Article

Results of the THERAPY trial: a prospective, randomized trial to define the role of mechanical thrombectomy as adjunctive treatment to IV rtPA in acute ischemic stroke

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  • Texas Stroke Institute
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... [8][9][10][11][12] These studies have been further supported by two more RCTs that reported a positive result or a positive trend after interim analyses. [13,14] On the strength of these positive findings, updated American Heart Association/American Stroke Association guideline recommends mechanical thrombectomy with a stent retriever as class I, level A evidenced-based treatment. [15] A recent meta-analysis concluded that endovascular treatment in addition to intravenous thrombolysis yields improved functional outcome and lower mortality after 3 months compared with intravenous thrombolysis alone. ...
... I 2 = 0%). 13 (13-20) 17 (12)(13)(14)(15)(16)(17)(18)(19)(20) 17 (13)(14)(15)(16)(17)(18)(19) 17 (12)(13)(14)(15)(16)(17)(18)(19) 20 ...
... I 2 = 0%). 13 (13-20) 17 (12)(13)(14)(15)(16)(17)(18)(19)(20) 17 (13)(14)(15)(16)(17)(18)(19) 17 (12)(13)(14)(15)(16)(17)(18)(19) 20 ...
Article
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Background and Purpose Recent randomized controlled trials have demonstrated consistent effectiveness of endovascular treatment (EVT) for acute ischemic stroke, leading to update on stroke management guidelines. We conducted this meta-analysis to assess the efficacy and safety of EVT overall and in subgroups stratified by age, baseline stroke severity, brain imaging feature, and anesthetic type. Methods Published randomized controlled trials comparing EVT and standard medical care alone were evaluated. The measured outcomes were 90-day functional independence (modified Rankin Scale ≤2), all-cause mortality, and symptomatic intracranial hemorrhage. Results Nine trials enrolling 2476 patients were included (1338 EVT, 1138 standard medical care alone). For patients with large vessel occlusions confirmed by noninvasive vessel imaging, EVT yielded improved functional outcome (pooled odds ratio [OR], 2.02; 95% confidence interval [CI], 1.64–2.50), lower mortality (OR, 0.75; 95% CI, 0.58–0.97), and similar symptomatic intracranial hemorrhage rate (OR, 1.12; 95% CI, 0.72–1.76) compared with standard medical care. A higher proportion of functional independence was seen in patients with terminus intracranial artery occlusion (±M1) (OR, 3.16; 95% CI, 1.64–6.06), baseline Alberta Stroke Program Early CT score of 8–10 (OR, 2.11; 95% CI, 1.25–3.57) and age ≤70 years (OR, 3.01; 95% CI, 1.73–5.24). EVT performed under conscious sedation had better functional outcomes (OR, 2.08; 95% CI, 1.47–2.96) without increased risk of symptomatic intracranial hemorrhage or short-term mortality compared with general anesthesia. Conclusions Vessel-imaging proven large vessel occlusion, a favorable scan, and younger age are useful predictors to identify anterior circulation stroke patients who may benefit from EVT. Conscious sedation is feasible and safe in EVT based on available data. However, firm conclusion on the choice of anesthetic types should be drawn from more appropriate randomized controlled trials.
... Five positive randomised trials have now been published, [1][2][3][4][5] which used predominantly stent retrievers in patients with occlusions in anterior circulation vessels only, and two more have reported interim outright positive results 6 or a trend to positive results 13 in the form of abstracts. The MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) 1 was the first to be completed. ...
... REVASCAT (Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset) 5 was halted at a pre-planned interim analysis because of loss of equipoise in the trial population and because the intervention was associated with significantly improved functional outcome. The THRACE (Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke) study 6 ran to completion and has reported positive interim results, whereas the THERAPY (Assess the Penumbra System in the Treatment of Acute Stroke) trial, 13 which used aspiration catheters, was terminated early, showing a trend to benefit. In this Rapid Review, we summarise the results of the latest trials and discuss the implications for stroke management. ...
Article
Results of initial randomised trials of endovascular treatment for ischaemic stroke, published in 2013, were neutral but limited by the selection criteria used, early-generation devices with modest efficacy, non-consecutive enrolment, and treatment delays. In the past year, six positive trials of endovascular thrombectomy for ischaemic stroke have provided level 1 evidence for improved patient outcome compared with standard care. In most patients, thrombectomy was performed in addition to thrombolysis with intravenous alteplase, but benefits were also reported in patients ineligible for alteplase treatment. Despite differences in the details of eligibility requirements, all these trials required proof of major vessel occlusion on non-invasive imaging and most used some imaging technique to exclude patients with a large area of irreversibly injured brain tissue. The results indicate that modern thrombectomy devices achieve faster and more complete reperfusion than do older devices, leading to improved clinical outcomes compared with intravenous alteplase alone. The number needed to treat to achieve one additional patient with independent functional outcome was in the range of 3·2-7·1 and, in most patients, was in addition to the substantial efficacy of intravenous alteplase. No major safety concerns were noted, with low rates of procedural complications and no increase in symptomatic intracerebral haemorrhage. WHERE NEXT?: Thrombectomy benefits patients across a range of ages and levels of clinical severity. A planned meta-analysis of individual patient data might clarify effects in under-represented subgroups, such as those with mild initial stroke severity or elderly patients. Imaging-based selection, used in some of the recent trials to exclude patients with large areas of irreversible brain injury, probably contributed to the proportion of patients with favourable outcomes. The challenge is how best to implement imaging in clinical practice to maximise benefit for the entire population and to avoid exclusion of patients with smaller yet clinically important potential to benefit. Although favourable imaging identifies patients who might benefit despite long delays from symptom onset to treatment, the proportion of patients with favourable imaging decreases with time. Health systems therefore need to be reorganised to deliver treatment as quickly as possible to maximise benefits. On the basis of available trial data, intravenous alteplase remains the initial treatment for all eligible patients within 4·5 h of stroke symptom onset. Those patients with major vessel occlusion should, in parallel, proceed to endovascular thrombectomy immediately rather than waiting for an assessment of response to alteplase, because minimising time to reperfusion is the ultimate aim of treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.
... Two new clinical trials, the Trial and Cost-Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke (THRACE) [127] and the Assess the Penumbra System in the Treatment of Acute Stroke (THERAPY) [128], have addressed these shortcomings by keeping selection criteria to a minimum except for the use of angiographic technique such as CTA or MRA to localize and confirm the arterial occlusion. The THRACE trial, conducted across 26 centres in France, included 336 patients, aged 18 to 80 years and NIHSS score ranging between 10 and 25, presenting within 5 h of symptom onset with moderate to a severe stroke caused by the large artery occlusion of the anterior circulation (radiologically confirmed on CTA), out of which 195 received IVT, and 141 received combined IVT and MT treatment, without a selection based on advanced imaging-based criteria. ...
... No significant differences in mortality and sICH risks were noted between the MT and control arms. The THERAPY trial, undertaken across four centres in the United States, selected patients with AIS presenting within 4.5 h of symptom onset who have evidence of large clot burden (clot length ≥ 8 mm) in the anterior circulation [128]. CTA was used to identify patients with large vessel occlusion. ...
Article
Full-text available
Following the success of recent endovascular trials, endovascular therapy has emerged as an exciting addition to the arsenal of clinical management of patients with acute ischemic stroke (AIS). In this paper, we present an extensive overview of intravenous and endovascular reperfusion strategies, recent advances in AIS neurointervention, limitations of various treatment paradigms, and provide insights on imaging-guided reperfusion therapies. A roadmap for imaging guided reperfusion treatment workflow in AIS is also proposed. Both systemic thrombolysis and endovascular treatment have been incorporated into the standard of care in stroke therapy. Further research on advanced imaging-based approaches to select appropriate patients, may widen the time-window for patient selection and would contribute immensely to early thrombolytic strategies, better recanalization rates, and improved clinical outcomes.
... Advanced imaging, specifically vascular imaging, was an essential component of the recent landmark clinical trials and their success. Multicenter Randomized Clinical Trial of Endovascular treatment for AIS in the Netherlands (MR CLEAN), Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke (THRACE), and Assess the Penumbra System in the Treatment of Acute Stroke (THERAPY) all required imaging evidence of LVO for enrollment (1)(2)(3). Even more selectively, THERAPY limited inclusion to LVOs of at least 8 mm in measured length (3). ...
... Multicenter Randomized Clinical Trial of Endovascular treatment for AIS in the Netherlands (MR CLEAN), Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke (THRACE), and Assess the Penumbra System in the Treatment of Acute Stroke (THERAPY) all required imaging evidence of LVO for enrollment (1)(2)(3). Even more selectively, THERAPY limited inclusion to LVOs of at least 8 mm in measured length (3). Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA) required not only detection of LVO but also an a priori determined favorable perfusion/ischemic mismatch profile within the affected vascular territory (4). ...
Article
Full-text available
Recent successful endovascular stroke trials have provided unequivocal support for these therapies in selected patients with large-vessel occlusive acute ischemic stroke. In this piece, we briefly review these trials and their utilization of advanced neuroimaging techniques that played a pivotal role in their success through targeted patient selection. In this context, the unique challenges and opportunity for advancement in current stroke networks' routine delivery of care created by these trials are discussed and recommendations to change current national stroke system guidelines are proposed.
... The eight RCTs comparing endovascular therapies with IV thrombolysis meeting the eligibility criteria included ESCAPE (9), EXTEND-IA (10), IMS III (5), MR CLEAN (8), MR RESCUE (7), REVASCAT (11), SWIFT PRIME (12), and SYN-THESIS (6). THERAPY (21) and THRACE (22), trials still awaiting publication, were not incorporated in this analysis. 1 Seven of the studies were multicenter trials based in several countries with REVASCAT the only trial to be conducted in one country (Spain). ...
Article
Acute ischemic strokes involving occlusion of large vessels usually recanalize poorly following treatment with intravenous thrombolysis. Recent studies have shown higher recanalization and higher good outcome rates with endovascular therapy compared with best medical management alone. A systematic review and meta-analysis investigating the benefits of all randomized controlled trials of endovascular thrombectomy where at least 25% of patients were treated with a thrombectomy device for the treatment of acute ischemic stroke compared with best medical treatment have yet to be performed. To perform a systematic review and a meta-analysis evaluating the effectiveness of endovascular thrombectomy compared with best medical care for treatment of acute ischemic stroke. Our search identified 437 publications, from which eight studies (totaling 2423 patients) matched the inclusion criteria. Overall, endovascular thrombectomy was associated with improved functional outcomes (modified Rankin Scale 0-2) [odds ratio 1·56 (1·32-1·85), P < 0·00001]. There was a tendency toward decreased mortality [odds ratio 0·84 (0·67-1·05), P = 0·12], and symptomatic intracerebral hemorrhage was not increased [odds ratio 1·03 (0·71-1·49), P = 0·88] compared with best medical management alone. The odds ratio for a favorable functional outcome increased to 2·23 (1·77-2·81, P < 0·00001) when newer generation thrombectomy devices were used in greater than 50% of the cases in each trial. There is clear evidence for improvement in functional independence with endovascular thrombectomy compared with standard medical care, suggesting that endovascular thrombectomy should be considered the standard effective treatment alongside thombolysis in eligible patients. © 2015 World Stroke Organization.
... There were several important differences in the study designs of the recent positive trials [9••, 10••, 11••, 12••, 13••, 76,77] as compared to the early neutral trials [68][69][70]. Firstly, these studies all required the confirmation of a proximal anterior circulation vascular occlusion using imaging (CT/CTA or MRA). ...
Article
Full-text available
More than 800,000 people in North America suffer a stroke each year, with ischemic stroke making up the majority of these cases. The outcomes of ischemic stroke range from complete functional and cognitive recovery to severe disability and death; outcome is strongly associated with timely reperfusion treatment. Historically, ischemic stroke has been treated with intravenous thrombolytic agents with moderate success. However, five recently published positive trials have established the efficacy of endovascular treatment in acute ischemic stroke. In this review, we will discuss the history of stroke treatments moving from various intravenous thrombolytic drugs to intra-arterial thrombolysis, early mechanical thrombectomy devices, and finally modern endovascular devices. Early endovascular therapy failures, recent successes, and implications for current ischemic stroke management and future research directions are discussed.
... [1][2][3][4][5] Two further trials have presented similar findings. 6,7 The success of these trials, compared with previous studies of IAT, was attributed to better patient selection (including the use of advanced imaging), streamlined study procedures to achieve rapid revascularisation, and the use of stent retriever devices, capable of producing high rates of recanalisation. 8 Introduction of IAT to routine acute stroke care requires re-organisation of stroke services, so that patients most likely to benefit are rapidly directed to centres where endovascular services are available. ...
Article
Introduction: Recent studies showed improved patient outcomes with endovascular treatment of acute stroke compared to medical care, including IV rtPA, alone. Seven trials have reported results, each using different clinical and imaging criteria for patient selection. We compared eligibility for different trial protocols to estimate the number of patients eligible for treatment. Patients and methods: Patient data were extracted from a single centre database that combined patients recruited to three clinical studies, each of which obtained both CTA and CTP within 6 h of stroke onset. The published inclusion and exclusion criteria of seven intervention trials (MR CLEAN, EXTEND-IA, ESCAPE, SWIFT-PRIME, REVASCAT, THERAPY and THRACE) were applied to determine the proportion that would be eligible for each of these studies. Results: A total of 263 patients was included. Eligibility for IAT in individual trials ranged from 53% to 3% of patients; 17% were eligible for four trials and under 10% for two trials. Only three patients (1%) were eligible for all studies. The most common cause of exclusion was absence of large artery occlusion (LAO) on CTA. When applying simplified criteria requiring an ASPECT score > 6, 16% were eligible for IAT, but potentially 40% of these patients were excluded by perfusion criteria and more than half by common NIHSS thresholds. Conclusion: Around 15% of patients presenting within 6 h of stroke onset were potentially eligible for IAT, but clinical trial eligibility criteria have much more limited overlap than is commonly assumed and only 1% of patients fulfilled criteria for all recent trials.
... ▸ Clot length-there is currently no evidence that short clots recanalise sufficiently often to justify waiting to see if thrombolysis works or omitting thrombectomy. Rates of pre-angiogram recanalisation were <10% in the trials (none excluded short clots except THERAPY, 32 which was neutral) ▸ Residual anterograde flow-requires dynamic angiography (eg, raw CTP data). There is evidence that thrombolysis works much better 33 but it is not sufficient to justify waiting to see if thrombolysis works or for omitting thrombectomy. ...
Article
Endovascular thrombectomy for large vessel ischaemic stroke substantially reduces disability, with recent positive randomised trials leading to guideline changes worldwide. This review discusses in detail the evidence provided by recent randomised trials and meta-analyses, the remaining areas of uncertainty and the future directions for research. The data from existing trials have demonstrated the robust benefit of endovascular thrombectomy for internal carotid and proximal middle cerebral artery occlusions. Uncertainty remains for more distal occlusions where the efficacy of alteplase is greater, less tissue is at risk and the safety of endovascular procedures is less established. Basilar artery occlusion was excluded from the trials, but with a dire natural history and proof of principle that rapid reperfusion is effective, it seems reasonable to continue treating these patients pending ongoing trial results. There has been no evidence of heterogeneity in treatment effect in clinically defined subgroups by age, indeed, those aged >80 years have at least as great an overall reduction in disability and reduced mortality. Similarly there was no heterogeneity across the range of baseline stroke severities included in the trials. Evidence that routine use of general anaesthesia reduces the benefit of endovascular thrombectomy is increasing and conscious sedation is generally preferred unless severe agitation or airway compromise is present. The impact of time delays has become clearer with description of onset to imaging and imaging to reperfusion epochs. Delays in the onset to imaging reduce the proportion of patients with salvageable brain tissue. However, in the presence of favourable imaging, rapid treatment appears beneficial regardless of the onset to imaging time elapsed. Imaging to reperfusion delays lead to decay in the clinical benefit achieved, particularly in those with less robust collateral flow. The brain imaging options to assess prognosis have various advantages and disadvantages, but whatever strategy is employed must be fast. Ongoing trials are investigating extended time windows, using advanced brain imaging selection. There is also a need for further technical advances to maximise rates of complete reperfusion in the minimum time.
... 39 Longer clot length as measured on thin-section NCCT has been associated in several studies with low probability of successful recanalization with IV tPA, [45][46][47] raising the possibility that this group might derive greater benefit from EVT. The only RCT that included clot length >8 mm as a selection criterion the unpublished THERAPY trial, 48 assessed the safety and effectiveness of the Penumbra System and was terminated prematurely with a sample size too small to identify a clear treatment effect. The interaction of clot length with EVT effect is therefore not established and further research is required. ...
... In 2015, five published trials and two conference proceeding articles, assessing the safety and efficacy of the EVT without or with IV t-PA comparing with IV t-PA, presented positive results and revolutionized the endovascular therapy. They are the Endovascular treatment for acute ischemic stroke in the Netherlands (MR CLEAN) [109], the Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) [110], the Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA) [111], Solitaire With the Intention For Thrombectomy as PRIMary Endovascular Treatment (SWIFT-PRIME) [112], the Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours (REVASCAT) [113], and the Assess the Penumbra System in the Treatment of Acute Stroke (THERAPY) and the Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke (THRACE) [114,115]. These trials are multicenter RCTs and have several characteristics in common on the design methods: radiological confirmation of LVO based on CTA or MRA; 3-months clinical outcomes assessed by mRS 0-2; only focus on occlusion involving the anterior circulation (the THRACE trial also included patients with occlusion in the posterior circulation); high rate of stent retriever devices use (more than 86% of overall average use rate among these seven trials). ...
Book
Stroke is the third leading cause of death and physical disability worldwide. Its burden is predicted to increase due to increased life expectancy and population aging. A stroke occurs when blood flow to the brain is abruptly obstructed by a clot (ischemic stroke) or when a blood vessel in the brain bursts, spilling blood into the spaces surrounding brain cells (hemorrhagic stroke). This book deals clearly and concisely the recent advancements done by Neurobiologist, scientist, and clinicians in the field of stroke biology. Here, we are trying to compile their cutting edge research work to provide the development of novel therapeutic interventions in the stroke patients. It will also be supportive content for the several neurosciences related masters programs such as brain and cognitive science. This is a life-enhancing book for people living with the effects of the stroke that provide advice on how to avoid stroke and significant input from dieticians and another therapist. We will provide enlightenment, about the pathogenic mechanisms related to ischemic strokes such as excitotoxicity, oxidative stress, inflammation, and apoptosis. It will cover the micro-RNAs regulation and its relevance with diagnosis, prognosis, and therapy. In addition to this, we will provide the overview of the progress made towards a role of stem cell including mesenchymal stem cell (MSCs), embryonic stem cell (ESCs), neural stem cell (NSC) and inducible pluripotent stem cells (iPSC) in stroke therapy. It will also explore the importance of nanomedicine to enhance the amount and concentration of therapeutic compounds in the brain. In the last chapter, we have reviewed the neuroimaging techniques such as CT scan, magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) to explore the cause and pinpoint the location of blockage in stroke patients.
Article
Five trials that investigated the efficacy of modern endovascular therapies for stroke - MR CLEAN, ESCAPE, SWIFT PRIME, EXTEND IA and REVASCAT - have been published within the past year, changing the landscape of acute stroke management. The trials used a variety of imaging modalities and combinations of treatment approaches, including the mandatory use of intravenous thrombolysis before the initiation of endovascular therapy. All five trials provided strong evidence to support the use of thrombectomy that is initiated within 6 h of stroke onset, prompting worldwide changes in the guidelines for management of acute stroke by endovascular treatment. The benefits of endovascular therapy were observed irrespective of a patient's age, their NIH Stroke Scale score, or whether they received intravenous thrombolysis. In this article, we review the main findings of these recent trials, focusing on key aspects of their designs, and discuss their impact on the future management of patients with acute stroke that results from large-vessel occlusion. We discuss the values of noncontrast CT ASPECTS, perfusion imaging and angiography for selecting patients to receive endovascular interventions. We also consider the role of thrombectomy beyond 6 h after stroke onset, and in patients with posterior circulation strokes.
Imaging is an increasingly key component of advances in stroke care. Its role in the success of multiple recently reported trials that have now driven new standards of practice highlights its expanding importance in acute stroke management. With significant gains already realized, routine practice only stands to benefit further from additional advances in imaging in the future. The degree to which imaging will impact stroke care, however, is uncertain and complex: multiple aspects of stroke research and its translation into updated practice contribute to it. In this article, a few of these critical issues and questions related to imaging and its potential, both present and future, to drive stroke care forward are addressed.
Article
The unambiguous benefit of thrombectomy in patients with emergent large vessel occlusion (ELVO) has now been demonstrated in five multicenter, prospective, randomized controlled trials.1–5 These trials ended just months after three randomized controlled trials had shown no benefit for thrombectomy.6–8 The positive trials differ from the negative trials in three important ways. First, modern thrombectomy devices (primarily stent retrievers) were used in each of the positive trials. Patients in the negative trials were primarily treated with intra-arterial thrombolytic infusions and the MERCI device, which have been shown to be much less effective in achieving an effective revascularization. Second, the positive trials mandated vascular imaging to confirm large vessel occlusion before enrollment. Confirmation of large vessel occlusion was a requirement for only the smallest of the earlier negative trials. A subsequent subgroup analysis of the largest trial indicated that for those patients with confirmation of large vessel occlusion there appeared to be a benefit for thrombectomy. Third, with experience derived from prior studies, the exclusion of patients with large areas of completed infarct and little likelihood of improving after endovascular therapy was recognized to be of critical importance. In three of the five positive trials, advanced imaging applications were incorporated into the screening process to help investigators exclude patients with large areas of completed infarction, and the others used either a ‘grey principle’ or the ASPECTS score to allow proceduralists to screen patients before enrollment. There were other differences in the design of the positive trials, but these three major differences, largely consistent across trials, accounted for their overwhelming and uniform positivity. These data have resulted …
Chapter
Stroke is a generic term for a clinical syndrome that includes focal cerebral infarction (ischaemic stroke), focal haemorrhage in the brain and subarachnoid haemorrhage [1]. Effective treatment of the patient who has sustained an acute stroke requires rapid assessment and early intervention. Acute stroke represents a true emergency for which time is crucial and, therefore, evaluation and treatment often proceed simultaneously. Advanced imaging techniques can provide information about the state of brain perfusion, metabolism and the cerebrovascular anatomy to help identify patients with viable brain tissue who may derive the greatest benefit from available therapies. Currently, several agents are available for rapid restoration of perfusion to the ischaemic brain. Development of stroke centres and systems of care have revolutionized the medical management of patients with acute stroke.
Book
This book provides detailed and comprehensive mechanistic insights of the various risk factors that lead to the ischemic stroke and the novel therapeutic interventions against it. The first section discusses the different ischemic cerebral stroke-induced inflammatory pathways and dysfunctionality of blood-brain barrier. The later sections of the book deals with the role of endoplasmic reticulum stress and mitophagy in cerebral stroke and introduces the different neuroimaging techniques such as Computed tomography (CT), Magnetic resonance imaging (MRI), Positron emission tomography (PET) and Single-Photon emission computed tomography (SPECT) that are used to identify the arterial blockages. The final section comprises of chapters that focus on various neuroprotective strategies and emerging therapeutic interventions for combating stroke pathophysiology. The chapters cover the role of stem cell therapy, the therapeutic effect of low-frequency electromagnetic radiations (LF-EMR), and implications of non-coding RNAs such as micro-RNAs as the biomarkers for diagnosis, prognosis, and therapy in ischemic stroke.
Article
Objective To determine the importance of mechanical thrombectomy (MT) in the treatment of ischemic stroke. Material and methods Analysis and comparison of randomized controlled trials (RCT) of MT versus i.v. thrombolysis (IVT) considering pathophysiological and logistic aspects. Results The use of MT is more effective than IVT for internal carotid artery terminus (ICAT), M1 segment and tandem occlusions, i.e. proximal internal carotid artery (ICA) occlusion or stenosis, even in patients older than 75–80 years of age. Due to the small sample sizes this question cannot be answered for patients with M2 occlusions. It is still uncertain whether MT is needed in patients with a low National Institutes of Health stroke scale (NIHSS) score, whether IVT is needed before MT and what type of imaging should be performed. Approximately one third of eligible patients currently undergo MT in Germany. Results from RCTs with stent retrievers for patients with vertebrobasilar artery occlusions are lacking. Conclusion After becoming established as a first-line therapy for patients with ICAT, M1 segment and tandem occlusions, the effectiveness of MT with stent retrievers has to proven in patients with more distal occlusions, low NIHSS scores and even vertebrobasilar artery occlusions.
Article
Recently, five independent randomized controlled clinical trials demonstrated the efficacy and safety of endovascular stroke treatment in stroke patients with occlusion of proximal intracranial arteries. The five trials MR CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME and REVASCAT randomized a total of 1287 stroke patients to either standard treatment, which in the majority of patients consisted of intravenous thrombolysis within 4.5 h of symptom onset or additional endovascular stroke treatment. In all the studies endovascular treatment resulted in a better clinical outcome with an odds ratio for a better clinical outcome 90 days after stroke ranging between 1.7 and 3.1 and an absolute increase in the proportion of patients with functionally independent outcome between 14 % and 31 %. The overwhelming benefit of endovascular treatment mainly results from mechanical thrombectomy using stent retriever devices and starting endovascular treatment within 6 h of symptom onset in stroke patients.
Article
Importance Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known.Objective To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT.Design, Setting, and Participants The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015.Main Outcomes and Measures Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion.Results Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours.Conclusion and Relevance For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion.Trial Registration trialregister.nl Identifier: NTR1804
Article
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Background and Purpose After numerous attempts to prove efficacy for endovascular treatment of ischemic stroke, a series of recent randomized controlled clinical trials (RCTs) established fast mechanical thrombectomy (MT) as a safe and effective novel treatment for emergent large vessel occlusion (ELVO) in the anterior cerebral circulation. Methods We reviewed five recent RCTs that evaluated the safety and efficacy of MT in ELVO patients and captured available information on recanalization/reperfusion, symptomatic intracranial hemorrhage (sICH), clinical outcome, and mortality. MT was performed with stent retrievers, aspiration techniques, or a combination of these endovascular approaches. We applied meta‐analytical methodology to evaluate the pooled effect of MT on recanalization/reperfusion, sICH, functional independence (modified Rankin scale score of 0–2) and 3‐month mortality rates in comparison to best medical therapy (BMT). Results MT was associated with increased likelihood of complete recanalization/reperfusion (RR: 2.22; 95%CI: 1.89–2.62; P < 0.00001) and 3‐month functional independence (RR: 1.72; 95%CI: 1.48–1.99; P < 0.00001) without any heterogeneity across trials (I ² = 0%). The absolute benefit increase in MT for complete recanalization/reperfusion and functional independence was 44 (NNT = 2) and 16 (NNT = 6), respectively. MT was not associated with increased risk of 3‐month mortality (15% with MT vs. 19% with BMT) and sICH (4.6% with MT vs. 4.3% with BMT), while small heterogeneity was detected across the included trials (I ² < 25%). Conclusions MT is a safe and highly effective treatment for patients with ELVO in the anterior circulation. For every six ELVO patients treated with MT three more will achieve complete recanalization at 24 h following symptom onset and one more will be functionally independent at 3 months in comparison to BMT.
Chapter
Stroke is one of the major causes of death worldwide, and the thrombolytic drug alteplase (tissue plasminogen activator or tPA) is the only treatment available for acute ischemic stroke; however, its use is limited by its short therapeutic window. Many potential therapeutic and diagnostic neuroprotectants to the brain are available, but, unfortunately, most of them are limited by the blood-brain barrier (BBB). Conversely, nanoparticles (NPs) easily cross the BBB with no undesired side effect and alteration of the integrity of BBB. Thus, NPs have created new facet in stroke therapy. The nanocarriers-based preclinical and clinical research in thrombolytic drug delivery is mentioned. Preclinical research carried out on different thrombolytic drug-loaded polymer, lipid, and magnetic nanoparticles showed an enhanced thrombolytic effect with least adverse effects. Targeted nanocarriers displayed an enhanced accumulation into thrombolytic area. NP-based drug delivery opens up new route for the management of thrombotic diseases.
Article
Purpose of review: The burden of disability from ischemic stroke continues to intensify. Any acute therapeutic option that reduces disability after ischemic stroke should be encouraged and further studied. In particular, the need for an effective treatment in patients with large vessel occlusion has been long overdue.Recent findings:Consistent trial evidence has answered this need in an emphatic fashion, demonstrating improved functional outcomes with endovascular therapy following better patient selection, new device technology, and reduced treatment times. The article discusses the current evidence and guidelines and highlights the inherent complexities of a specialized intervention whose demand will grow exponentially. The scope for future investigation especially using advanced imaging to expand patient selection will be considered.Summary:Endovascular thrombectomy is an established and highly efficacious acute treatment for ischemic stroke that we need to apply and implement to maximize benefit to the population.
Article
Acute ischemic stroke (AIS) is a leading cause of disability and death worldwide. To date, intravenous tissue plasminogen activator and mechanical thrombectomy have been standards of care for AIS. There have been many advances in diagnostic imaging and endovascular devices for AIS; however, most neuroprotective therapies seem to remain largely in the preclinical phase. While many neuroprotective therapies have been identified in experimental models, none are currently used routinely to treat stroke patients. This review seeks to summarize clinical studies pertaining to neuroprotection, as well as the different preclinical neuroprotective therapies, their presumed mechanisms of action, and their future applications in stroke patients.
Chapter
Since the 1960s with the first reported endovascular catheterization, the diagnostic and therapeutic horizon of neurointervention has continued to expand. This is in part due to the conception, development, and rapid evolution of catheter, device, and embolic materials. Endovascular treatment of fistulas, arteriovenous malformations, aneurysms, and acute ischemic stroke due to large vessel occlusion has become more refined and increasingly widespread. The persistent refinement of these tools will serve to challenge the field in seeking further continued improvement in patient outcomes.
Article
Objectives: To evaluate the efficacy and safety of endovascular treatment, particularly adjunctive intra-arterial mechanical thrombectomy, in patients with ischaemic stroke. Design: Systematic review and meta-analysis. Data sources: Medline, Embase, Cochrane Central Register of Controlled Trials, Web of Science, SciELO, LILACS, and clinical trial registries from inception to December 2015. Reference lists were crosschecked. Eligibility criteria for selecting studies: Randomised controlled trials in adults aged 18 or more with ischaemic stroke comparing endovascular treatment, including thrombectomy, with medical care alone, including intravenous recombinant tissue plasminogen activator (rt-PA). Trial endpoints were functional outcome (modified Rankin scale scores of ≤2) and mortality at 90 days after onset of symptoms. No language or time restrictions applied. Results: 10 randomised controlled trials (n=2925) were included. In pooled analysis endovascular treatment, including thrombectomy, was associated with a higher proportion of patients experiencing good (modified Rankin scale scores ≤2) and excellent (scores ≤1) outcomes 90 days after stroke, without differences in mortality or rates for symptomatic intracranial haemorrhage, compared with patients randomised to medical care alone, including intravenous rt-PA. Heterogeneity was high among studies. The more recent studies (seven randomised controlled trials, published or presented in 2015) proved better suited to evaluate the effect of adjunctive intra-arterial mechanical thrombectomy on its index disease owing to more accurate patient selection, intravenous rt-PA being administered at a higher rate and earlier, and the use of more efficient thrombectomy devices. In most of these studies, more than 86% of the patients were treated with stent retrievers, and rates of recanalisation were higher (>58%) than previously reported. Subgroup analysis of these seven studies yielded a risk ratio of 1.56 (95% confidence interval 1.38 to 1.75) for good functional outcomes and 0.86 (0.69 to 1.06) for mortality, without heterogeneity among the results of the studies. All trials were open label. Risk of bias was moderate across studies. The full results of two trials are yet to be published. Conclusions: Moderate to high quality evidence suggests that compared with medical care alone in a selected group of patients endovascular thrombectomy as add-on to intravenous thrombolysis performed within six to eight hours after large vessel ischaemic stroke in the anterior circulation provides beneficial functional outcomes, without increased detrimental effects. Systematic review registration: PROSPERO CRD42015019340.
Book
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Chapter
Acute ischemic strokes still account for substantial morbidity and mortality worldwide despite decades of research aimed at reducing the burden of this disease. Since the establishment of intravenous thrombolysis as the standard of care, advances in device technology have rapidly progressed while randomized clinical trials have struggled to keep pace. Early trials were hampered by inconsistent use of technology and poor patient selection, leading to overall futility. However, a string of recent studies utilizing the most modern technology has unequivocally proven the superiority of endovascular treatment for acute ischemic strokes caused by large vessel occlusion in select patients. We describe the sequential progression of this therapeutic paradigm in parallel with the clinical trials that have proven its efficacy and identify clinical questions that remain yet unanswered.
Article
Full-text available
The treatment of acute ischemic stroke has undergone dramatic changes recently subsequent to the demonstrated efficacy of intra-arterial (IA) device-based therapy in multiple trials. The selection of patients for both intravenous and IA therapy is based on timely imaging with either computed tomography or magnetic resonance imaging, and if IA therapy is considered noninvasive, angiography with one of these modalities is necessary to document a large-vessel occlusion amenable for intervention. More advanced computed tomography and magnetic resonance imaging studies are available that can be used to identify a small ischemic core and ischemic penumbra, and this information will contribute increasingly in treatment decisions as the therapeutic time window is lengthened. Intravenous thrombolysis with tissue-type plasminogen activator remains the mainstay of acute stroke therapy within the initial 4.5 hours after stroke onset, despite the lack of Food and Drug Administration approval in the 3-to 4.5-hour time window. In patients with proximal, large-vessel occlusions, IA device-based treatment should be initiated in patients with small/moderate-sized ischemic cores who can be treated within 6 hours of stroke onset. The organization and implementation of regional stroke care systems will be needed to treat as many eligible patients as expeditiously as possible. Novel treatment paradigms can be envisioned combining neuroprotection with IA device treatment to potentially increase the number of patients who can be treated despite long transport times and to ameliorate the consequences of reperfusion injury. Acute stroke treatment has entered a golden age, and many additional advances can be anticipated.
Article
OBJECTIVE The impact of extracranial carotid stenosis on interventional revascularization of acute anterior circulation stroke is unknown. The authors examined the effects of high-grade carotid stenosis on the results of endovascular treatment of patients in the Interventional Management of Stroke (IMS)-III trial. METHODS The 278 patients in the endovascular arm of the IMS-III trial were categorized according to the degree of carotid stenosis as determined by angiography. In comparing patients with severe stenosis or occlusion (≥ 70%) to those without severe stenosis (< 70%), the authors evaluated the time to endovascular reperfusion, modified Thrombolysis in Cerebrovascular Infarction (mTICI) scores, 24-hour mean infarct volumes, symptomatic intracerebral hemorrhage rates, and modified Rankin Scale (mRS) scores at 90 days. RESULTS Compared with the 249 patients with less than 70% stenosis, patients with severe stenosis (n = 29) were found to have a significantly longer mean time to reperfusion (105.7 vs 77.7 minutes, p = 0.004); differences in mTICI scores, infarct volumes, hemorrhage rates, and mRS scores at 90 days did not reach statistical significance. Multiple regression analysis revealed that severe carotid stenosis (p < 0.0001) and higher baseline National Institutes of Health Stroke Scale (NIHSS) scores (p = 0.004) were associated with an increase in time to reperfusion. Older age (p < 0.0001), higher NIHSS score (p < 0.0001), and the absence of reperfusion (p = 0.001) were associated with worse clinical outcomes. CONCLUSIONS Severe ipsilateral ICA stenosis was associated with a significantly longer time to reperfusion in the IMS-III trial. Although these findings may not translate directly to modern devices, this 28-minute delay in reperfusion has significant implications, raising concern over the treatment of tandem ICA stenosis and downstream large-vessel occlusion.
Article
Background: Recent randomized trials demonstrated the superiority of the mechanical thrombectomy over the best medical treatment in patients with acute ischemic stroke due to an occlusion of arteries of proximal anterior circulation. In this updated meta-analysis, we aimed to summarize the total clinical effects of the treatment, including the last trials. Methods: We performed literature search of Randomized Crontrolled Trials (RCTs) published between 2010 and October 2016, comparing endovenous thrombolysis plus mechanical thrombectomy (intervention group) with best medical care alone (control group). We identified 8 trials. Primary outcomes were reduced disability at 90 days from the event and symptomatic intracranial hemorrhage. Statistical analysis was performed pooling data into the 2 groups, evaluating outcome heterogeneity. The Mantel-Haenszel method was used to calculate odds ratios (ORs). Results: We analyzed data for 1845 patients (interventional group: 911; control group: 934). Mechanical thrombectomy contributed to a significant reduction in disability rate compared to the best medical treatment alone (OR: 2.087; 95% confidence interval [CI]: 1.718-2.535; P < .001). We calculated that for every 100 treated patients, 16 more participants have a good outcome as a result of mechanical treatment. No significant differences between groups were observed concerning the occurrence of symptomatic hemorrhage (OR: 1.021; 95% CI: 0.641-1.629; P = .739). Conclusion: Mechanical thrombectomy contributes to significantly increase the functional benefit of endovenous thrombolysis in patients with acute ischemic stroke caused by arterial occlusion of proximal anterior circulation, without reduction in safety. These findings are relevant for the optimization of the acute stroke management, including the implementation of networks between stroke centers.
Article
Full-text available
Cerebrovascular disease is the second cause of death and the sixth cause of morbidity worldwide, which will rise to fourth place by 2020. The treatment strategies for acute ischemic stroke (AIS) divided into two groups, including intravenous or intra-arterial thrombolysis and mechanical thrombectomy. Regarding growing development in the realm of diagnosis and treatment of stroke through state-of-the-art approaches, including emergent thrombectomy, there are new opportunities for investigation in this area. This is while a rough rate of 85% for strokes is occupied by, and the remained is hemorrhagic. Hence, the present study aimed to review recent advances in AIS with a focus on emergent thrombectomy. Here, we first provided the relevant history, and then the recent advances were discussed. The library data collection method was employed so that such databases as Web of Science, PubMed, and Science Direct used for data extraction. The evidence confirms the importance of emergent thrombectomy as all believe the famous statement "time is the brain." However, further investigations are required to find more strong evidence accordingly.
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