Pre-stroke frailty and cognition as predictors to select patients for acute stroke treatment

Section Editors: Marc Fisher MD Antoni Davalos MD The Food and Drug Administration (FDA) evaluates applications for new human drugs, biologics, and complex medical devices. Companies must obtain FDA approval to legally market these products. In August, the FDA gave Concentric Medical clearance to market its Merci Retriever system to “remove blood clots from the brain in patients experiencing an ischemic stroke.” Given that the FDA is charged with “protecting the public health by assuring the safety, efficacy, and security of… biological products and medical devices…, ” “advancing public health by helping to speed innovations that make medicines … more effective, safer, and more affordable,” and “helping the public get the accurate, science-based information they need to use medicines … to improve their health,”1 the FDA’s decision to approve the Merci Retriever system is of concern. The pathways to approval are reviewed by Felten et al in the accompanying article and are outlined in Figure 1. Figure 1. Potential pathways for device approval. The decision to approve the Merci Retriever was based on data from the MERCI (Mechanical Embolus Removal in Cerebral Ischemia) Trial; the approval was granted through the 510(k) process. The Merci Retriever system includes a flexible nickel titanium (nitinol) wire that obtains a helical shape once it is passed through the tip of the guidance catheter. In practice, the catheter/wire is passed distal to the thrombus, the catheter is removed, and the helical configuration assumed by the wire; the clot is then trapped in the helix and withdrawn from the vasculature (Figure 2). The 510(k) clearance means that the Merci Retriever was felt to be substantially equivalent to a predicate device. In this case, the predicate device was the Concentric Retriever, which itself received 510(k) clearance by the FDA in May 2001 for “use in …

In the recent Humana Lecture,1 Harold Adams quoted what might be the prevailing sentiment guiding the search for a treatment for acute ischemic stroke: “When we have a treatment for stroke, we will know it.” The implicit assumption is that there is a treatment that will dramatically improve acute stroke outcome. The current approach to finding a treatment for ischemic stroke is based on single-agent trials, sponsored mainly by pharmaceutical companies, that may produce a “winner,” to be followed by a “therapeutic cocktail” to combat the complex events set in motion by cerebral ischemia. Progress in ischemic stroke treatment trials over the last two decades has included improved statistical design, radically shortened entry windows, standardized rating instruments, and shared sponsorship between industry and government. We wish to raise concerns about the current approach to testing new stroke treatments and the impact that changes in healthcare delivery in the United States may have on the conduct of acute stroke trials. The success of clinical research in the treatment of acute stroke depends not only on trial design but on local, regional, and national factors that determine the environment in which acute stroke care is provided and that affect the feasibility of trial execution. In this editorial, we present some of the important issues facing those who design and implement acute stroke treatment studies. Our opinions pertain primarily to the medical environment in the United States. Our goal is to stimulate discussion and suggest a forum for the critical evaluation of trial design issues and also the development of a national strategy for stroke. We are concerned about the optimal use of critical resources needed to conduct stroke treatment trials. By “resources” we mean the investigators and stroke research teams; acute stroke patients available for enrollment; cooperative referring doctors and emergency-services …

The 27th International Stroke Conference San Antonio, Texas, February 7-9, 2002.

of Neurological Disorders and Stroke (NINDS) for the next 10 years.The PRG produced a progress report in 2006, and a final report in 2012.The PRG process used expert study groups covering 16 areas of research.Each group was tasked to summarize progress in their field and then come up with research priorities.

See related article, pages 1751–1758. Since the ischemic penumbra was discovered and since a therapeutic window for acute ischemic stroke has been postulated, stroke experts are looking for safe and effective drugs to treat as many acute ischemic stroke patients as possible. Maturation of ischemic damage is a complex process, triggered by hypoperfusion at critical levels and spontaneously evolving toward cell death. It is a self-perpetuating process in which some critical steps (such as ion pumps failure and iNOS production) maintain and enhance the process.1 Reperfusion may reverse the ischemic cascade but, at the same time, induces a further damage. The risk/benefit ratio of reperfusion depends on the amount of penumbral salvageable tissue, that is “individual” and only partially predictable.2,3 Spontaneous reperfusion may occur, and symptoms may reverse, partially or totally, but the percentages of spontaneous reperfusion so far reported account for approximately the 24% of all stroke cases.4 A review of published articles about cerebral angiography in stroke reported that the percentage of spontaneous reperfusion …

This article includes a review of major intravenous and endovascular stroke trials, treatment options, and future aspects of acute stroke treatment in hemispheric and vertebrobasilar stroke. Since the invention of local intraarterial thrombolysis by Hermann Zeumer in 1981, acute stroke diagnostics and treatment have undergone dramatic improvement. This article addresses major topics in recent stroke treatment debates: optimization of patient selection, intravenous versus endovascular therapy, time window limitations, combined treatment with intravenous/intraarterial bridging therapies (intravenous/intraarterial recombinant tissue plasminogen activator [rtPA] bridging and intravenous glycoprotein IIb/IIIa inhibitor/intraarterial rtPA bridging) and modern endovascular treatment modes like percutaneous transluminal angioplasty (PTA)/stenting and mechanical thrombectomy devices. Modern acute stroke therapy networks should optimize their noninvasive diagnostic capacity to early identify candidates for endovascular therapy with rapid access to specialized neuroendovascular centers using standard protocols. The most promising approach in acute stroke treatment seems to be a combination of intravenous and endovascular revascularization procedure, combining early treatment initiation with direct clot manipulation and PTA/stenting in underlying stenosis with atherothrombotic occlusions. Further randomized studies comparing intravenous and endovascular treatment, mainly in the anterior circulation, have to be expected and need wide support of the neurologic and neuroradiologic stroke community.

Stroke continues to be a significant cause of morbidity and mortality in the United States. Approximately 700 000 Americans have a new or recurrent stroke each year, and stroke remains the third leading cause of death in the United States when considered independently from other cardiovascular diseases. Stroke also remains a leading cause of serious, long-term disability in the United States.1 Major advances have been made during the past several decades in stroke prevention, treatment, and rehabilitation. Despite successes in delivering effective new therapies, significant obstacles remain in ensuring that scientific advances are consistently translated into clinical practice. In many instances, these obstacles can be related to a fragmentation of stroke-related care caused by inadequate integration of the various facilities, agencies, and professionals that should closely collaborate in providing stroke care. There is increased emphasis on improving the components of stroke care, including recommendations from the Brain Attack Coalition for primary stroke centers and a formal process provided through the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) for the certification of primary stroke centers.2–4 It is critically important to look carefully at how the distinct components can be better integrated into systems of stroke care. The American Stroke Association (ASA), a division of the American Heart Association (AHA), is dedicated to improving stroke prevention, treatment, and rehabilitation through research, education, advocacy, and the development and application of scientifically based standards and guidelines. The ASA convened a multidisciplinary group, the Task Force on the Development of Stroke Systems, to describe the current fragmentation of stroke care, to define the key components of a stroke system, and to recommend methods for encouraging the implementation of stroke systems. The term “stroke system” is used in this article to avoid the corporate and financial connotations associated with the words “network” and …

Background: It has been 50 years since the first explorations of the physiology of cerebral ischemia by measuring cerebral blood flow (CBF), and 25 years since the approval of tissue plasminogen activator for treating acute ischemic stroke. My personal career began and matured during those eras. Here, I provide my perspective on the evolution of acute stroke research and treatment from 1971 to the present, with some in-depth discussion of the National Institutes of Neurologic Disease and Stroke (NINDS) tissue-type plasminogen activator (tPA) stroke trial and development of mobile stroke units. Summary: Studies of CBF and metabolism in acute stroke patients revealed graded tissue injury that was dependent on the duration of ischemia. Subsequent animal research unraveled the biochemical cascade of events occurring at the cellular level after cerebral ischemia. After a decade of failed translation, the development of a relatively safe thrombolytic allowed us to achieve reperfusion and apply the lessons from earlier research to achieve positive clinical results. The successful conduct of the NINDS tPA stroke study coupled with positive outcomes from companion tPA studies around the world created the specialty of vascular neurology. This was followed by an avalanche of research in imaging, a focus on enhancing reperfusion through thrombectomy, and improving delivery of faster treatment culminating in mobile stroke units. Key Messages: The last half century has seen the birth and evolution of successful acute stroke treatment. More research is needed in developing new drugs and catheters to build on the advances we have already made with reperfusion and also in evolving our systems of care to get more patients treated more quickly in the prehospital setting. The history of stroke treatment over the last 50 years exemplifies that medical “science” is an evolving discipline worth an entire career’s dedication. What was impossible 50 years ago is today’s standard of care, what we claim as dogma today will be laughed at a decade from now, and what appears currently impossible will be tomorrow’s realities.

Abstractt‐PA therapy has been able to be performed based on RCT study results in the world from 25 years ago. However, the Japan government approved the use of t‐PA 15 years ago. In the last 15 years, diagnostic imaging and treatment for acute stroke have been changed remarkably. The appearance of diffusion‐weighted images as diagnostic imaging for acute stroke and mechanical thrombectomy as treatment for acute stroke can markedly improve patient outcome. We experienced many severe patients treated with such therapies discharged by walk. Therefore, we would like to emphasize that stoke treatment has been changed drastically. Unfortunately, at present, stroke patients who do not have benefit from t‐PA therapy and mechanical thrombectomy therapies are not so many. In order to solve those problems, we should need to establish a stroke medical care system in Japan as soon as possible. In this presentation, we will outline the image of acute stroke, acute treatment, and stroke medical care system.

Cerebral ischemia in gerbils: effects of acute and chronic treatment with adenosine A 2A receptor agonist and antagonist

Essential Workflow and Performance Measures for Optimizing Acute Ischemic Stroke Treatment in India.

Background and Objective: Lack of achieving complete recanalization in acute strokes using only IV thrombolysis has led to the evolution of a multimodal acute ischemic stroke paradigm which includes combination of intra-arterial tPA, mechanical thrombectomy and stenting. There is limited data on safety of administering intra-arterial and intra-venous antiplatelet agents within the acute stroke treatment paradigm to maintain target vessel recanalization. Methods: Of the total patients with acute ischemic strokes presented between 2010-13 to our university affiliated comprehensive stroke center, patients that received IA and IV Eptifibatide were retrospectively classified into two groups: Group A underwent emergent intracranial stenting with IV and or IA r-tPa and/or mechanical thrombectomy. Group B underwent IV r-tPa/ IA r-tPa /IA Eptifibatide and/or mechanical thrombectomy with no intracranial stenting. Eptifibatide was administered intra-arterially as a 135-μg/kg single-dose bolus, and then continued on intravenous infusion of 0.5-μg/kg/min post-procedurally. Charts were reviewed for all patients to assess for complications including groin hematoma, asymptomatic and symptomatic hemorrhages, epistaxis and gross hematuria. Results: Of the total of 2016 patients with ischemic strokes, 326 patients received acute stroke treatment and a total of 138 patients received IA and IV Eptifibatide. Group A with acute stenting (82 patients, mean age 68, 49% males [n=40]) and Group B without stenting (56 patients, mean age 73, 54% males [n=30]) received IV Eptifibatide infusion for a mean duration of 19 hours (range 0 to 364 hours). In Group A, 7.3% [n= 6] showed symptomatic ICH, 4.9% [n=4] asymptomatic ICH, 3.7% [n=3] groin hematomas, 2.4% [n=2] nose bleeds. In Group B, 7.1 % [n=4] had asymptomatic hemorrhages and 1.8% [n=1] showed gross hematuria. Conclusion: The complications of IV and IA Eptifibatide are not significantly higher than those associated with the existing acute ischemic stroke treatment paradigm. Larger, multi-centered prospective trials are warranted to corroborate our findings.

Impact of estimated-weight-base dose of alteplase in acute stroke treatment on clinical outcome

RationaleStroke presents a serious health problem in China. Despite progresses made in recent years, there is still a lack of effective treatments for acute ischemic stroke (AIS) in clinical practices.AimsThe Chinese Acute Ischemic Stroke Treatment Outcome Registry (CASTOR) is designed to evaluate the patterns and cost-effectiveness of current treatments for AIS in real-world settings in China.DesignCASTOR is a prospective, multi-center study registered with ClinicalTrials.gov (NCT02470624) with a target sample size of 10,000 patients who are experiencing AIS. The patients are treated for AIS following the Chinese stroke guideline and local practice. Real-world data on treatment regimens, outcomes and costs are collected at baseline (Visit 1) and during subsequent visits (Visit 2 to Visit 5) after medication treatments.OutcomeThe primary objective of the present study is to analyze the current treatment status of AIS in real world settings. The secondary objectives include: 1) to compare the effectiveness of common treatment regimens, 2) to analyze the cost-effectiveness of different treatment regimens for AIS, 3) to analyze the incidence of adverse events and complications in enrolled patients with AIS, 4) to analyze the effect of Trial of Org 10,172 in Acute Stroke Treatment (TOAST) classification on the specific therapies during acute phase treatment period.DiscussionIn face of changing treatment patterns and increasing demand from medical insurers for cost-effectiveness data in China, a large-scale registry study examining the real-world patterns of AIS in hospitals is needed. The CASTOR study will help to find favorable cost-utility treatment regimens for AIS and improve the overall treatment outcome of Chinese patients with AIS.

Physicians often base their decisions to offer acute stroke therapies to patients around the question of whether the patient will benefit from treatment. This has led to a plethora of attempts at accurate outcome prediction for acute ischemic stroke treatment, which have evolved in complexity over the years. In theory, physicians could eventually use such models to make a prediction about the treatment outcome for a given patient by plugging in a combination of demographic, clinical, laboratory, and imaging variables. In this article, we highlight the importance of considering the limits and nuances of outcome prediction models and their applicability in the clinical setting. From the clinical perspective of decision-making about acute treatment, we argue that it is important to consider 4 main questions about a given prediction model: (1) what outcome is being predicted, (2) what patients contributed to the model, (3) what variables are in the model (considering their quantifiability, knowability at the time of decision-making, and modifiability), and (4) what is the intended purpose of the model? We discuss relevant aspects of these questions, accompanied by clinically relevant examples. By acknowledging the limits of outcome prediction for acute stroke therapies, we can incorporate them into our decision-making more meaningfully, critically examining their contents, outcomes, and intentions before heeding their predictions. By rigorously identifying and optimizing modifiable variables in such models, we can be empowered rather than paralyzed by them.