Endovascular treatment strategies for acute ischemic stroke

The limitations of intravenous thrombolysis therapy have paved the way for the development of novel endovascular technologies for use in the setting of acute stroke. These technologies range from direct intraarterial thrombolysis to various thrombus disruption or retrieval devices to angioplasty and stenting. The tools in the armamentarium of the neuroendovascular interventionalist enable fast, effective revascularization to be offered to a wider population of patients that may otherwise have few therapeutic options available to them. In this paper, we review the current state-of-the-art in neuroendovascular intervention for acute ischemic stroke. Particular emphasis is placed on delineating the indications and outcomes for use of these various technologies.     

Advances in revascularization for acute ischemic stroke treatment

Intravenous thrombolysis with recombinant tissue plasminogen activator is the established treatment for acute ischemic stroke patients presenting within 3 h after stroke onset. In a significant number of patients, however, intravenous thrombolysis with recombinant tissue plasminogen activator remains ineffective. New thrombolytic agents, such as reteplase, tenecteplase or desmoteplase, offer pharmacokinetic and dynamic advantages over recombinant tissue plasminogen activator and have been or are currently being tested for safety and efficacy in clinical trials. Endovascular revascularization is an evolving treatment option enabling mechanical clot disruption or extraction in combination with thrombolysis. Several new endovascular devices have been successfully tested for safety in acute ischemic stroke patients and are now being tested for efficacy in larger clinical trials. Continued innovation and refinement of endovascular technology and techniques is expected to increase technical success with a minimal procedure-related morbidity in the treatment of acute ischemic stroke.     

Advances in revascularization for acute ischemic stroke treatment: an update

Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) is the established treatment for acute ischemic stroke patients presenting within 4.5 h of stroke onset based on the results of the National Institute of Neurological Disorders and Stroke Study Group trial and European Cooperative Acute Stroke Study III. In a significant number of patients, however, intravenous thrombolysis with rt-PA remains ineffective, with lower rates of recanalization, especially for proximal occlusions and a large thrombus burden. Newer thrombolytic agents, such as reteplase, tenecteplase or desmoteplase, offer pharmacokinetic and hemodynamic advantages over rt-PA and have been, or are currently being, tested for safety and efficacy in clinical trials. Agents such as direct fibrinolytics that do not depend on the availability of plasminogen are also being studied in ongoing trials. Endovascular revascularization is an evolving treatment option enabling mechanical clot disruption or extraction in combination with local directed pharmacological thrombolysis. Several new endovascular devices have been successfully tested for safety in acute ischemic stroke patients and are now being tested for efficacy in larger clinical trials. Continued innovation and refinement of endovascular technology and techniques, including combination therapy such as bridging therapy and the use of stent-like devices, is expected to increase technical success and improve overall efficacy and time to recanalization with minimal procedure-related morbidity in the treatment of acute ischemic stroke.     

Neuroprotective agents for the treatment of acute ischemic stroke

Neuroprotective treatments are therapies designed to interrupt the cellular, biochemical, and metabolic elaboration of injury during or following exposure to ischemia; they encompass a rapidly expanding array of pharmacologic interventions. Various classes of neuroprotective agents have reached phase III efficacy trials in focal ischemic stroke, but none has proven effective, despite successful preceding animal studies. This notwithstanding, recent favorable results of hypothermia in human cardiac arrest trials have validated the general concept of neuroprotection. In addition, the promise of neuroprotective therapy for focal acute ischemic stroke has been renewed by innovations in strategies of preclinical drug development and clinical trial design that rectify past defects, including trial testing of combination therapies rather than single agents and novel approaches to accelerating time to initiation of experimental treatment.     

Recent progress in drug treatment for acute ischemic stroke

The publication of the positive results of the National Institute of Neurological Disorders and Stroke (NINDS) trial of alteplase (a recombinant tissue plasminogen activator; rt-PA) for acute stroke patients in 1995 and its approval by the US Food and Drug Administration as well as the American Academy of Neurology and American Heart Association increased the interest and attention of the medical community in acute stroke treatment. However, the implication of this NINDS Stroke Study and other thrombolytic trials in clinical practice remains controversial and debated. Furthermore, the recent publication of the results from the European Cooperative Acute Stroke Study II (ECASS II) and Alteplase Thrombolysis of Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) studies will feed the controversy, since the results of these two studies are disappointing and do not confirm the positive results of the NINDS Stroke Study as expected by clinicians managing patients with acute stroke. The Standard Treatment with Alteplase to Reverse Stroke (STARS) and Cleveland studies, which involved a large number of community hospitals to assess the safety profile and the benefit of rt-PA thrombolysis for acute stroke patients in clinical practice, have shown controversial results. Consequently, the issue arises of which is the more reasonable position concerning thrombolysis by alteplase, which seems to work but has not been proven yet beyond reasonable doubt? The recent publication of the results from the Prolyse in Acute Cerebral Thromboembolism (PROACT II) study has shown that intra-arterial thrombolysis with prourokinase is a benefit treatment in stroke patients with a proven middle cerebral artery occlusion within 6 h of stroke onset. Numerous trials devoted to neuroprotection against acute ischemic stroke have been prematurely stopped because of safety concerns or poor risk-benefit ratios, but some new neuroprotective drugs seem promising and are being tested in ongoing studies. The third issue under study concerns the use of antithrombotic drugs in the acute phase of stroke, particularly the new potent platelet glycoprotein IIb/IIIa antagonists such as abciximab. In this paper, we have reviewed selected recent clinical trials focusing on recent advances in acute stroke therapy.     

Other endovascular treatment strategies for acute ischemic stroke.

This article discusses the efforts being made to develop a safe, efficacious method of clot removal in the treatment of acute ischemic stroke. Four endovascular treatment strategies are discussed: mechanical clot disruption, endovascular thrombectomy, stents, and therapeutic carotid occlusion.     

急性缺血性脑卒中的神经保护治疗

脑卒中是影响人类健康的主要疾病之一,为我国城市人口死亡的首位原因。约三分之一的脑卒中幸存者残留不同程度的神经功能障碍。急性缺血性脑卒中治疗的最重要途径为改善脑血流(溶栓)和阻断神经元缺血性病理生化级联反应,即神经保护治疗。一、神经保护治疗的合理性脑梗死的发生取决于两个基本条件,即脑血流量(cerebralbloodflow,CBF)下降的严重程度和缺血持续的时间。脑缺血后,若脑循环在一段时间内恢复,脑功能可获完全恢复,该时间为“再灌注时间窗”。由于脑缺血后引起的病理生理变化持续存在,即使重新建立起足够的脑循环,仍可能产生延迟…     

Advances in treatment of acute ischemic stroke

Stroke carries a severe toll in terms of loss of life and disability for patients and their families. Until 10 years ago, physicians, and in particular neurologists, had a conservative, nonaggresive approach to this devastating disease. The advent of thrombolytic therapy not only proved that acute ischemic stroke is treatable, but also that early reperfusion can dramatically change the outcome of acute stroke patients. As a result of these trials, intravenous (IV) tissue plasminogen activator (t-PA) has been approved for treatment of acute ischemic stroke within 3 hours after symptom onset in the United States, Canada, Australia, and the European Union. The near future is extremely promising. Imaging modalities, such as diffusion- and perfusion-weighted images, as well as CT perfusion and CT angiography, to better select patients for treatment are now routinely performed in most academic medical centers. Novel IV and intra-arterial (IA) agents have been developed and tested. Emerging therapies will soon be available to increase the therapeutic windows for thrombolysis both by better screening patients using MRI or CT and by new IV and IA treatments. Several multicenter controlled trials in both imaging-guided decisions and therapeutic agents are either completed or being performed. We review data on advancement in imaging and treatment of acute ischemic stroke, in particular focusing on pharmacologic and mechanical IA thrombolysis.     

急性缺血性脑卒中的诊治

急性缺血性脑卒中的分型有助于确定治疗原则。静脉溶栓治疗及血管取栓治疗是最有效的恢复脑再灌注的特异治疗方法。抗栓治疗、改善循环、降纤、扩容、神经保护、传统医药及对并发症的管理对预后有重要影响。康复治疗是促进卒中患者功能恢复、减少并发症、提高生活质量的重要措施。卒中后应尽早开始二级预防。     

Advances in treatment of acute ischemic stroke

Stroke carries a severe toll in terms of loss of life and disability for patients and their families. Until 10 years ago, physicians, and in particular neurologists, had a conservative, non-aggressive approach to this devastating disease. The advent of thrombolytic therapy not only proved that acute ischemic stroke is treatable, but also that early reperfusion can dramatically change the outcome of acute stroke patients. As a result of these trials, intravenous (IV) tissue plasminogen activator (t-PA) has been approved for treatment of acute ischemic stroke within 3 hours after symptom onset in the United States, Canada, Australia, and the European Union. The near future is extremely promising. Imaging modalities, such as diffusion- and perfusion-weighted images, as well as CT perfusion and CT angiography, to better select patients for treatment are now routinely performed in most academic medical centers. Novel IV and intra-arterial (IA) agents have been developed and tested. Emerging therapies will soon be available to increase the therapeutic windows for thrombolysis both by better screening patients using MRI or CT and by new IV and IA treatments. Several multicenter controlled trials in both imaging-guided decisions and therapeutic agents are either completed or being performed. We review data on advancement in imaging and treatment of acute ischemic stroke, in particular focusing on pharmacologic and mechanical IA thrombolysis.     

Up-dating in acute ischemic stroke treatment.

Stroke is the second commonest cause of death world-wide, and the loss of quality-adjusted life years caused by stroke globally is bigger than for any other disease. The economic burden will be enormous if the nihilistic attitude that nothing can be done for stroke patients is not replaced by an active attitude. Clinical trials have shown that thrombolysis with rtPA is effective in acute ischemic stroke. A meta-analysis of these trials revealed that thrombolysis decreases the risk of death and dependency. All trials studying neuroprotecting agents have failed in man, although they have been successful in experimental animals. Protocolized intervention during the acute phase of ischemic stroke is proposed to correct physiological variables that have been disturbed in these patients. This intervention has been shown to have evident prognostic benefits. However, many of these measures are empirical and there is no clear evidence of their benefits. Organising the stroke units to be able to provide early thrombolysis for eligible patients will help all stroke patients in future treatments for ischemic stroke.

Neurología 2004;19(Supl 2):28-39

     

High-dose intravenous naloxone for the treatment of acute ischemic stroke

To evaluate the safety and possible efficacy of high-dose naloxone for the treatment of acute cerebral ischemia, 38 patients received a loading dose of 160 mg/m2 over 15 minutes followed by a 24-hour infusion at the rate of 80 mg/m2/hr. Nausea and/or vomiting were common side effects. Naloxone was discontinued in seven patients (because of hypotension in one, bradycardia and hypotension in two, myoclonus in one, focal seizures in two, and hypertension in one); all seven patients responded to treatment and no permanent sequelae to naloxone were noted. Twelve of the 38 patients showed early neurologic improvement (by completion of the naloxone loading dose). However, there was no correlation between such a loading dose response and clinical outcome at 3 months. Our experience suggests that naloxone is safe at the dose used, but data for efficacy are inconclusive.     

Thrombolytic and newer mechanical device treatment for acute ischemic stroke

For 8 years, only intravenous tissue plasminogen activator was approved by the US FDA for acute stroke treatment. The US FDA has now cleared the Merci Retriever (Concentric Medical, Inc.), a corkscrew-like device attached to a catheter, for the removal of clots causing ischemic strokes. Since the clearance was based on nonrandomized treatment trials, practitioners must scrutinize available data describing effects of the device on recanalization of the vessel, outcomes and important adverse events, such as symptomatic intracranial hemorrhage. This article reviews the study findings that are likely to contribute to current treatment decisions.     

Neuroprotective therapy for the treatment of acute ischemic stroke]

Following cerebral ischemia, various biochemical reactions are provoked in a stepwise manner leading neuronal cells to ischemic death. The prevention of these biochemical reactions may exert neuroprotective actions and consequently reduce the magnitude of ischemic cerebral injury. On the basis of such a view, numerous neuroprotective drugs have been developed during the last decade. Quite a few drugs were found effective in reducing the infarct volume in experimental studies, and more than 15 of them were subjected to clinical phase III trials to see a therapeutic effectiveness. However, the results of phase III trials were disappointing in the majority drugs. Only three drugs, nicaravene, ebselen and edaravone, all radical scavengers, were judged effective by small-sized trials with a wide therapeutic window, 48-72 hours after stroke, in Japan. The fact suggests that a one-point prevention of biochemical reactions by single drug is unable to rescue ischemic neuronal cells. Ischemic insult causes damages of vascular wall including the endothelium which play an important role in the development of hemorrhagic changes or cerebral edema. Vascular protection is considered as important as neuroprotection in treatment of clinical stroke. Mild hypothermia has neuroprotective and vascular protective actions and hence may be more effective than neuroprotective drugs for the treatment of stroke. The prevention of fever, which often occurs in severe stroke, may exert the similar effect as hypothermia in neuroprotection. Neuroprotective therapy in the future should proceed toward the simultaneous protections of neurons and vessels using combination of multiple drugs.     

Desmoteplase in the treatment of acute ischemic stroke

Desmoteplase, developed by Paion, Forest and Lundbeck, is a novel plasminogen activator that selectively activates fibrin-bound plasminogen and is currently being investigated for the treatment of acute ischemic stroke within the time window of 3-9 h after symptom onset. Desmoteplase is believed to offer pharmacologic advantages over currently approved treatment options. To date, two published Phase II perfusion imaging-based clinical trials have reported the safety and potential efficacy of desmoteplase in ischemic stroke. Results from a recently completed Phase III trial in Europe, Asia and the USA are awaited. This article reviews the available data on desmoteplase, including discussion of its favorable features and potential benefit beyond the 3-h time window in the treatment of ischemic stroke.     

Rescue treatment with abciximab in acute ischemic stroke

In acute ischemic stroke, reocclusion after an initially successful thrombolysis treatment can occur and is associated with increased morbidity and mortality. The authors present the successful use of abciximab, a platelet glycoprotein IIb/IIIa receptor inhibitor, in a patient with a thrombotic occlusion of the proximal middle cerebral artery, which was refractory to combined IV and intra-arterial thrombolysis and percutaneous intracranial balloon angioplasty.     

Thrombolysis for acute ischemic stroke: Future directions

Intravenous tissue plasminogen activator remains the standard for treating acute ischemic stroke. Citicoline, dizocilpine, nimodipine, tirilizad, and other agents have been tested with thrombolytics in preclinical trials with mixed but encouraging results. Lessons from prior failed attempts to develop neuroprotectives as monotherapies should be applied to the development of combination therapies. In the future, there will be efforts to improve reperfusion rates without increasing intracranial hemorrhage rates. In addition to studying intra-arterial thrombolysis, there is a need for further testing of newer fibrinolytics and combination antithrombotics. Advancements in neuroimaging also will allow more tailored use of thrombolytic therapy.