Intra-arterial neuroprotective therapy as an adjunct to endovascular intervention in acute ischemic stroke: A review of the literature and future directions.
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SUBMITTER: Link TW
PROVIDER: S-EPMC7446578 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Intra-arterial therapy (IAT) for acute ischemic stroke refers to endovascular catheter-based approaches to achieve recanalization using mechanical clot disruption, locally injected thrombolytic agents or both. IAT may be used in addition to intravenous tissue plasminogen activator (tPA) or in patients who do not qualify for tPA, usually because they are outside the approved 3-h timeframe window or have contraindications, such as elevated international normalized ratio or partial thromboplastin time. Recanalization rates correlate with clinical improvement, and with the newest catheters it is possible to achieve recanalization in roughly 80% of patients treated. However, while the catheters are approved by the Food and Drug Administration, there are still no randomized trial data demonstrating the role of current IAT therapy vs either tPA or standard management. IAT is reserved for patients with large artery occlusions in the basilar, distal carotid, or proximal middle cerebral arteries. Imaging the penumbra using magnetic resonance imaging or computed tomographic perfusion is currently the most frequently used way to identify patients who might benefit. However, the imaging and clinical criteria for identifying which patients benefit, and perhaps more importantly those who will do poorly despite IAT, remain unclear.
| S-EPMC3250276 | biostudies-other
Project description:Ischemic stroke is the main cause of death and the most common cause of acquired physical disability worldwide. Recent demographic changes increase the relevance of stroke and its sequelae. The acute treatment for stroke is restricted to causative recanalization and restoration of cerebral blood flow, including both intravenous thrombolysis and mechanical thrombectomy. Still, only a limited number of patients are eligible for these time-sensitive treatments. Hence, new neuroprotective approaches are urgently needed. Neuroprotection is thus defined as an intervention resulting in the preservation, recovery, and/or regeneration of the nervous system by interfering with the ischemic-triggered stroke cascade. Despite numerous preclinical studies generating promising data for several neuroprotective agents, successful bench-to-bedside translations are still lacking. The present study provides an overview of current approaches in the research field of neuroprotective stroke treatment. Aside from "traditional" neuroprotective drugs focusing on inflammation, cell death, and excitotoxicity, stem-cell-based treatment methods are also considered. Furthermore, an overview of a prospective neuroprotective method using extracellular vesicles that are secreted from various stem cell sources, including neural stem cells and bone marrow stem cells, is also given. The review concludes with a short discussion on the microbiota-gut-brain axis that may serve as a potential target for future neuroprotective therapies.
| S-EPMC10002358 | biostudies-literature
Project description:BackgroundMost disabling strokes are due to a blockage of a large artery in the brain by a blood clot. Prompt removal of the clot with intra-arterial thrombolytic drugs or mechanical devices, or both, can restore blood flow before major brain damage has occurred, leading to improved recovery. However, these so-called endovascular interventions can cause bleeding in the brain. This is a review of randomised controlled trials of endovascular thrombectomy or intra-arterial thrombolysis, or both, for acute ischaemic stroke.ObjectivesTo assess whether endovascular thrombectomy or intra-arterial interventions, or both, plus medical treatment are superior to medical treatment alone in people with acute ischaemic stroke.Search methodsWe searched the Trials Registers of the Cochrane Stroke Group and Cochrane Vascular Group (last searched 1 September 2020), CENTRAL (the Cochrane Library, 1 September 2020), MEDLINE (May 2010 to 1 September 2020), and Embase (May 2010 to 1 September 2020). We also searched trials registers, screened reference lists, and contacted researchers.Selection criteriaRandomised controlled trials (RCTs) of any endovascular intervention plus medical treatment compared with medical treatment alone in people with definite ischaemic stroke.Data collection and analysisTwo review authors (MBR and MJ) applied the inclusion criteria, extracted data, and assessed trial quality. Two review authors (MBR and HL) assessed risk of bias, and the certainty of the evidence using GRADE. We obtained both published and unpublished data if available. Our primary outcome was favourable functional outcome at the end of the scheduled follow-up period, defined as a modified Rankin Scale score of 0 to 2. Eighteen trials (i.e. all but one included trial) reported their outcome at 90 days. Secondary outcomes were death from all causes at in the acute phase and by the end of follow-up, symptomatic intracranial haemorrhage in the acute phase and by the end of follow-up, neurological status at the end of follow-up, and degree of recanalisation.Main resultsWe included 19 studies with a total of 3793 participants. The majority of participants had large artery occlusion in the anterior circulation, and were treated within six hours of symptom onset with endovascular thrombectomy. Treatment increased the chance of achieving a good functional outcome, defined as a modified Rankin Scale score of 0 to 2: risk ratio (RR) 1.50 (95% confidence interval (CI) 1.37 to 1.63; 3715 participants, 18 RCTs; high-certainty evidence). Treatment also reduced the risk of death at end of follow-up: RR 0.85 (95% CI 0.75 to 0.97; 3793 participants, 19 RCTs; high-certainty evidence) without increasing the risk of symptomatic intracranial haemorrhage in the acute phase: RR 1.46 (95% CI 0.91 to 2.36; 1559 participants, 6 RCTs; high-certainty evidence) or by end of follow-up: RR 1.05 (95% CI 0.72 to 1.52; 1752 participants, 10 RCTs; high-certainty evidence); however, the wide confidence intervals preclude any firm conclusion. Neurological recovery to National Institutes of Health Stroke Scale (NIHSS) score 0 to 1 and degree of recanalisation rates were better in the treatment group: RR 2.03 (95% CI 1.21 to 3.40; 334 participants, 3 RCTs; high-certainty evidence) and RR 3.11 (95% CI 2.18 to 4.42; 268 participants, 3 RCTs; high-certainty evidence), respectively.Authors' conclusionsIn individuals with acute ischaemic stroke due to large artery occlusion in the anterior circulation, endovascular thrombectomy can increase the chance of survival with a good functional outcome without increasing the risk of intracerebral haemorrhage or death.
| S-EPMC8203212 | biostudies-literature
Project description:The objective of this study was to determine the cost-effectiveness of intra-arterial treatment within the 0- to 6-hour window after intravenous tissue-type plasminogen activator within 0- to 4.5-hour compared with intravenous tissue-type plasminogen activator alone, in the US setting and from a social perspective.A decision analytic model estimated the lifetime costs and outcomes associated with the additional benefit of intra-arterial therapy compared with standard treatment with intravenous tissue-type plasminogen activator alone. Model inputs were obtained from published literature, the Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands (MR CLEAN) study, and claims databases in the United States. Health outcomes were measured in quality-adjusted life years (QALYs). Treatment benefit was assessed by calculating the cost per QALY gained. One-way and probabilistic sensitivity analyses were performed to estimate the overall uncertainty of model results.The addition of intra-arterial therapy compared with standard treatment alone yielded a lifetime gain of 0.7 QALY for an additional cost of $9911, which resulted in a cost of $14 137 per QALY. Multivariable sensitivity analysis predicted cost-effectiveness (?$50 000 per QALY) in 97.6% of simulation runs.Intra-arterial treatment after intravenous tissue-type plasminogen activator for patients with anterior circulation strokes within the 6-hour window is likely cost-effective. From a societal perspective, increased investment in access to intra-arterial treatment for acute stroke may be justified.
| S-EPMC4480156 | biostudies-literature
Project description:Ischemic stroke is a heterogeneous condition influenced by a combination of genetic and environmental factors. Recent advancements have explored genetics in relation to various aspects of ischemic stroke, including the alteration of individual stroke occurrence risk, modulation of treatment response, and effectiveness of post-stroke functional recovery. This article aims to review the recent findings from genetic studies related to various clinical and molecular aspects of ischemic stroke. The potential clinical applications of these genetic insights in stratifying stroke risk, guiding personalized therapy, and identifying new therapeutic targets are discussed herein.
| S-EPMC10743455 | biostudies-literature
Project description:BackgroundThe smoking-paradox of a better outcome in ischemic stroke patients who smoke may be due to increased efficacy of thrombolysis. We investigated the effect of smoking on outcome following endovascular therapy (EVT) with mechanical thrombectomy alone versus in combination with intra-arterial (IA-) thrombolysis.MethodsThe primary endpoint was defined by three-month modified Rankin Scale (mRS). We performed a generalized linear model and reported relative risks (RR) for smoking (adjustment for age, sex, hypertension, atrial fibrillation, stroke severity, time to EVT) in patient data stemming from the Virtual International Stroke Trials Archive-Endovascular database.ResultsAmong 1,497 patients, 740(49.4%) were randomized to EVT; among EVT patients, 524(35.0%) received mechanical thrombectomy alone and 216(14.4%) received it in combination with IA-thrombolysis. Smokers (N = 396) had lower mRS scores (mean 2.9 vs. 3.2; p = 0.02) and mortality rates (10% vs. 17.3%; p<0.001) in univariate analysis. In all patients and in patients treated with mechanical thrombectomy alone, smoking had no effect on outcome in regression analyses. In patients who received IA-thrombolysis (N = 216;14%), smoking had an adjusted RR of 1.65 for an mRS≤1 (95%CI 0.77-3.55). Treatment with IA-thrombolysis itself led to reduced RR for favorable outcome (adjusted RR 0.30); interaction analysis of IA-thrombolysis and smoking revealed that non-smokers with IA-thrombolysis had mRS≤2 in 47 cases (30%, adjusted RR 0.53 [0.41-0.69]) while smokers with IA-thrombolysis had mRS≤2 in 23 cases (38%, adjusted RR 0.61 [0.42-0.87]).ConclusionsSmokers had no clear clinical benefit from EVT that incorporates IA-thrombolysis.
| S-EPMC8136663 | biostudies-literature
Project description:The three randomised controlled trials, Interventional Management of Stroke III (IMS3), Mechanical Retrieval and Revascularization of Stroke Clots Using Embolectomy (MR RESCUE) and Synthesis Expanasion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischaemic Stroke (SYNTHESIS EXP) showed no significant difference in clinical outcomes comparing intra-arterial (IA) therapy with intravenous thrombolysis. This article will explore the reasons for failure to show superiority of IA therapy.There are many reasons for the disappointing results of the three randomised controlled trials. Opposing views on IA therapy exist. Critics argue that only a small percentage of patients will be eligible for IA therapy and that it will never be cost-effective. Additionally, current trials have failed to address superior recanalization rates of new generation devices and lack of patient selection by advanced imaging. Time-to-treatment is longer in these randomised controlled trials and stroke outcomes were worse than anticipated. The current randomised controlled trials also took long periods to complete. There is emerging evidence that general anesthetic negatively influences outcome. Next generation trials will attempt to address these issues. Key Messages: There are disparate explanations for the disappointing results from the three IA therapy randomized controlled studies. Poor recanalisation rates with first generation endovascular devices, lack of advanced neuroimaging to aid in patient selection, lack of data surrounding the use of general anaesthesia, and prolonged time-to-treatment are potential contributors to negative results. The new generation of trials has the potential of addressing these pressing issues.
| S-EPMC4062314 | biostudies-other
Project description:Large vessel ischemic stroke represents the most disabling subtype. While t-PA and endovascular thrombectomy can recanalize the occluded vessel, good clinical outcomes are not uniformly achieved. We propose that supplementing endovascular thrombectomy with superselective intra-arterial (IA) verapamil immediately following recanalization could be safe and effective. Verapamil, a calcium channel blocker, has been shown to be an effective IA adjunct in a pre-clinical mouse focal ischemia model. To demonstrate translational efficacy, mechanism, feasibility, and safety, we conducted a group of translational experiments. We performed in vivo IA dose-response evaluation in our animal stroke model with C57/Bl6 mice. We evaluated neuroprotective mechanism through in vitro primary cortical neuron (PCN) cultures. Finally, we performed a Phase I trial, SAVER-I, to evaluate feasibility and safety of administration in the human condition. IA verapamil has a likely plateau or inverted-U dose-response with a defined toxicity level in mice (LD50 16-17.5?mg/kg). Verapamil significantly prevented PCN death and deleterious ischemic effects. Finally, the SAVER-I clinical trial showed no evidence that IA verapamil increased the risk of intracranial hemorrhage or other adverse effect/procedural complication in human subjects. We conclude that superselective IA verapamil administration immediately following thrombectomy is safe and feasible, and has direct, dose-response-related benefits in ischemia.
| S-EPMC5669346 | biostudies-literature
Project description:Treatment with CD34+ hematopoietic stem/progenitor cells has been shown to improve functional recovery in nonhuman models of ischemic stroke via promotion of angiogenesis and neurogenesis. We aimed to determine the safety and feasibility of treatment with CD34+ cells delivered intra-arterially in patients with acute ischemic stroke. This was the first study in human subjects. We performed a prospective, nonrandomized, open-label, phase I study of autologous, immunoselected CD34+ stem/progenitor cell therapy in patients presenting within 7 days of onset with severe anterior circulation ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score?8). CD34+ cells were collected from the bone marrow of the subjects before being delivered by catheter angiography into the ipsilesional middle cerebral artery. Eighty-two patients with severe anterior circulation ischemic stroke were screened, of whom five proceeded to treatment. The common reasons for exclusion were age>80 years (n=19); medical instability (n=17), and significant carotid stenosis (n=13). The procedure was well tolerated in all patients, and no significant treatment-related adverse effects occurred. All patients showed improvements in clinical functional scores (Modified Rankin Score and NIHSS score) and reductions in lesion volume during a 6-month follow-up period. Autologous CD34+ selected stem/progenitor cell therapy delivered intra-arterially into the infarct territory can be achieved safely in patients with acute ischemic stroke. Future studies that address eligibility criteria, dosage, delivery site, and timing and that use surrogate imaging markers of outcome are desirable before larger scale clinical trials.
| S-EPMC4214837 | biostudies-literature
Project description:Despite great improvement during the past several decades, the management of stroke is still far from satisfactory, which warrants alternative or adjunctive strategies. Remote ischemic conditioning (RIC), an easy-to-use and noninvasive therapy, can be performed in various clinical scenarios (e.g., prehospital transportation, intrahospital, and at home), and it has been widely investigated for stroke management. RIC has been demonstrated to be well tolerated in patients with acute ischemic stroke and aneurysm subarachnoid hemorrhage, and it may benefit these patients by improving clinical outcomes; in patients with intracranial atherosclerosis, long-term repeated RIC could be safely performed and benefit patients by reducing recurrent ischemic stroke and transient ischemic attack, as well as improving cerebral perfusion status; long-term repeated RIC may also benefit patients with cerebral small vessel disease by slowing cognitive decline and reducing volume of white matter hyperintensities on brain MRI; in patients with severe carotid atherosclerotic stenosis undergoing stenting, preprocedural RIC could reduce the odds of new brain lesions on postprocedural MRI. Previous clinical studies suggest broad future prospects of RIC in the field of cerebrovascular diseases. However, the optimal RIC protocol and the mechanisms that RIC protects the brain is not fully clear, and there is lack of sensitive and specific biomarkers of RIC, all these dilemmas prevent RIC from entering clinical practice. This review focuses on recent advances in clinical studies of RIC in stroke management, its challenges, and the potential directions of future studies.
| S-EPMC6331204 | biostudies-literature