Tenecteplase for the treatment of acute ischemic stroke: a review of completed and ongoing randomized controlled trials

Alteplase has been the mainstay of thrombolytic treatment since the National Institutes of Neurological Disorders and Stroke trial was published in 1995. Over recent years, several trials have investigated alternative thrombolytic agents. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, has a longer half-life, allowing single intravenous bolus administration without infusion, is more fibrin specific, produces less systemic depletion of circulating fibrinogen, and is more resistant to plasminogen activator inhibitor compared to alteplase. Tenecteplase is established as the first-line intravenous thrombolytic drug for myocardial infarction, where it has been shown to achieve comparable reperfusion with reduced risk of systemic bleeding in comparison to alteplase. We review the literature on tenecteplase for the treatment of acute ischemic stroke, with a focus on the major completed and ongoing trials. Overall, tenecteplase shows promise for treatment of acute ischemic stroke, both in populations currently eligible for alteplase and also in groups not currently treated with thrombolysis

Automated final lesion segmentation in posterior circulation acute ischemic stroke using deep learning

Final lesion volume (FLV) is a surrogate outcome measure in anterior circulation stroke (ACS). In posterior circulation stroke (PCS), this relation is plausibly understudied due to a lack of methods that automatically quantify FLV. The applicability of deep learning approaches to PCS is limited due to its lower incidence compared to ACS. We evaluated strategies to develop a convolutional neural network (CNN) for PCS lesion segmentation by using image data from both ACS and PCS patients. We included follow-up non-contrast computed tomography scans of 1018 patients with ACS and 107 patients with PCS. To assess whether an ACS lesion segmentation generalizes to PCS, a CNN was trained on ACS data (ACS-CNN). Second, to evaluate the performance of only including PCS patients, a CNN was trained on PCS data. Third, to evaluate the performance when combining the datasets, a CNN was trained on both datasets. Finally, to evaluate the performance of transfer learning, the ACS-CNN was fine-tuned using PCS patients. The transfer learning strategy outperformed the other strategies in volume agreement with an intra-class correlation of 0.88 (95% CI: 0.83–0.92) vs. 0.55 to 0.83 and a lesion detection rate of 87% vs. 41–77 for the other strategies. Hence, transfer learning improved the FLV quantification and detection rate of PCS lesions compared to the other strategies

Public Health and Cost Benefits of Successful Reperfusion After Thrombectomy for Stroke

Background and Purpose- The benefit that endovascular thrombectomy offers to patients with stroke with large vessel occlusions depends strongly on reperfusion grade as defined by the expanded Thrombolysis in Cerebral Infarction (eTICI) scale. Our aim was to determine the lifetime health and cost consequences of the quality of reperfusion for patients, healthcare systems, and society. Methods- A Markov model estimated lifetime quality-adjusted life years (QALY) and lifetime costs of endovascular thrombectomy-treated patients with stroke based on eTICI grades. The analysis was performed over a lifetime horizon in a United States setting, adopting healthcare and societal perspectives. The reference case analysis was conducted for stroke at 65 years of age. National health and cost consequences of improved eTICI 2c/3 reperfusion rates were estimated. Input parameters were based on best available evidence. Results- Lifetime QALYs increased for every grade of improved reperfusion (median QALYs for eTICI 0/1: 2.62; eTICI 2a: 3.46; eTICI 2b: 5.42; eTICI 2c: 5.99; eTICI 3: 6.73). Achieving eTICI 3 over eTICI 2b reperfusion resulted on average in 1.31 incremental QALYs as well as healthcare and societal cost savings of $10 327 and$20 224 per patient. A 10% increase in the eTICI 2c/3 reperfusion rate of all annually endovascular thrombectomy-treated patients with stroke in the United States is estimated to yield additional 3656 QALYs and save $21.0 million and$36.8 million for the healthcare system and society, respectively. Conclusions- Improved reperfusion grants patients with stroke additional QALYs and leads to long-term cost savings. Procedural strategies to achieve complete reperfusion should be assessed for safety and feasibility, even when initial reperfusion seems to be adequate

Effect of atrial fibrillation on endovascular thrombectomy for acute ischemic stroke. A meta-analysis of individual patient data from six randomised trials: Results from the HERMES collaboration

Background: Atrial fibrillation is an important risk factor for ischemic stroke, and is associated with an increased risk of poor outcome after ischemic stroke. Endovascular thrombectomy is safe and effective in acute ischemic stroke patients with large vessel occlusion of the anterior circulation. This meta-analysis aims to investigate whether there is an interaction between atrial fibrillation and treatment effect of endovascular thrombectomy, and secondarily whether atrial fibrillation is associated with worse outcome in patients with ischemic stroke due to large vessel occlusion. Methods: Individual patient data were from six of the recent randomised clinical trials (MR CLEAN, EXTEND-IA, REVASCAT, SWIFT PRIME, ESCAPE, PISTE) in which endovascular thrombectomy plus standard care was compared to standard care alone. Primary outcome measure was the shift on the modified Rankin scale (mRS) at 90 days. Secondary outcomes were functional independence (mRS 0–2) at 90 days, National Institutes of Health Stroke Scale score at 24 h, symptomatic intracranial hemorrhage and mortality at 90 days. The primary effect parameter was the adjusted common odds ratio, estimated with ordinal logistic regression (shift analysis); treatment effect modification of atrial fibrillation was assessed with a multiplicative interaction term. Results: Among 1351 patients, 447 p

Automatic segmentation of cerebral infarcts in follow-up computed tomography images with convolutional neural networks

Background and purpose: Infarct volume is a valuable outcome measure in treatment trials of acute ischemic stroke and is strongly associated with functional outcome. Its manual volumetric assessment is, however, too demanding to be implemented in clinical practice. Objective: To assess the value of convolutional neural networks (CNNs) in the automatic segmentation of infarct volume in follow-up CT images in a large population of patients with acute ischemic stroke. Materials and methods: We included CT images of 1026 patients from a large pooling of patients with acute ischemic stroke. A reference standard for the infarct segmentation was generated by manual delineation. We introduce three CNN models for the segmentati

Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data (vol 18, pg 46, 2019)

Paroxysmal Cerebral Disorder

DWI Reversal Is Associated with Small Infarct Volume in Patients with TIA and Minor Stroke

The implications of the reversal of DWI abnormalities in patients with TIA and minor strokes were assessed. Patients were imaged within 24 hours of symptoms and followed for 3 months and baseline and final infarct volumes were calculated using DWI and FLAIR, respectively. Over 55% of patients had DWI lesions and 37% had perfusion deficits. DWI reversal occurred in 6% of patients with lesion volume being considerably smaller than in those that did not reverse. Perfusion abnormalities were less common in reversible lesions as well. The authors concluded that DWI lesion reversal is uncommon and more likely with smaller lesions

Supplementary Material for: Pre-Stroke CHADS₂ and CHA₂DS₂-VASc Scores Are Useful in Stratifying Three-Month Outcomes in Patients with and without Atrial Fibrillation

<b><i>Background:</i></b> CHADS₂ and CHA₂DS₂-VASc scores are validated tools for assessing stroke risk in patients with atrial fibrillation (AF). We investigated whether these scores are associated with 3-month stroke outcomes and evaluated the utility of these scores in stratifying 3-month stroke outcomes in both patients with and without AF. <b><i>Methods:</i></b> We analysed 6,612 acute ischaemic stroke patients from the Virtual International Stroke Trials Archive who received either placebo or ineffective active treatments not associated with significant cardiac complications. Outcomes included 3-month mortality, good functional outcomes defined as modified Rankin Scale score ≤1 and serious cardiac adverse events (SCAEs) defined as one of acute coronary syndrome, symptomatic heart failure, cardiopulmonary arrest, life-threatening arrhythmia and cardiac death. The association between the pre-stroke CHADS₂ and CHA₂DS₂-VASc scores and 3-month stroke outcomes was assessed using binary logistic regression. The utility of the two scores in estimating 3-month stroke outcomes was assessed using area under the receiver operator characteristic curves (AUC) and compared using the χ² test. <b><i>Results:</i></b> In this cohort, 26.5% had AF, 35.3% received IV tissue plasminogen activator (tPA), 17.7% died, 25.1% achieved good functional outcomes and 9.5% had ≥1 SCAE at 3 months. High-risk (≥2) pre-stroke CHADS₂ and CHA₂DS₂-VASc scores are both associated with 3-month mortality (CHADS₂: odds ratio, OR, 2.33, 95% confidence interval 1.81-3.00; CHA₂DS₂-VASc: OR 3.01, 2.00-4.80), good functional outcomes (CHADS₂: OR 0.47, 0.39-0.57; CHA₂DS₂-VASc: OR 0.55, 0.42-0.71) and SCAEs (CHADS₂: OR 1.76, 1.28-2.42; CHA₂DS₂-VASc: OR 2.69, 1.53-4.73) after adjusting for baseline differences in neurological impairment, tPA use and AF. The pre-stroke CHA₂DS₂-VASc score is better than the CHADS₂ score in estimating 3-month stroke outcomes in both patients with and without AF (p ≤ 0.005 in all AUC comparisons). High-risk pre-stroke CHA₂DS₂-VASc score has high sensitivity for mortality (AF: 0.96, 0.94-0.98; no AF: 0.88, 0.86-0.91) and negative predictive value for SCAE (AF: 0.93, 0.87-0.96; no AF: 0.96, 0.95-0.97) within 3 months. Low risk pre-stroke CHA₂DS₂-VASc score has high specificity for good functional outcome (AF: 0.99, 0.98-0.994; no AF: 0.94, 0.93-0.95) at 3 months. <b><i>Conclusions:</i></b> The pre-stroke CHA₂DS₂-VASc score appears to be a simple tool for identifying patients at lower risk of poor outcomes and serious cardiac complications within 3 months following ischaemic stroke in patients with and without AF