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  • CLINICAL PUBLISHING

    Therapeutic Strategies inCER

    EBR

    AL

    ISCH

    EMIA

    LiebeskindCLIN

    ICAL P

    UBLIS

    HING

    This work reflects on those aspects of cerebrovascular ischemia thatcurrently pose potentially formidable challenges to effective treatment or,alternatively, that offer tremendous opportunities for the future. Theauthors provide a scholarly review of current interventions, theiradvantages and shortcomings, as well as offering important insights intothe likely direction of future therapeutic targets and strategies. This bookmaintains a clear clinical viewpoint throughout on topics includingpreventive strategies, hemodynamics, neuroprotection, minor strokes andTIA, as well as the latest translational research in animal models.

    RELATED TITLES

    Diagnostic Strategies in Cerebral IschemiaD. S. LiebeskindISBN 978 1 84692 085 1

    Ischemic Stroke: Atlas of Investigation and TreatmentI. E. Silverman, M. M. RymerISBN 978 1 84692 017 2

    Hemorrhagic Stroke: Atlas of Investigation and TreatmentI. E. Silverman, M. M. RymerISBN 978 1 84692 039 4

    www.clinicalpublishing.co.uk

    Therapeutic Strategies in

    CEREBRAL ISCHEMIATherapeutic Strategies in

    CEREBRALISCHEMIAD. S. Liebeskind

    TS Cerebral Ischemia COVER a/w_TS Cerebral Ischemia cover 19/01/2011 15:11 Page 1

  • THERAPEUTIC STRATEGIES IN CEREBRAL ISCHEMIA

    Edited by

    David S. LiebeskindAssociate Professor of Neurology

    Neurology Director, Stroke ImagingAssociate Neurology Director, UCLA Stroke Center

    University of California, Los AngelesUSA

    CLINICAL PUBLISHING

    OXFORD

    TSCI_Prelims.indd iii 17/01/11 21:22:36

  • Clinical Publishingan imprint of Atlas Medical Publishing Ltd

    Oxford Centre for InnovationMill Street, Oxford OX2 0JX, UKTel: +44 1865 811116Fax: +44 1865 251550Email: [email protected]: www.clinicalpublishing.co.uk

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    Atlas Medical Publishing Ltd 2011

    First published 2011

    All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Clinical Publishing or Atlas Medical Publishing Ltd.

    Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention.

    Clinical Publishing and Atlas Medical Publishing Ltd bear no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication, and do not guarantee that any content on such websites is, or will remain, accurate or appropriate.

    A catalogue record for this book is available from the British Library.

    ISBN 13 978 1 84692 045 5ISBN e-book 978 1 84692 632 7

    The publisher makes no representation, express or implied, that the dosages in this book arecorrect. Readers must therefore always check the product information and clinical procedureswith the most up-to-date published product information and data sheets provided by themanufacturers and the most recent codes of conduct and safety regulations. The authors andthe publisher do not accept any liability for any errors in the text or for the misuse ormisapplication of material in this work.

    Project manager: Gavin Smith, GPS Publishing Solutions, Hertfordshire, UKTypeset by Mizpah Publishing Services Private Limited, Chennai, IndiaPrinted by Marston Book Services Ltd, Abingdon, Oxon, UKCover images taken from Hemorrhagic Stroke: Atlas of Investigation and Treatment (Oxford: Clinical Publishing; 2010), courtesy of Dr IE Silverman and Dr MM Rymer

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  • Contents

    Editor and Contributors vii

    Preface ix

    1 Therapeutic challenges in cerebral ischemia 1 D. S. Liebeskind

    2 Arterial recanalization potential and limitations 3 M. H. Qureshi, A. I. Qureshi

    3 Collateral perfusion, microcirculation and venous pathophysiology 17 D. S. Liebeskind

    4 Venous steal in cerebral ischemia 29 O. Pranevicius, M. Pranevicius, D. S. Liebeskind

    5 Systemic hemodynamic therapies for acute ischemic stroke 41 A. W. Alexandrov

    6 Oxygen therapy for acute ischemic stroke 61 A. B. Singhal

    7 Neuroprotection in acute ischemic stroke 81 M. S. Hussain, A. Shuaib

    8 Hemorrhagic transformation causes, definitions and treatment 95 S. E. Kohake, P. Khatri

    9 Management of transient or mild ischemia and early secondary prevention 109 A. Y. Poppe, N. Sanossian, S. B. Coutts, A. M. Demchuk

    10 From rat to RCT translational hurdles in novel stroke therapies 123 S. I. Savitz

    11 Vascular endpoints in clinical trials and practice 133 D. S. Liebeskind

    List of abbreviations 141

    Index 145

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  • Editor

    DAVID S. LIEBESKIND, MD, FAHA, Associate Professor of Neurology; Neurology Director, Stroke Imaging; Associate Neurology Director, UCLA Stroke Center, University of California, Los Angeles, CA, USA

    Contributors

    ANNE W. ALEXANDROV, PhD, FAAN, Professor of Nursing, Professor of Emergency Medicine, Program Director, NET SMART Neurovascular Fellowship, Program Director, Doctor of Nursing Practice, School of Nursing, Department of Acute and Critical Care, School of Medicine, Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    SHELAGH B. COUTTS, MD, FRCPC, Assistant Professor, Stroke Neurology, Calgary Stroke Program, Department of Clinical Neurosciences and Radiology, University of Calgary, Calgary, AB, Canada

    ANDREW M. DEMCHUK, MD, FRCPC, Associate Professor, Department of Clinical Neurosciences and Department of Radiology, Calgary Stroke Program, Department of Clinical Neurosciences and Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, AB, Canada

    MUHAMMAD SHAZAM HUSSAIN, MD, FRCPC, Staff, Cerebrovascular Center, Cleveland Clinic, Cleveland, Ohio, USA

    POOJA KHATRI, MD, FAHA, Associate Professor of Neurology, University of Cincinnati, Cincinnati, OH, USA

    SHANNON E. KOHAKE, MD, Research Medical Center Stroke Program, HCA Midwest Health System, Kansas City, MO, USA

    DAVID S. LIEBESKIND, MD, FAHA, Associate Professor of Neurology; Neurology Director, Stroke Imaging; Associate Neurology Director, UCLA Stroke Center, University of California, Los Angeles, CA, USA

    ALEXANDRE Y. POPPE, MDCM, FRCPC, Clinical Assistant Professor of Medicine, Stroke Neurologist, Cerebrovascular Disease Centre, Hpital Notre-Dame, Centre Hospitalier de lUniversit de Montral, Montral, Quebec, Canada

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  • MINDAUGAS PRANEVICIUS, MD, Assistant Professor of Anesthesiology, Department of Anesthesiology, Albert Einstein College of Medicine, Bronx, NY, USA

    OSVALDAS PRANEVICIUS, MD, PhD, Department of Anesthesiology, New York Hospital Queens, Flushing, NY, USA

    MUSHTAQ H. QURESHi, MD, Clinical Research Fellow, Zeenat Qureshi Stroke Research Centre, Department of Neurology, University of Minnesota, Minneapolis, MN, USA

    ADNAN I. QURESHI, MD, FACC, Professor of Neurology, Neurosurgery, and Radiology, Zeenat Qureshi Stroke Research Centre, Department of Neurology, University of Minnesota, Minneapolis, MN, USA

    NERSES SANOSSIAN, MD, FAHA, Assistant Professor of Neurology, Department of Neurology, University of Southern California, Los Angeles, CA, USA

    SEAN I. SAVITZ, MD, FAHA, Associate Professor of Neurology, Stroke Program, Department of Neurology, University of Texas Medical School at Houston, Houston, TX, USA

    ASHFAQ SHUAIB, MD, FRCPC, FAHA, Professor of Medicine; Director, Stroke Program, Division of Neurology, School of Internal Medicine, University of Alberta, Edmonton, AB, Canada

    ANEESH B. SINGHAL, MD, Associate Professor of Neurology, Harvard Medical School, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    viii Editor and Contributors

    TSCI_Prelims.indd viii 17/01/11 21:22:36

  • Preface

    This book on therapeutic strategies and the companion book on diagnostic strategies for cerebral ischemia encapsulate a philosophy and perspective on stroke that stand apart from other volumes on the subject. These texts embody a collective restlessness with the current impasse in reversing stroke, composed by a generation that seeks to change the next. The books are dedicated to the memory and aspirations of my family, across several generations.

    As a child, I remember the devastating effects of recurrent stroke on my grandfather, Oleg, at a time before CT and MRI. My mother, Doreen, and father, Arie, both later utilized angiography, CT, MRI and ultrasound as neuroradiologists to demystify stroke, and these books are devoted to their memory. This personal history with stroke fueled my trajectory from engineering into neurology, where I could tackle stroke, one of the greatest challenges in modern medicine despite recent innovations. My love for the field is mirrored by my intense love of my family, revolving around my incredible wife and friend, Kira. I adore and seek to inspire my children, Alexander, Bernard, and Mia, who encourage me to love every minute and live for the moment.

    Every day and night, my colleagues and I witness the instant terror that heralds stroke onset. Life is halted, with miraculous recovery in only the lucky, yet everyone is reminded of our ephemeral status. I deeply appreciate the efforts of my co-authors on these books, who share my philosophy and friendship. I also anticipate that these books will motivate others to move forward in combating stroke, incorporating new perspectives and evolving paradigms.

    David S. Liebeskind, MD

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  • 1Therapeutic challenges in cerebral ischemiaD. S. Liebeskind

    INTRODUCTION

    The treatment of cerebral ischemia remains a daunting task, as few therapeutic strategies have proven effective. Systemic thrombolysis with intravenous tissue plasminogen activator (tPA) remains the only proven treatment to improve clinical outcome of patients with acute ischemic stroke [1]. The breakthrough heralded by tPA achieves only limited results in reversing cerebral ischemia, as thrombolysis results in recanalization of only a subset of cases. This subset is already a sliver of the far more extensive stroke population that suffers from abrupt onset of potentially devastating neurological deficits due to cerebral ischemia on a daily basis around the world. More recent development of endovascular devices for arterial revascularization has considerably increased the proportion of cases that may experi-ence recanalization, yet such sophisticated procedures are performed in an even smaller subset of stroke cases. The treatment of atheromatous disease has similarly been limited to preventive efforts, as surgical excision or endovascular treatment of arterial plaque in the acute setting remains largely unproven. As a result, the manipulation of occlusive thrombus or arterial plaque to minimize ischemic injury has been the overwhelming focus of thera-peutic strategies for cerebral ischemia. Paradoxically, these approaches may address only one limited aspect of ischemia. Arterial revascularization offers the potential to remove the causative lesion that initially produced downstream ischemia, yet within minutes after arter ial occlusion a vast array of pathophysiological sequelae ensue. Arterial revasculariza-tion does nothing to address ischemic injury in parenchyma, tissue swelling, the cascade of molecular events triggered by ischemia, microcirculatory dysfunction, endothelial ischemia, deleterious venous changes, or any aspect of endogenous compensatory mechanisms from collateral circulation to subsequent neurorepair. In fact, therapeutic revascularization may engender or accelerate untoward effects of reperfusion hemorrhage. Perhaps most impor-tantly, reperfusion of downstream ischemic regions is almost always limited, even when complete arterial recanalization is achieved with thrombolysis or thrombectomy [2]. Aside from exhaustive prevention measures, the principal therapeutic goal of offsetting cerebral ischemia remains largely unrealized during the acute phase when most damage occurs.

    Immense efforts have been devoted to the study of ischemic pathophysiology in animals and the advent of modern diagnostic imaging tools has provided an opportunity to illus-trate numerous aspects of cerebral ischemia in humans. An extraordinary number of experi-mental agents have been used to avert or reduce ischemic injury in the brain, yet only recently has clinical trial design implemented neuroimaging techniques to select optimal candidates for such specific treatments [3]. A companion text explores how improved diag-

    Atlas Medical Publishing Ltd

    David S. Liebeskind, MD, FAHA, Associate Professor of Neurology; Neurology Director, Stroke Imaging; Associate Neurology Director, UCLA Stroke Center, University of California, Los Angeles, CA, USA.

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  • nostic strategies may identify larger populations for acute treatment, tailor therapeutic approaches to specific individuals, delineate novel therapeutic targets, and enhance man-agement of each patient at successive stages of ischemia beyond the current paradigm where acute therapy revolves around a single intervention considered in isolation from all other aspects of care. This book reflects on aspects of therapeutic strategies that pose poten-tially formidable challenges to effective treatment of cerebral ischemia, or alternatively offer tremendous opportunities in the future when carefully considered. Some aspects of cerebral ischemia considered in this book are rooted in age- old knowledge about neurovas-cular disorders, whereas other aspects represent novel concepts or targets. A discussion of arterial revascularization is complemented with coverage of collateral perfusion and the role of the venous system. Fundamentals of supportive care such as hemodynamics and oxygen administration are followed by reconsideration of neuroprotection in general. The challenges of minor stroke and transient ischemic attacks are considered and hemorrhagic transformation associated with more severe ischemia is also detailed. Early preventive strategies during the subacute phase are emphasized. Finally, the continuum from animal to clinical research is placed in current perspective with introspection on translational approaches and the use of vascular endpoints in the clinical realm.

    Each challenge or potential hurdle to advancing therapy of cerebral ischemia outlined in this text presents an opportunity for innovation. Arterial revascularization offers numerous areas for improvement. Collateral therapeutics and approaches that address the venous aspects of cerebral ischemia are open frontiers. Supportive care and systemic hemodynam-ics can readily be addressed, but have been largely ignored to date. Oxygen therapy seems so rational, yet investigative efforts have been stymied by the complexities of clinical trials. Neuroprotection has gained tremendous exposure in clinical trials, without a single success. Hemorrhagic transformation remains the double- edged counterpart to revascularization, where severe ischemia may incite hemorrhage and abrupt revascularization may beget transformation of the ischemic bed. Finally, the framework for development of stroke ther-apies may be imperfect, emphasizing the need for change before more fruitless efforts mark yet another generation of stroke research [4, 5].

    REFERENCES

    1. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt- PA Stroke Study Group. N Engl J Med 1995; 333:15811587.

    2. Khatri P, Neff J, Broderick JP, Khoury JC, Carrozzella J, Tomsick T. Revascularization end points in stroke interventional trials: recanalization versus reperfusion in IMS- I. Stroke 2005; 36:24002403.

    3. OCollins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol 2006; 59:467477.

    4. Fisher M, Feuerstein G, Howells DW et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 2009; 40:22442250.

    5. Saver JL, Albers GW, Dunn B, Johnston KC, Fisher M. Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for extended window acute stroke therapy trials. Stroke 2009; 40:25942600.

    2 Therapeutic Strategies in Cerebral Ischemia

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  • 2Arterial recanalization potential and limitationsM. H. Qureshi, A. I. Qureshi

    INTRODUCTION

    Stroke remains the third leading cause of death, accounting for 143 579 lives in the United States alone during 2005. Perhaps more importantly, stroke continues to be the foremost cause of long- term disability. Cerebral ischemia accounts for 80% of these astounding fig-ures on morbidity and mortality, yet treatment options remain exceedingly limited. The impact of new treatments for acute stroke was investigated in a study that examined the changes between 19901991 and 20002001 in in- hospital mortality rates and hospital charges for adult patients with stroke [1]. This study demonstrated that there were 1 736 352 admissions for cerebrovascular disorders to hospitals in the United States during 19901991 and 1 958 018 during 20002001. These figures represent an increase of 12.8% despite the reduction in the mean length of hospital stay. The proportion of patients with ischemic stroke admitted to urban teaching hospitals also increased significantly over this 10- year period, by 13%.

    ARTERIAL OBSTRUCTION AND DOWNSTREAM ISCHEMIC INJURY

    Stroke is often caused by luminal obstruction of an artery by thrombus, atheromatous plaque, or a combination of these constituents that block nutritive arterial flow to down-stream regions of the vascular territory. Immediately following arterial occlusion, distal intraluminal pressure decreases with compensatory dilatation of these segments and col-lateral inflow from adjacent territories. Although the degree of collateral perfusion varies amongst individuals, there is typically a reduction in regional cerebral blood flow (rCBF) to the territory. Despite heterogeneity in the distribution of rCBF reductions, a central zone of maximal ischemia, or the ischemic core, is commonly noted. Less severe ischemia in inter-spersed areas or peripherally situated regions of the ischemic penumbra are prone to neuro-logical injury if reperfusion is not established. Collateral perfusion is responsible for the relative maintenance of rCBF within the ischemic penumbra [2]. Using positron emission tomography (PET) studies, the ischemic core can be defined as the region of severe ischemia (less than 7 ml/100 g/min) and the ischemic penumbra can be defined as the region of moder-ate ischemia (717 ml/100 g/min). Ischemic brain injury usually occurs when the rCBF falls

    Atlas Medical Publishing Ltd

    Mushtaq H. Qureshi, MD, Clinical Research Fellow, Zeenat Qureshi Stroke Research Centre, Department of Neurology, University of Minnesota, Minneapolis, MN, USA.

    Adnan I. Qureshi, MD, FACC, Professor of Neurology, Neurosurgery, and Radiology, Zeenat Qureshi Stroke Research Centre, Department of Neurology, University of Minnesota, Minneapolis, MN, USA.

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  • below 10 ml/100 g/min [3]. Experimental studies have shown that reperfusion of the core within 1 h of focal ischemia onset can result in salvage of the neurons [4]. However, PET studies in patients with ischemic stroke have illustrated that ischemic penumbra can be detected up to 24 h after stroke symptom onset, suggesting a theoretical benefit of reper-fusion up to 24 h, although the expected benefit likely diminishes after the earliest epochs [5].

    THERAPEUTIC REVASCULARIZATION WITH ARTERIAL RECANALIZATION

    Arterial revascularization of an occlusive lesion to re- establish antegrade flow is the most intuitive approach to achieve effective reperfusion of the downstream ischemic territory. Thrombolytic therapy is based on the recanalization hypothesis, i.e. reopening of occluded vessels to improve clinical outcome in acute ischemic stroke through reperfusion and sal-vage of threatened tissues [6]. Myriad biologic factors, however, may affect the relationship between recanalization and neurological outcome in acute ischemic stroke patients [7]. Recanalization of large arteries may not yield effective tissue reperfusion because of persist-ing distal emboli, microcirculatory occlusions, or further downstream hemodynamic factors of the no reflow phenomenon. In a subset of patients, recanalization may also occur too late to reduce damage to ischemic tissues. Additionally, reperfusion may aggravate tissue injury by promoting reperfusion injury, cerebral edema, or hemorrhagic transformation. Adequate collateral circulation may also variably maintain viability of tissue even without proximal arterial recanalization.

    THE CONCEPT OF A THERAPEUTIC TIME WINDOW

    The efficacy of tissue plasminogen activator (tPA) to achieve a greater chance of recovery in acute stroke patients has been proven in several large clinical trials. Beyond the earliest few hours after stroke symptom onset, however, the risk of hemorrhagic transformation appears to increase. As a result of the decreasing probability of penumbral salvage and concomitant increasing risk of hemorrhagic transformation as time lapses, thrombolytic therapy for revascularization has a theoretical time window. This restrictive time window of 3 h was recently expanded to 4.5 h after symptom onset, yet time is of the essence in reversing isch-emia with revascularization. Numerous factors contribute to delays or missed opportunities to be treated within this time window and consequently only a small fraction of stroke patients receive intravenous tPA. Other thrombolytic agents have been considered in the past and novel drugs with potentially longer therapeutic windows are also of interest. Selective delivery of thrombolytics via an intra- arterial approach provides yet another means for revascularization where time windows may be longer.

    HISTORICAL PERSPECTIVE ON ARTERIAL REVASCULARIZATION

    STREPTOKINASE

    Thrombolysis for acute ischemic stroke was initiated as early as the 1950s. The first modern randomized trials, which involved intravenous streptokinase, did not demonstrate any clinical benefit. The Multicenter Acute Stroke Trial of Europe (MAST- E) [8], the Multicenter Acute Stroke Trial of Italy (MAST- I) [9], and the Australian Streptokinase Trial (ASK) [10], were stopped early because of increased early mortality and excessive intracranial hemorrhage (ICH) rates. The trials used 1.5 million units of streptokinase over 1 h started within 6 h of symptom onset (MAST) or within 4 h (ASK). The MAST- I trial attempted to study the effect of aspirin in addition to streptokinase. Heparin use was not controlled, and the streptokinase dose was not determined by a dose- escalation paradigm. The ASK

    4 Therapeutic Strategies in Cerebral Ischemia

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  • Arterial recanalization potential and limitations 5

    investigators prospectively divided patients into two groups, those treated in the 0 to 3- h window, and those treated after 3 h. They concluded that treatment with streptokinase within 3 h of onset was safer than treatment after 3 h, but it did not show clinical benefit over placebo in either group. At present, treatment with streptokinase is not warranted and no further trials of streptokinase are planned.

    INTRAVENOUS TISSUE PLASMINOGEN ACTIVATOR

    Intravenous thrombolysis utilizing tPA is currently the only mode of treatment for acute ischemic stroke approved by the United States Food and Drug Administration (FDA). This drug has been shown to reduce death and disability when administered within the first 3 h after symptom onset [11]. Several acute ischemic stroke trials using intravenous tPA have been completed in Europe and in the United States as described below.

    European Cooperative Acute Stroke Trial (ECASS)The European Cooperative Acute Stroke Trial (ECASS) [12] was a double- blind, randomized, placebo- controlled trial of intravenous tPA (1.1 mg per kg over 1 h, 10% as a bolus, maximum 100 mg). The infusion was initiated within 6 h of symptom onset. Patients with severe neurologic deficits or initial computed tomographic (CT) scans with major signs of infarction involving more than one- third of the middle cerebral artery (MCA) distribution were excluded. Two analyses were performed, including an intent- to- treat analysis and the target population analysis that considered only those that met strict inclusion criteria. One hundred and nine patients were excluded from the intent- to- treat population, mostly for CT based exclusion criteria violations (n = 66), leaving 511 subjects in the target population analysis. The mean time to treatment was 4.4 h. The mortality rate in the intent- to- treat analysis was greater among the tPA group treated at 90 days (22.4% versus 15.8%; P = 0.040). The target population analysis also had a higher mortality among the tPA- treated group, but it did not reach statistical significance (19.4% versus 14.8%; P = 0.170). Forty- eight percent of those treated with tPA who had major signs of infarction on initial CT (n = 31) died. The rate of large parenchymal hematomas was significantly greater among the tPA group in both analyses (intent- to- treat, 19.8% versus 6.5%; and target population, 19.4% versus 6.8%). ECASS failed to demonstrate an improvement with tPA in functional outcome (90- day Barthel Index) (Table 2.1) in either analysis. The modified Rankin Scale (mRS) score less than or equal to 2 was achieved in 41% of the tPA target population compared with 29% of the placebo target population at 90 days. Based on these results, the authors concluded that tPA therapy could improve outcome in a carefully selected subgroup of patients, especially those without major signs of infarction on the initial CT scan. Conversely, treating patients who do not meet strict eligibility criteria may carry a high risk of ICH or death. Thrombolytic

    Table 2.1 Stroke scales of long- term functional outcome used in recent studies

    Stroke scale Scoring Description

    Modified Rankin Scale 0 to 5 point scale 0: no symptoms; 2: functionally independent;4 to 5: severe disability

    Barthel Index 0 to 100 points 5 to 10: points per activity of daily living;

    > 65: functionally independent;95 to 100: minimal or no disability

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  • 6 Therapeutic Strategies in Cerebral Ischemia

    treatment within 6 h of symptom onset was therefore not recommended for widespread use because such subgroups may be difficult to identify.

    NINDS tPA Stroke TrialIn the United States, a series of trials funded by National Institutes of Neurological Disorders and Stroke (NINDS) ultimately demonstrated the safety and efficacy of intravenous tPA for acute ischemic stroke when administered within 3 h of symptom onset. The NINDS trials were preceded by two open- label, dose-ranging pilot studies and a pilot randomized trial. The NINDS tPA Stroke Trial was conducted at eight centers (totaling 45 hospitals, five aca-demic medical centers, and 40 community hospitals). The trial was conducted as two con-secutive trials and results were reported together as Part 1 and Part 2. These two trials were double- blind, randomized, placebo- controlled trials of intravenous tPA using 0.9 mg per kg over 1 h, 10% as a bolus, maximum 90 mg) versus placebo recruiting a total of 624 patients.

    In Part 1, the primary purpose was to test drug activity at 24 h; 3- month functional out-come data were also collected. There was no significant difference in the primary outcome measure between the tPA group and the placebo group; 47% versus 39% of patients achieved a 4- point improvement on the National Institutes of Health Stroke Scale (NIHSS) score at 24 h (P = 0.210). However, 17% of patients treated with tPA returned to normal or near- normal status (NIHSS 0 or 1) at 24 h compared with 3% of those treated with placebo. Three-month functional outcome data in Part 1 showed a strong and consistent improvement in the tPA group with an absolute difference of 15% to 20% more patients attaining a favorable out-come at 3 months. The odds ratio (OR) of 2.1 (95% confidence interval [CI] 1.3 to 3.2; P = 0.001) favored treatment with tPA.

    Part 2 was the pivotal study that established long- term efficacy, with a primary endpoint of normal or near- normal function at 3 months. There was an absolute increase of 11% to 13% in the proportion of patients achieving this favorable outcome in the tPA- treated group compared with the placebo group (or a 24% to 35% relative increase). The OR for improve-ment with tPA was 2.0 (95% CI 1.3 to 3.1) after adjusting for baseline differences in age, weight, and aspirin use. This positive effect was consistently present in subgroups defined by age, baseline NIHSS, stroke subtype (lacunar, large vessel, and cardioembolic), and asp-irin use before treatment. The FDA considered the secondary (3- month) outcomes of Part 1 confirmatory evidence of long- term efficacy.

    Although the use of tPA was associated with good clinical outcome, symptomatic intra-cranial hemorrhage (SICH) (within 36 h of stroke) occurred in 6.4% of the tPA- treated patients and in 0.6% of placebo- treated patients (P < 0.001). The patients with SICH had a higher median NIHSS at baseline than those without (20 versus 14). The rate of asymptomatic intracranial hemorrhage was not statistically different (4.5% versus 2.9%). Despite the increased risk of hemorrhage with tPA treatment and a 50% mortality rate associated with SICH (in either placebo or tPA group), the 3- month mortality rate was not different; 17% of the tPA- treated patients and 21% of the placebo- treated patients died within 3 months (P = 0.300).The authors concluded that, despite an increased risk of SICH, treatment with tPA provided a consistent benefit in functional outcome at 3 months without increasing mortality.

    ECASS IIECASS II was a non- angiographic, randomized, double- blind, placebo- controlled trial evaluat-ing the use of 0.9 mg per kg of tPA in 800 patients at 108 centers in Europe as well as in Australia and New Zealand. Each group of 10 patients was randomized in a stratified manner to receive treatment either 0 to 3, or 3 to 6 h after onset of symptoms. The primary endpoint was the mRS 90 days after treatment, dichotomized into favorable (score 0 or 1) and unfavorable (score 2 to 6) outcomes. Furthermore, another dichotomization for independence (mRS score 0 to 2) versus dependence or death (mRS score 3 to 6) was used. There was a non-significant 3.7%

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  • Arterial recanalization potential and limitations 7

    absolute difference (10% relative difference) in the primary endpoint in favor of tPA treatment, but the increase of independent patients was significant (54.3% versus 46.0%; P = 0.024). The rate of parenchymal hematoma type 2 was increased 10- fold in tPA- treated patients (8.1% versus 0.8%); this difference did not lead to an excess in mortality in the tPA group because of a higher rate of fatal outcomes due to space- occupying edema in the placebo group. The abso-lute treatment differences in ECASS II were very similar in those patients treated in the first 3 h of stroke compared with those treated between 3 and 6 h. This is also true for the bleeding rate (parenchymal hematoma type 2), which was 7% within the first 3 h and 8.3% between 3 and 6 h in tPA- treated patients. However, these results should be viewed with caution because only 158 patients (19.9%) were enrolled in ECASS II within 3 h of stroke onset (81 tPA, 77 placebo).

    ECASS IIIIn this randomized, placebo- controlled study, patients with acute ischemic stroke benefited from treatment with intravenous tPA administered 3 to 4.5 h after the onset of stroke symptoms. ECASS III was the second randomized trial (after the NINDS tPA Stroke Trial [11]) to show a significant treatment effect with intravenous tPA in the unadjusted analysis of the primary endpoint. The treatment effect remained significant after adjustment for all prognostic baseline characteristics. The overall rate of SICH was increased with alteplase as compared with placebo, but mortality was not affected. Both of these findings are consistent with results from other randomized, controlled trials of thrombolysis in patients with acute ischemic stroke [11, 13, 14]. The results of the analysis of secondary endpoints and of the post hoc stratified analysis mirrored the primary efficacy results in favor of alteplase. In this study, intravenous alteplase given 3 to 4.5 h (median, 3 h 59 min) after the onset of stroke symptoms was associated with a modest but significant improvement in the clinical outcome, without a higher rate of SICH than that reported previously among patients treated within 3 h. Although the findings suggest that treatment with alteplase may be effective in patients who present 3 to 4.5 h after the onset of stroke symptoms, patients should be treated with alteplase as early as possible to maximize the benefit. It is interesting to note that there has been a gradual decline in the overall initial severity of stroke and in mortality rates among patients enrolled in major randomized studies of acute ischemic stroke over the past two decades [11, 13, 14].

    Previously, some trials of alteplase for acute ischemic stroke included patients who received treatment within 0 to 6 h after the onset of symptoms. However, these trials failed to show a significant advantage of alteplase therapy [12, 1517]. Potential explanations for the failure to show a significant difference in previous trials include the choice of endpoints, a time window of up to 6 h, and a lack of statistical power. It should be noted that in ECASS II [15] and in the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trial [16], the cohorts that were treated 3 to 4.5 h after the onset of symptoms were far smaller and these studies were therefore not powered to detect an effect size of 7 to 10%.

    AncrodAncrod is a selective defibrinogenating agent derived from the venom of the Malaysian pit viper [18]. Ancrod acts by lowering the fibrinogen level, thereby decreasing serum viscosity and increasing rCBF. It also acts as an anticoagulant, preventing thrombus formation, while promoting thrombolysis by stimulating endogenous tPA release, inhibiting plasminogen activator inhibitor, plasmin inhibitor, and platelet function. The Stroke Treatment with Ancrod Trial (STAT) was a double- blind, randomized, placebo- controlled trial of ancrod with placebo within 3 h of onset of symptoms. Ancrod was infused for 5 days and the dose adjusted to maintain a target fibrinogen level of 4070 mg/dl. Forty- two percent of the patients in the ancrod group and 34% in the placebo group (P < 0.05) achieved functional independence at 90 days. SICH occurred in 5.2% with ancrod and 2.0% with placebo; the

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  • 8 Therapeutic Strategies in Cerebral Ischemia

    mortality rates were identical at 10% at 90 days. Patients in whom fibrinogen level decreased below 40 mg/dl had a SICH rate of 13%.

    Intra- arterial thrombolysisThe rationale for intra- arterial delivery or endovascular thrombolysis centers around the abil-ity for selective administration of a relatively higher concentration of thrombolytic agent, in direct contact with the arterial occlusion. The catheter and other mechanical tools used for thrombolytic drug delivery also promote thrombolysis through mechanical disruption of the clot. Although it was observed in uncontrolled trials that recanalization rates were higher with an intra- arterial approach as compared to an intravenous approach for thrombolysis, the delay in initiating the treatment may obscure the magnitude of resultant clinical benefits. In those patients who are expected to have a decreased response to intravenous treatment, use of intra- arterial thrombolysis has therefore gained popularity. Although not approved by the FDA, the proposed criteria for selection of patients with intra- arterial thrombolysis include NIHSS greater than 10, presentation between 3 and 6 h after symptom onset, recent history of major surgical procedures (within 14 days) and occlusion of proximal extra or intracranial arteries.

    Prolyse in Acute Cerebral Thromboembolism (PROACT) I & IIProlyse in Acute Cerebral Thromboembolism (PROACT) I and II were randomized clinical trials evaluating the efficacy of intra- arterial pro- urokinase (plus intravenous heparin) com-pared with placebo (plus intravenous heparin) among patients presenting with MCA occlu-sions less than 6 h old [19, 20]. Mechanical disruption of the clot was not permitted. PROACT I [19] randomized 46 patients and demonstrated that intra- arterial pro- urokinase infusion was associated with higher recanalization rates compared with placebo. The SICH rate was 15.4% in the pro-urokinase group versus 7.1% in the placebo group. In PROACT II [20], there was a statistically significant benefit with 40% of pro- urokinase-treated patients hav-ing a good 3- month functional outcome (modified Rankin score < 2) compared with 25% of the control group. SICH occurred in 10% of the pro- urokinase group and 2% of the control group (P = 0.063). Because pro- urokinase is not available in the United States for clinical use, tPA and urokinase have been used instead for intra- arterial thrombolysis with favorable outcomes in selected patients [1921].

    Meta- analysis of intra- arterial thrombolysisIntra- arterial thrombolytic therapy for acute stroke is not approved by the FDA, but may be considered in patients with MCA occlusions who can be treated within 3 to 6 h after symp-tom onset and who have no (or minimal) signs of infarction on their baseline CT scans [21, 22]. Given the high mortality associated with basilar artery and internal carotid artery bifur-cation (carotid T) occlusions, patients with these lesions may also be considered for intra- arterial thrombolytic therapy on a case-by-case basis [21, 22].

    Combination intravenous and intra- arterial thrombolysisSeveral pilot studies have evaluated the use of combining intravenous and intra- arterial thrombolysis. The National Institutes of Health- funded Interventional Management of Stroke (IMS) I trial investigated the feasibility and safety of a combined intravenous and intra- arterial approach to recanalization among patients with ischemic stroke and a substantial neurological deficit (NIHSS greater than or equal to 10) [23]. The study enrolled 80 patients and their outcome was compared with historical controls derived from the NINDS tPA Stroke Trial. The patients received 0.6 mg per kg of intravenous tPA over 30 min within 3 h from stroke symptom onset followed by intra- arterial tPA within 5 h if an arterial occlusion was still present on follow-up angiography. The 3- month mortality rate and the SICH rate in IMS I patients were similar to intravenous tPA- treated patients in the NINDS

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  • Arterial recanalization potential and limitations 9

    tPA Stroke Trial. IMS subjects showed a non- significant trend toward better clinical outcomes than historical intravenous tPA controls (OR 1.35; 95% CI, 0.782.37). The results of this study and other pilot studies suggest that a combined intravenous plus intra- arterial approach to revascularization is feasible and safe. Further studies assessing the efficacy of this combined approach to recanalization are presently ongoing and have incorporated the use of various endovascular mechanical devices.

    Endovascular mechanical clot disruption/removalAlthough patients have been treated with tPA since 1996 when it was approved by the FDA [11], it has been noted that approximately 70 to 80% of patients with a NIHSS of 10 or greater have persistent arterial occlusions at angiography [23, 24]. During the past decade, interest has turned to mechanical devices that are delivered via an endovascular approach to recanalize intracranial arteries. Intravenous and intra- arterial thrombolytic therapies tend to be limited by restrictive time windows. Concurrently, there is an increased risk of SICH. Several endovascular devices have been developed in recent years to remove clots from the cerebral circulation. These devices have been tested in patients with acute stroke who are ineligible for or who failed intravenous tPA treatment [2529].

    Endovascular photo acoustic recanalizationThe earliest reported multicenter safety trial of mechanical embolectomy was performed using the Endovascular Photo Acoustic Recanalization device (Endovasix Inc., Belmont, California, USA) [26]. This device produces laser energy that is converted into acoustic energy when it is absorbed by the clot, which emulsifies inside the catheter tip. Patients were included in the study if they had a large artery occlusion in the anterior circulation that could be treated within 6 h, or a posterior circulation occlusion that could be treated within 12 h. Thirty- four patients were enrolled, and 18 patients completed treatment using the re canalization device as intended per protocol. In these 18 optimally- treated patients, mechanical thrombectomy appeared to recanalize arteries quickly. Mean lasing time was 9.65 min (range 1.3319.92 min). Arterial recanalization occurred in 61.1% (11/18) and good outcomes (mRS 02) were seen in 22.2% of these patients (4/18) at the 30- day follow-up. Lack of funding prevented an efficacy trial from being completed.

    Merci clot retrievalThe Mechanical Embolus Removal in Cerebral Ischemia (Merci) retrieval device has been studied most extensively after initial investigation in acute stroke patients who are ineligible or have failed intravenous tPA therapy [29]. In August 2004, the Merci Retriever (Concentric Medical, Mountain View, California, USA), an intra- arterially delivered corkscrew- like device (Figure 2.1), received clearance from the FDA to remove clots from the brain in patients experiencing an ischemic stroke [30]. This regulatory action was based on a non-randomized trial that showed that the device could recanalize arteries with acceptable safety in patients treated within 8 h of symptom onset [29, 31]. A subsequent study followed, reported in two parts, incorporating a second- generation device and allowing patients who had persistent large artery occlusion following intravenous tPA treatment to be included [32]. Two randomized trials involving the Merci device are ongoing, as is an international registry investigating use of the Concentric Retriever System devices [33]. Figure 2.2 illus-trates sequential endovascular treatment incorporating the Merci device.

    Mechanical embolus removal in cerebral ischemia (MERCI)The MERCI trial included patients with occlusions of the MCA, internal carotid artery, basilar and vertebral arteries, and a symptom duration of up to 8 h. The trial compared the ability of the Merci Retriever to revascularize vessels with spontaneous recanalization

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    of MCA occlusions in the control arm of the PROACT II trial [20, 29]. Patients were 18 years of age or older and had an NIHSS score of 8 or more. Patients with an elevated international normalized ratio (INR) of up to 1.7 were included in Part I and those with an INR of up to 3 were included in Part II of the study [31, 34]. The study was performed at 26 centers in the USA, enrolling a total of 151 patients, with device deployment in 141. Revascularization with the device alone occurred in 48% of patients in whom it was deployed and in 46% of the intent- to- treat group, both of which were significantly better than the spontaneous recanalization rates in the control arm of the PROACT II trial (P < 0.0001). Recanalization rates were similar in the posterior circulation (50%) and internal carotid artery (53%), and lowest in the MCA (45%) [29]. Mortality occurred in 43% of patients and good functional outcome (indicated by a mRS score 2) was observed in 28%. The MERCI trial found recanalization rates to be the strongest predictor of outcome [29].

    The definition of SICH in MERCI included all patients with blood products on the scan, even petechial ones, and a 4- point decline on the NIHSS [29]. This is in contrast to the definition employed in the PROACT II trial, in which causation was implied between the hemorrhagic transformation and 4- point neurologic deterioration (or 1- point deterioration in the level of consciousness) [20]. Symptomatic hemorrhages occurred in 7.8% of patients in the MERCI trial. Five of the 11 (45%) hemorrhages were subarachnoid in location, probably procedurally induced [29]. Use of adjuvant therapies, pharmacologic and mechan ical, did not increase rates of hemorrhage. Clinically significant procedural complications were reported in 7.1% (10/141) of patients, including embolization of a previously un involved vascular territory, vascular perforations, subarachnoid hemorrhages, and groin hematomas.

    Multi MERCIThe Multi MERCI trials included patients with occlusions in the same vascular distributions as in MERCI and also included patients up to 8 h after symptom onset with NIHSS scores of 8 or more [32, 34]. Multi MERCI differed from MERCI in incorporating the use of a second- generation retriever device (Figure 2.3) for at least the first treatment pass and in allowing patients who had received intravenous tPA but had persistent occlusions to be included.

    A B

    Figure 2.1 The Merci device (A) and illustration of the clot removal process (B) (courtesy of Concentric Medical, Inc., Mountain View, CA; with permission: all rights reserved 2008).

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  • Arterial recanalization potential and limitations 11

    A B

    C D

    Figure 2.2 (A) Antero- posterior view demonstrating complete occlusion of the superior M2 branch and partial occlusion of the inferior M2 branch. (B) A microcatheter placed across the occlusion for infusion of thrombolytics. (C) A Merci L5 retriever was deployed in the proximal left M2 segment over the thrombus. (D) A 4 mm 7 mm HyperForm balloon was positioned in the superior left M2 branch. Angioplasty was then performed. Continued overleaf

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  • 12 Therapeutic Strategies in Cerebral Ischemia

    Forty- eight patients (29.3%) received intravenous tPA before the intra- arterial procedure [34]. In Multi MERCI, 36% of patients had a mRS of 02 at 90 days [34]. A higher proportion of patients in whom arterial recanalization was achieved had good outcomes than of those in whom it was not achieved (P < 0.001), and less mortality (P < 0.001). Rates of recanaliza-tion tended to be higher in patients treated with the L5 device, reaching 57% after the retriever alone and 70% after adjunctive therapies. The rate of SICH (defined as it was in MERCI to include all patients with blood products on the scan and a 4- point decline on the NIHSS) did not differ between patients who received and those who did not receive initial intravenous tPA treatment in Multi MERCI.

    Ongoing trials with MerciThe Magnetic Resonance and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) Trial is an ongoing randomized study of the Merci device. This NINDS- funded trial is comparing the Merci Retriever with medical therapy in patients with anterior circulation strokes up to 8 h after symptom onset and with an NIHSS score of at least 6. Effects of therapy are stratified by magnetic resonance imaging (MRI) findings for presence or absence of pen-umbra at randomization. The Merci retrieval devices also comprise one of the intra- arterial treatment options for persistent arterial occlusion after low- dose intravenous tPA in the ongo-ing IMS III trial [24]. Finally, the Merci Registry is providing post- market, international data on the use of the Merci Retriever in patients for whom it is indicated for thrombus removal in acute ischemic stroke [33]. Collected information includes post- procedure revasculariza-tion success, hemorrhage rates at 24 h, and 90- day outcomes and mortality.

    Penumbra clot aspirationThe Penumbra system (Figure 2.4) became the second endovascular device cleared for use in acute stroke patients. The Penumbra system was initially evaluated in a phase 1 feasibility

    Figure 2.2 (E) Successful recanalization with reinstitution of flow to the superior and inferior M2 branches after intra- arterial thrombolytic infusion and balloon angioplasty.

    E

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  • Arterial recanalization potential and limitations 13

    study conducted in Europe [35]. Patients were at least 18 years old with a deficit measurable on the NIHSS and symptom onset within 8 h. Those presenting within 3 h were required to be ineligible for or refractory to intravenous tPA. Occluded vessels accessible by the Penumbra system were treated. In the first 20 patients treated with the device, occlusions were located in the MCA, internal carotid and basilar arteries. The primary occlusion was recanalized in 100% of cases. Intra- arterial tPA or urokinase was used to treat occlusions distal to the primary occlusion in 35% (7/20) of cases. Good outcomes (mRS 02 or a 4- point improve-ment on the NIHSS) were observed in 42% of patients and 45% died. SICH occurred in 15% (3 patients). A subarachnoid hemorrhage that was not associated with neurologic deteriora-tion and a groin hematoma requiring transfusion were the only procedural adverse events.

    Figure 2.3 Schematic of the L5 Merci retriever engaging a clot.

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  • 14 Therapeutic Strategies in Cerebral Ischemia

    Penumbra Pivotal Stroke TrialThe Penumbra Pivotal Stroke Trial was a single- arm study of 125 patients at centers in Europe and the USA including patients aged between 18 and 79 years with an NIHSS score of 8 or more presenting within 8 h of symptom onset [36, 37]. Patients refractory to intra-venous tPA were eligible. Success criteria included a 48% or more revascularization rate and device-related serious adverse event rate of 15% or less. After the procedure, 81.6% of the treated vessels were successfully revascularized to Thrombolysis in Myocardial Ischemia (TIMI) scores of 23. There were 18 procedural events reported in 16 patients (12.8%) and 3 patients (2.4%) had events that were considered serious. A total of 35 patients (28%) were found to have intracranial hemorrhage on 24- h CT of which 14 (11.2%) were symptomatic. All-cause mortality was 32.8% at 90 days, with 25% of the patients achieving a modified Rankin Scale score of less than or equal to 2 [37].

    OPENING ARTERIES FIRST OF MANY

    Arterial recanalization with thrombolysis was the first therapeutic strategy proven to off-set the deleterious effects of acute cerebral ischemia. Modifications to intravenous thrombo-lysis have followed through successive trials and in clinical practice, yet numerous limitations exist. Optimal selection of therapeutic candidates remains a key challenge and adverse effects of hemorrhagic transformation must be minimized. The dramatic response or Lazarus effect noted in a subset of cases provides encouragement that ischemia in the brain truly can be reversed. Adjunctive use of ultrasound, microspheres, and more with intra venous thrombolysis will undoubtedly further extend possible treatment options during early phases of ischemia. Endovascular approaches, using drugs, devices, and various combinations thereof, have rapidly expanded the ability to restore patency to proximal arteries in the brain. Distal embolization, no reflow, and other factors that limit reperfusion despite recanalization, comprise key targets for next steps in enhancing arte-rial revascularization efforts. Serial use of detailed multimodal imaging may also help guide many aspects of arterial revascularization, that is increasingly employing more devices, more techniques, and more intensive, adjunctive management. Tailoring therapy to a given patient and defining successful revascularization remain formidable challenges. For a given case, arterial recanalization may be only the first of many therapeutic interven-tions. In the future, balancing arterial recanalization with the numerous other therapeutic considerations considered in subsequent chapters of this book will allow stroke therapeu-tics to mature beyond the early days that revolved solely around removing the occlusive arterial lesion.

    A B

    Figure 2.4 Schematic of the Penumbra system used for clot aspiration (A) and clot extraction (B) (courtesy of Penumbra Inc., San Leandro, California, USA).

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  • Arterial recanalization potential and limitations 15

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