-72 h) neurological improvement, defined as either NIHSS score 0 or reduction of at least 8 points compared to baseline. Recanalization was a secondary outcome. The noninferiority margin was set at 6.5%. Search strategy yielded 5 randomized clinical trials (1585 patients: 828 TNK, 757 ALT). Mean age was 70.8, 58.8% were men, mean baseline NIHSS was 7, and mean onset to treatment time was 148 min. Patients in intervention group received TNK at doses of 0.1 mg/kg (6.8%), 0.25 mg/kg (24.6%), and 0.4 mg/kg (68.6%), while all ALT patients received 0.9 mg/kg. In random effects meta analysis, TNK was noninferior to ALT for the primary outcome, early major neurological improvement (risk difference 8% in favor of TNK, 95% CI 1%-15%). Recanalization was also noninferior for the TNK compared to the ALT group (risk difference 9% in favor of TNK, 95% CI 6% to 23%). Fixed effects models yielded similarly noninferior results and signaled for a possible TNK superiority for both early neurological improvement and recanalization. TNK is noninferior to ALT at the short term efficacy outcomes: early neurological improvement and recanalization.

Association of Multiple Passes during Mechanical Thrombectomy with Incomplete Reperfusion and Lesion Growth

Introduction: Despite complete recanalization by mechanical thrombectomy, abnormal perfusion can be detected on MRI obtained post-endovascular therapy (EVT). The presence of residual perfusion abnormalities post-EVT may be associated with blood-brain barrier breakdown in response to mechanical disruption of the endothelium from multiple-pass thrombectomy. We hypothesize that multiple-pass versus single-pass thrombectomy is associated with a higher rate of residual hypoperfusion and increased lesion growth at 24 h. Materials and Methods: For this analysis, we included patients presenting to one of two stroke centers between January 2015 and February 2018 with an acute ischemic stroke within 12 h from symptom onset if they had a large vessel occlusion of the anterior circulation documented on magnetic resonance angiography or CTA, baseline MRI pre-EVT with imaging evidence of hypoperfusion, underwent EVT, and had a post-EVT MRI with qualitatively interpretable perfusion-weighted imaging data at 24 h. MRI Tmax maps using a time delay threshold of >6 s were used to quantitate hypoperfusion volumes. Residual hypoperfusion at 24 h was solely defined as Tmax volume >10 mL with >6 s delay. Complete recanalization was defined as modified treatment in cerebral infarction visualized on angiography at EVT completion. Hyperintense acute reperfusion injury marker was assessed on post-EVT pre-contrast fluid-attenuated inversion recovery at 24 h. Major early neurological improvement was defined as a reduction of the admission National Institutes of Health Stroke Scale by ≥8 points or a score of 0–1 at 24 h. Good functional outcome was defined as 0–2 on the modified Rankin Scale on day 30 or 90. Results: Fifty-five patients were included with median age 67 years, 58% female, 45% Black/African American, 36% White/Caucasian, median admission National Institutes of Health Stroke Scale 19, large vessel occlusion locations: 71% M1, 14.5% iICA, 14.5% M2, 69% treated with intravenous recombinant tissue plasminogen activator. Of these, 58% had multiple-pass thrombectomy, 39% had residual perfusion abnormalities at 24 h, and 64% had severe hyperintense acute reperfusion injury marker at 24 h. After adjusting for complete recanalization, only multiple-pass thrombectomy (odds ratio, 4.3 95% CI, 1.07–17.2; p = 0.04) was an independent predictor of residual hypoperfusion at 24 h. Patients with residual hypoperfusion had larger lesion growth on diffusion-weighted imaging (59 mL vs. 8 mL, p < 0.001), lower rate of major early neurological improvement (24% vs. 70%, p = 0.002) at 24 h, and worse long-term outcome based on the modified Rankin Scale at 30 or 90 days, 5 versus 2 (p < 0.001). Conclusions: Our findings suggest that incomplete reperfusion on post-EVT MRI is present even in some patients with successful recanalization at the time of EVT and is associated with multiple-pass thrombectomy, lesion growth, and worse outcome. Future studies are needed to investigate whether patients with residual hypoperfusion may benefit from immediate adjunctive therapy to limit lesion growth and improve clinical outcome.

Collateral status evaluation coupled with time window by dynamic axial computed tomographic angiography with a focus on the middle cerebral artery for mechanical thrombectomy

BackgroundDynamic axial computed tomographic angiography (dynax–CTA), covering a thin width, with a focus on the bilateral middle cerebral artery (MCA), can quickly visualize the internal carotid artery (ICA) or MCA occlusion. We aimed to investigate whether dynax–CTA appropriately evaluated the collateral status coupled with the upper limit of the onset-to-reperfusion (OtR) time to achieve a major neurological improvement (MNI) at a 24-h follow-up examination after mechanical thrombectomy (MT).MethodsWe included acute ischemic stroke patients admitted from 2018 to 2020 who underwent dynax–CTA on admission and emergent MT for ICA or MCA occlusion. We performed dynax–CTA using an 80-row CT scanner and acquired 25 volume scans, consisting of 40 images of 1-mm thickness and 4-cm width. We classified the collateral status as good, intermediate, and poor based on MCA branch opacification. We evaluated the collateral status and the upper OtR time limit to achieve MNI.ResultsForty-eight patients met our inclusion criteria. Dynax–CTA findings demonstrated MCA and ICA occlusion in 30 and 18 patients, respectively. The collateral status was good, intermediate, and poor in four, 25, and 19 patients, respectively. The upper limits of the OtR time for MNI were 3.63, 8.08, and 8.67 h in patients with poor, intermediate, and intermediate or good collateral status, respectively.ConclusionsDynax–CTA appropriately evaluated the collateral status coupled with the upper limit of the OtR time before performing MT.

Real-world comparative safety and efficacy of tenecteplase versus alteplase in acute ischemic stroke patients with large vessel occlusion.

Background and aims:Tenecteplase has recently emerged as an alternative thrombolytic agent in acute ischemic stroke (AIS) patients with large vessel occlusion (LVO), possibly superior in achieving early reperfusion compared with alteplase. We aimed to compare the safety and efficacy of intravenous tenecteplase with intravenous alteplase for AIS patients with LVO in everyday clinical practice settings.Methods:We prospectively evaluated patients with AIS due to LVO, treated with intravenous thrombolysis (IVT) with or without mechanical thrombectomy in two tertiary stroke centers. Patients were treated with standard-dose alteplase (0.9 mg/kg) or 0.25 mg/kg tenecteplase. Safety outcomes included prevalence of symptomatic intracranial hemorrhage (sICH) and mortality. Efficacy outcomes included averted thrombectomy, major neurological improvement at 24 h (defined as decrease in baseline NIHSS score of 8 points or greater) and functional status on discharge and on 3 months assessed by modified Rankin Scale (mRS).Results:Nineteen AIS patients with LVO received tenecteplase and 39 received alteplase. We observed a non-significant higher rate of averted thrombectomies (32% versus 18%, p = 0.243) and a non-significant higher rate of sICH (16% versus 5%, p = 0.201) in the tenecteplase group. The rate of 24 h major neurological improvement was higher in the tenecteplase group (64% versus 33%, p = 0.046) but this was marginally attenuated in multivariable analyses (adjusted OR 10.22, 95% CI: 0.73–142.98; p = 0.084). Discharge mRS, 3-months mRS, and 3-month functional independence (mRS scores of 0–2) did not differ (p > 0.2) between the two groups. The rates of 3-month mortality (11% versus 18%, p = 0.703) were similar in the two groups. No independent association between thrombolytic agent and safety or efficacy outcomes emerged in multivariable regression analyses.Conclusion:The present pilot observational study highlights that AIS patients with LVO treated with 0.25 mg/kg bolus administration of tenecteplase had increased likelihood to achieve early neurological improvement compared with AIS patients treated with alteplase, but this association was attenuated after adjustment for potential confounders. There were no significant differences in 3-month functional or safety outcomes between the two groups. This preliminary real-world observation requires independent confirmation in larger, multicenter studies.

Predicting major neurologic improvement and long-term outcome after thrombolysis using artificial neural networks

ObjectiveTo develop artificial neural network (ANN)-based functional outcome prediction models for patients with acute ischemic stroke (AIS) receiving intravenous thrombolysis based on immediate pretreatment parameters. MethodsThe derived cohort consisted of 196 patients with AIS treated with intravenous thrombolysis between 2009 and 2017 at Shuang Ho Hospital in Taiwan. We evaluated the predictive value of parameters associated with major neurologic improvement (MNI) at 24 h after thrombolysis as well as the 3-month outcome. ANN models were applied for outcome prediction. The generalizability of the model was assessed through 5-fold cross-validation. The performance of the models was assessed according to the accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC), ResultsThe parameters associated with MNI were blood pressure (BP), heart rate, glucose level, consciousness level, National Institutes of Health Stroke Scale (NIHSS) score, and history of diabetes mellitus (DM). The parameters associated with the 3-month outcome were age, consciousness level, BP, glucose level, hemoglobin A1c, history of DM, stroke subtype, and NIHSS score. After adequate training, ANN Model 1 to predict MNI achieved an AUC of 0.944. Accuracy, sensitivity, and specificity were 94.6%, 89.8%, and 95.9%, respectively. ANN Model 2 to predict the 3-month outcome achieved an AUC of 0.933, with accuracy, sensitivity, and specificity of 88.8%, 94.7%, and 86.5%, respectively. ConclusionsThe ANN-based models achieved reliable performance to predict MNI and 3-month outcomes after thrombolysis for AIS. The models proposed have clinical value to assist in decision-making, especially when invasive adjuvant strategies are considered.

Efficacy and Safety of Intravenous Thrombolysis in Patients with Acute Ischemic Stroke and Pre⁻Existing Disability.

Little is known about intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients with pre-existing disability. Disabled patients are often excluded from IVT treatment. Previous studies investigated the role of pre-existing disability on outcomes in AIS patients after IVT. However, no studies have been conducted to date to determine whether IVT may improve clinical outcomes in AIS patients with pre-existing disability. The aim of our study was to evaluate efficacy and safety of IVT in patients with pre-existing moderate and moderately severe disability (pre-stroke modified Rankin Scale score = 3 or 4) affected by AIS. This study was based on a retrospective analysis of a prospectively collected database of consecutive patients admitted to the Udine University Hospital with AIS from January 2015 to May 2018. The efficacy endpoints were the rate of favorable outcome and rate of major neurological improvement. The safety endpoints were the rate of mortality at three months, presence of intracranial hemorrhage (ICH), and presence of symptomatic intracranial hemorrhage (sICH). The study population included 110 AIS patients with pre-existing moderate and moderately severe disability, 36 of which received (IVT+) and 74 did not receive IVT (IVT−). AIS disabled patients treated with IVT had higher rates of favorable outcome (66.7% vs. 36.5%, p = 0.003) and major neurological improvement (39.4% vs. 17.4%, p = 0.01) compared to non-treated ones. Two in three disabled patients returned to their pre-stroke functional status when treated with IVT. Prevalence of three-month mortality, ICH, and sICH did not differ in the two groups. Disabled patients affected by AIS significantly improved after IVT. Moderate and moderately severe disability alone should not be considered, per se, as a contraindication to IVT treatment.

Treatment with exenatide in acute ischemic stroke trial protocol: A prospective, randomized, open label, blinded end-point study of exenatide vs. standard care in post stroke hyperglycemia.

Rationale Post-stroke hyperglycemia occurs in up to 50% of patients presenting with acute ischemic stroke. It reduces the efficacy of thrombolysis, increases infarct size, and worsens clinical outcomes. Insulin-based therapies have generally not been beneficial in treating post-stroke hyperglycemia as they are difficult to implement, may cause hypoglycaemia, possibly increase mortality and worsen clinical outcomes. Exenatide may be a safer, simpler, and more effective alternative to insulin in acute ischemic stroke. Design TEXAIS is a three year, Phase 2, multi-center, prospective, randomized, open label, blinded end-point trial comparing exenatide to standard of care. It aims to recruit 528 patients with a primary end point of major neurological improvement at 7 days defined as a ≥8-point improvement in NIHSS score, or NIHSS 0-1. Secondary outcomes of hyper- and hypoglycaemia at 5 days and NIHSS and mRS at 90 days will be measured. The treatment arm will receive exenatide 5 µg subcutaneously twice daily. The control arm will receive standard stroke unit care. Continuous glucose monitors will track the dynamic variability of glucose. Conclusion TEXAIS aims to show that exenatide is safe and effective in the treatment of post-stroke hyperglycemia. It has been designed to be highly generalizable with an ability to enroll a large percentage of patients with acute ischemic stroke, regardless of admission blood glucose level, diabetes status, or stroke severity, with very low risk of hypoglycemia. Trial registration: ClinicalTrials.gov/ANZCTR NTA1127.

Efficacy and Safety of Intravenous Tenecteplase Bolus in Acute Ischemic Stroke: Results of Two Open-Label, Multicenter Trials.

Tenecteplase (TNK-tPA) is a promising third-generation plasminogen activator, because of its greater fibrin specificity and longer half-life than alteplase. There is a paucity of studies on intravenous thrombolysis using TNK-tPA in developing countries. The present study has been undertaken to compare the efficacy and safety of TNK-tPA with alteplase. Two studies were conducted. Study I was an open-label, randomized study in which two doses of TNK-tPA (0.1 and 0.2mg/kg) were compared. Study II was an open-label study in which TNK-tPA 0.2mg/kg bolus was compared with historical controls. The primary endpoint for studyI and studyII was an improvement of ≥ 8 points or a score of 0 on the National Institutes of Health Stroke Scale (NIHSS) [major neurological improvement (MNI)] at 24h. Secondary endpoints for both studies were neurological improvement as assessed using the NIHSS score, modified Rankin Scale (mRS) score and the Barthel Index (BI) on days 7, 30 and 90. Minimal disability was defined as an mRS score of 0 or 1 and good functional recovery as a BI score of 50-90. Safety was assessed by the proportion of patients having symptomatic intracranial hemorrhage (sICH) within 36h and asymptomatic intracranial hemorrhage at 48h after treatment. In study I, 20 patients received 0.1mg/kg and 30 received 0.2mg/kg TNK-tPA. There was no significant difference in MNI at 24h between 0.1 and 0.2mg/kg TNK-tPA doses. The patients given 0.2mg/kg TNK-tPA had a significantly better 3-month outcome (minimal disability, p = 0.007). There was no sICH in studyI. In studyII, 62 patients(one lost to follow-up) received 0.2mg/kg TNK-tPA. MNI was noted in ten patients (16.4%), 3-month minimal disability was noted in 37 patients (60.7%), and good functional recovery was seen in 33 patients (54.1%). sICH occurred in one patient, and four patients died. Pooled data of patients in studyI and studyII receiving 0.2 mg/kg TNK-tPA were compared with data from the historical National Institute of Neurological Disorders and Stroke (NINDS) trial. For comparison, the primary endpoint of the NINDS trial (improvement on NIHSS of ≥ 4 points or a score of 0 at 24h) was taken. The primary endpoint though was not significantly different (58.2% vs. 47%, p = 0.08), but with TNK-tPA, greater neurological improvement, minimal disability (70.3 vs. 39%, p < 0.001) and good functional recovery (36.3 vs. 16%, p < 0.001) was noted at 3months. There was a lower incidence of sICH (1.1 vs. 6.4%, p = 0.05) and lower 3-month mortality (5.5 vs. 17%, p = 0.01) noted with TNK-tPA compared with alteplase. Intravenous TNK-tPA 0.2mg/kg administered within 3 hours of symptom onset seems to be well tolerated and effective optionin patients with acute ischemic stroke. Clinical Trials Registry-India, www.ctri.nic.in ; unique identifiers: CTRI/2009/091/000251 and CTRI/2015/02/005556.