Reperfusion Therapies for Acute Ischemic Stroke: An Update

Acute ischemic stroke is a major cause of morbidity and mortality in developed countries. Intravenous thrombolysis with tissue plasminogen activator (tPA) within 4.5 hours of symptoms onset significantly improves clinical outcomes in patients with acute ischemic stroke. This narrow window for treatment leads to a small proportion of eligible patients to be treated. Intravenous or intra-arterial trials, combined intravenous/intra-arterial trials, and newer devices to mechanically remove the clot from intracranial arteries have been investigated or are currently being explored to increase patient eligibility and to improve arterial recanalization and clinical outcome. New retrievable stent-based devices offer higher revascularization rates with shorter time to recanalization and are now generally preferred to first generation thrombectomy devices such as Merci Retriever or Penumbra System. These devices have been shown to be effective for opening up occluded vessels in the brain but its efficacy for improving outcomes in patients with acute stroke has not yet been demonstrated in a randomized clinical trial. We summarize the results of the major systemic thrombolytic trials and the latest trials employing different endovascular approaches to ischemic stroke.     

Innovative strategies in the management of acute stroke

Advances in acute stroke therapy are rapidly changing our approach to management of patients with ischemic stroke. Intravenous tissue-plasminogen activator (tPA) was the first treatment demonstrated in a randomized controlled trial to improve outcome if given within the first 3 hours of stroke onset. Subsequent trials failed to extend the time window for intravenous therapy beyond 3 hours. Intra-arterial thrombolysis provides an alternative approach, with several advantages over intravenous therapy. The major drawback is the additional time needed for the interventional procedure, and the equipment and personnel requirements. New strategies aimed at reducing the total time from stroke onset to recanalization of occluded arteries include a combined intravenous/ intra-arterial delivery of thrombolysis and mechanical devices. For the millions of stroke survivors, investigations are now underway into the possibility of improvement of function through neuronal transplantation.     

Innovative Strategies in the Management of Acute Stroke

Opinion statement Advances in acute stroke therapy are rapidly changing our approach to the management of patients with ischemic stroke. Intravenous tissue plasminogen activator was the first treatment demonstrated in a randomized controlled trial to improve outcome if given within the first 3 hours of stroke onset. Subsequent trials failed to extend the time window for intravenous therapy beyond 3 hours. Intraarterial thrombolysis provides an alternative approach, with several advantages over intravenous therapy. The major drawback is the additional time needed for the interventional procedure, and the equipment and personnel requirements. New strategies aimed at reducing the total time from stroke onset to recanalization of occluded arteries include a combined intravenous/intra-arterial delivery of thrombolysis and mechanical devices. For the millions of stroke survivors, investigations are now underway into the possibility of improvement of function through neuronal transplantation.     

Treatment of Acute Ischemic Stroke With Clot Retrieval Devices

OPINION STATEMENT: Mechanical clot retrieval is increasingly used for flow-restoration and thrombectomy in acute embolic stroke. Emerging as a treatment option in addition to intravenous or intra-arterial thrombolysis, it is currently being further developed and investigated as a potential first-line and stand-alone treatment. The ability to rapidly restore flow and effectively retrieve clots from large intracranial arteries is reflected by angiographic data and preliminary clinical results. This article reviews the principles and technical aspects of this new technique, its emergence from the spectrum of intravenous and endovascular stroke treatment, and summarizes the first clinical results for acute ischemic anterior and posterior circulation stroke. Clot retrieval devices are a very promising option for treatment of acute ischemic stroke in the setting of large vessel occlusion. However, there currently exists a reported discrepancy between excellent recanalization rates and less satisfactory clinical outcomes. This problem urgently needs to be addressed in a prospective randomized fashion and improvements of treatment be recognized and implemented before clot retrieval can be considered an established form of acute stroke treatment.     

动脉内局部溶栓治疗急性缺血性卒中

动脉内局部溶栓对包括心源性栓塞在内的急性缺血性卒中均有较好的疗效,动静脉联合溶栓的安全性较高。最近的研究表明,急诊动脉内局部溶栓联合血管成形术在急性缺血性卒中的治疗中起重要作用。     

急性缺血性卒中的溶栓治疗进展

重组组织型纤溶酶原激活剂静脉溶栓是目前惟一一种证实有效的治疗急性缺血性卒中的药物。在许多情况下,费用低廉的尿激酶不失为一种较好的选择。虽然溶栓治疗日趋成熟,但一些问题仍需进一步探讨,如新的溶栓药物用于发病3h以上的急性缺血性卒中患者、评价各种新的再灌注方法、静脉和动脉内药物溶栓联合应用、溶栓和新型抗小板药的联合应用,以及应用机械装置或经颅多普勒超声促进药物溶栓的作用等等。     

Management of ischaemic stroke in the acute setting: review of the current status

Abstract

Acute ischaemic stroke can be treated by clot busting and clot removal. Thrombolysis using intravenous recombinant-tissue plasminogen activator (IV r-TPA) is the current gold standard for the treatment of acute ischaemic stroke (AIS). The main failure of this type of treatment is the short time interval from stroke onset within which it has to be used for any benefit. The evidence is that IV r-TPA has to be used within 4.5 hours.Other modalities of treatment are not as effective and need more scrutiny and examination. The available modalities are intra-arterial thrombolysis and clot-retrieval devices. Not unexpectedly, recanalisation treatments have flourished at a rapid rate. Although vessel recanalisation is vital to increasing the possibility of significant tissue reperfusion, clinical trials need to emphasise functional outcomes rather than reperfusion/recanalisation rates to adequately assess success of these devices/techniques.Our view is that until these treatments become proven in large-scale studies, a greater endeavour should be made in resource-limited settings to expand facilities to enable intravenous r-tPA treatment within the 4.5-hour period following onset of stroke. The resources required are small with the main costs being a CT scan of the brain and the cost of r-tPA. This can easily be done in any emergency facility in any part of the world. What is needed is public awareness, and campaigns of ‘stroke attack’ should be revisited, especially in the resource-limited context. This approach at present will halt to some extent the stroke pandemic that we are facing.     

急性缺血性卒中的溶栓治疗策略

溶栓治疗是急性缺血性卒中的主要治疗方法.组织型纤溶酶原激活剂是美国食品药品管理局唯一批准的卒中治疗药物,但由于治疗时间窗狭窄和存在出血并发症风险等原因限制了其临床应用.为了解决这个问题,大量的临床试验开始致力于动脉溶栓、机械溶栓和超声溶栓治疗的研究.     

急性缺血性卒中患者血管内介入治疗的循证医学证据

血管内介入治疗已成为急性缺血性卒中治疗的研究热点,主要包括动脉溶栓、动静脉联合溶栓、机械再通、血管成形和支架置入术等。文章对血管内介入治疗急性缺血性卒中患者的循证证据进行了综述。     

Current and future recanalization strategies for acute ischemic stroke

Abstract. Alexandrov AV (University of Alabama Hospital, Birmingham, AL, USA). Current and future recanalization strategies for acute ischemic stroke (Review). J Intern Med 2010; 267: 209–219. In a quest for stroke treatment, reperfusion proved to be the first key to the puzzle. Systemic tissue plasminogen activator (tPA), the first and currently the only approved treatment, is also the fastest way to initiate thrombolyis for acute ischemic stroke. tPA works by induction of mostly partial recanalization since stroke patients often have large thrombus burden. Thus, early augmentation of fibrinolysis and multi‐modal approach to improve recanalization are desirable. This review focuses on the following strategies available to clinicians now or being tested in clinical trials: (a) faster initiation of tPA infusion; (b) sonothrombolysis; (c) intra‐arterial revascularization, bridging intravenous and intra‐arterial thrombolysis, mechanical thrombectomy and aspiration; and (d) novel experimental approaches. Despite these technological advances, no single strategy was yet proven to be a ‘silver bullet’ solution to reverse acute ischemic stroke. Better outcomes are expected with faster treatment leading to early, at times just partial flow improvement rather than achieving complete recanalization with lengthy procedures. Arterial re‐occlusion can occur with any of these approaches, and it remains a challenge since it leads to poor outcomes and no clinical trial data are available yet to determine safe strategies to prevent or reverse re‐occlusion.     

Endovascular stroke therapy

BackgroundFollowing the development of intravenous thrombolysis as a successful treatment for ischaemic stroke, advances in neurointerventional radiology have facilitated endovascular approaches to treatment. This article reviews the available endovascular therapeutic options and their evidence-base.SummaryInitial studies demonstrated that endovascular treatment of ischaemic stroke with intra-arterial thrombolysis and/or the use of clot-retrieval, thrombus aspiration and stent-retriever devices produced early recanalisation and reperfusion and improved neurological outcome. More recent randomised trials, however, have failed to show translation of recanalisation into successful clinical outcome with ‘time to treatment’ proving crucial. In this rapidly evolving field, combined therapy incorporating intravenous and intra-arterial thrombolysis in combination with endovascular clot-retrieval has been developed and further studies are expected to yield better evidence to guide the optimal treatment of acute cerebral ischaemia.     

Advances in endovascular treatment of acute ischaemic stroke

Over the past decade, there have been rapid advancements in ischaemic stroke reperfusion treatments. However, clear clinical benefit is yet to be shown in large clinical trials. In this review, the major studies in different types of endovascular treatments including intra‐arterial thrombolysis, aspiration devices, mechanical clot retrievers and the new stent retrievers are discussed. First‐generation mechanical thrombectomy devices such as the MERCI Retriever (Stryker, Kalamazoo, MI, USA) and Penumbra aspiration device (Penumbra Inc., Alameda, CA, USA) demonstrated safety and higher rates of recanalisation in the MERCI and Penumbra Pivotal Stroke Trial; however, there was no significant improvement in clinical outcome. Second‐generation endovascular stent retrieval devices Solitaire (ev3 Neurovascular, Irvine, CA, USA) and Trevo (Stryker) have shown promising results. In preliminary trials, SOLITAIRE with the Intention for Thrombectomy (SWIFT) and Thrombectomy Revascularization of Large Vessel Occlusions (TREVO), both showed rates of recanalisation close to 90% and significantly improved clinical outcomes compared with the MERCI study, but the recent landmark studies for endovascular treatment (Interventional Management of Stroke (IMS III), Mechanical Retrieval and Recanalisation of Stroke Clots Using Embolectomy (MR‐RESCUE) and SYNTHESIS) did not show any clinical benefit from endovascular treatment compared with standard intravenous therapy. However, moving forward, the recent Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR‐CLEAN) study results have shown marked improvements in recanalisation, reperfusion and functional outcome in patients receiving endovascular treatment (97% using stent retrievers) within 6 h in addition to standard medical care. Overall, although evidence regarding the efficacy of endovascular treatment in acute stroke has been equivocal, recent publications of large multicentre randomised controlled trials indicate benefit of intra‐arterial stent retriever reperfusion in patients selected by appropriate imaging and treated early by experienced operators, and it will likely remain an important adjunct to established medical treatment with intravenous tPA.     

Experimental treatments for acute ischaemic stroke

Treatments for acute ischaemic stroke continue to evolve. Experimental approaches to restore cerebral perfusion include techniques to augment recanalising therapies, including combination of antiplatelet agents with intravenous thrombolysis, bridging therapy of combining intravenous with intra-arterial thrombolysis, and trials of new thrombolytic agents. Trials with MRI selection criteria are underway to expand the window of opportunity for thrombolysis. Sonothrombolysis and novel endovascular mechanical devices to retrieve or dissolve acute cerebral occlusions are being tested. Approaches to improve cerebral perfusion with other devices and induced hypertension are also being considered. Although numerous neuroprotective agents have not shown benefit, trials of hypothermia, magnesium, caffeinol, high doses of statins, and albumin are continuing. The findings of these randomised trials are anticipated to allow improved treatment of patients with acute stroke.     

缺血性卒中的溶栓治疗现状和前景

缺血性卒中的溶栓治疗已经受到广泛的关注。目前溶栓治疗主要包括静脉溶栓、动脉溶栓、动静脉结合溶栓和机械溶栓。本文主要介绍这一方面的研究进展。     

机械取栓装置在缺血性卒中患者治疗中的应用

目前,在发病4．5h内进行静脉溶栓仍然是治疗急性缺血性卒中患者的最有效方法。对于不符合静脉溶栓治疗标准、静脉溶栓后症状无明显改善甚至恶化的患者,血管内介入治疗是一种安全的替代治疗方法。经动脉机械取栓装置能实现迅速和完全的血管再通,为急性缺血性卒中患者提供了更多的治疗选择。文章对近年来机械取栓装置相关的技术演变和临床试验进行了综述。     

Acute Ischemic Stroke Successfully Treated Using Sequenced Intravenous and Intra-Arterial Thrombolysis and Argatroban Anticoagulation: A Case Study

BACKGROUND: Direct thrombin inhibitors, a class of anticoagulants distinct from heparins, have not been evaluated for immediate use after thrombolytic therapy in acute ischemic stroke. We report a case of ischemic stroke and prothrombotic state treated using sequenced intravenous and intra-arterial thrombolytic therapy and argatroban anticoagulation. CASE DESCRIPTION: A 19-year-old man with a complicated history of recurrent life-threatening thrombosis presented at the emergency department with acute ischemic stroke. The patient received standard-dose intravenous alteplase starting 2.25 hours after symptom onset without change in his global aphasia and right hemiparesis. Five hours after symptom onset, intra-arterial reteplase was administered for treatment of a left internal carotid "T" occlusion, with successful recanalization of the left internal carotid artery, A1 and M1 segments, and right middle cerebral anterior division and with improvement in symptoms. Argatroban therapy was started after completion of intra-arterial thrombolysis, i.e., 8.5 hours after symptom onset, and was maintained for 14 days. Although the patient sustained a small left basal ganglia infarct, he improved significantly over the course of therapy and was discharged to home without bleeding or further thrombotic episodes. CONCLUSIONS: Sequenced intravenous and intra-arterial thrombolytic therapy and argatroban anticoagulation was used successfully to safely treat a patient with ischemic stroke and comorbid prothrombotic state within 8.5 hours of symptom onset.     

Does intra‐arterial thrombolysis have a role as first‐line intervention in acute ischaemic stroke?

Minimization of the clinical impact of acute ischaemic stroke depends largely on prompt restoration of blood flow to underperfused regions of the brain. Intravenous thrombolysis (IVT) is currently the first-line intervention for acute ischaemic stroke, with proven efficacy in randomized controlled trials. There are several major limitations associated with IVT, in particular, the relatively poor outcomes in large artery occlusions. A major emerging modality in acute stroke management is intra-arterial thrombolysis (IAT), whereby clot-retrieval or thrombolytics are applied under angiographic guidance to the site of the clot. Strong arguments exist for the use of IAT as first-line ischaemic stroke management in preference of IVT, especially with large intracranial artery occlusion. Despite these arguments, the lack of data from randomized controlled studies in IAT means that it is appropriate to continue the current practice of IVT as first-line treatment for the majority of acute ischaemic strokes at this stage. Advanced neuroimaging techniques, in particular a 'multimodal' computed tomography (CT) approach combining non-contrast CT, CT angiography and perfusion CT, may serve as a valuable triage tool for patient selection. Ongoing research is required in endovascular approaches to stroke; in particular, randomized controlled trials with a focus on clinical outcomes and tackling the inherent delays between symptom onset and treatment.     

No space left for intravenous thrombolysis in acute stroke: PROS

Five recently published RCTs (MR CLEAN, EXTEND-IA, SWIFT PRIME, REVASCAT and ESCAPE) employing mechanical thrombectomy with modern stent retriever devices clearly demonstrated the superiority of endovascular treatment compared to thrombolysis alone, which is now considered standard first-line therapy for selected patients with acute severe ischemic stroke and large vessel in the anterior circulation. RCT results led to recommendations outlined in “Mechanical thrombectomy in acute ischemic stroke by ESO-Karolinska Stroke Update 2014/2015, supported by ESO, ESMINT, ESNR and EAN”. Moreover, endovascular procedures in the 5 RCTs to date were performed at high-volume referral centers with, in some trials, rigid requirements for the interventionalist to participate, which may have contributed substantially to the excellent results, supporting the concept of centralization of intra-arterial thrombolysis resources and expertise. Therefore, patients with suspected large-artery occlusion and deemed candidates for thrombectomy, should be treated at a Comprehensive Stroke Centre with 24/7 endovascular treatment services. There seems to be limited space left for intravenous thrombolysis alone in acute stroke patients with large-vessel occlusions as thrombectomy plus thrombolysis continues to be reported as being superior with regard to outcome.     

尿激酶动脉溶栓与重组组织型纤溶酶原激活剂静脉溶栓治疗急性缺血性卒中的疗效比较

目的 评价尿激酶动脉溶栓与重组组织纤溶酶原激活剂(recombinant tissue plasminogen activator,rtPA)静脉溶栓治疗急性缺血性卒中的疗效和安全性.方法 发病6 h内的急性脑梗死患者43例,其中动脉溶栓组31例行超选择性动脉溶栓,静脉溶栓组12例行rtPA静脉溶栓.观察动脉溶栓组血管再通.90 d时改良Rankin量表(modified Ranlkin scale,mRS)评分评价2组转归.结果 动脉溶栓组完全再通18例(58.1%),部分再通7例(22.6%),血管再通率为80.6%,并发有症状颅内出血3例,死亡1例.尿激酶动脉溶栓组与rtPA静脉溶栓组90 d时转归良好率(74.2%对66.7%,x2=0.24,P=0.622)和有症状颅内出血发生率(9.68%对8.33%,x2=0.19,P=0.892)均无显著差异.结论 在治疗时间窗内尿激酶动脉溶栓能显著提高闭塞血管再通率,改善患者急性期临床症状和远期转归,近期疗效和远期转归均与rtPA静脉溶栓相当.     

Stroke Treatment Using Intravenous and Intra-Arterial Tissue Plasminogen Activator

OPINION STATEMENT: Acute ischemic stroke is the most common cause of adult disability in the world and the third most common cause of death. Early restoration of perfusion to ischemic brain has been a highly successful strategy to decrease the disability associated with acute ischemic stroke. For acute stroke, intravenous (IV) tissue plasminogen activator (t-PA) is the only proven acute treatment that results in improved clinical outcomes. IV t-PA is indicated for ischemic stroke when administered within 4.5?h or less of symptom onset. This 4.5-hour treatment window represents a significant expansion from the previous 3-hour treatment window for therapy. Despite a longer time window, patients have the greatest chance for an improved outcome when treatment occurs as soon as possible from the time of symptom onset. The Emergency Department goal for treatment is a door to t-PA administration time of 60?min. In order to facilitate rapid evaluation and treatment, systems of care that streamline treatment should be developed at every institution that cares for acute ischemic stroke patients. For those with contraindications to t-PA and those outside the treatment window, catheter-directed intra-arterial (IA) t-PA administration or mechanical clot extraction is a potential means of restoring brain perfusion. These therapies should not preclude the use of IV t-PA when feasible and are frequently only available at tertiary care centers. Technological advances in IA devices for mechanical clot extraction make this a promising and growing area for advancing stroke therapy but remain under ongoing investigation to establish improved clinical outcomes.