Springer Series in Translational Stroke Research
Series Editor
John Zhang
Loma Linda, USA
More information about this series at http://www.springer.com/series/10064
Paul A. Lapchak • John H. Zhang Editors
Neuroprotective Therapy for Stroke and Ischemic Disease
Editors
Paul A. Lapchak Department of Neurology and Neurosurgery
Cedars-Sinai Medical Center
Los Angeles, CA, USA
John H. Zhang
Loma Linda University School of Medicine
Loma Linda, CA, USA
ISSN 2363-958X
ISSN 2363-9598 (electronic)
Springer Series in Translational Stroke Research
ISBN 978-3-319-45344-6 ISBN 978-3-319-45345-3 (eBook)
DOI 10.1007/978-3-319-45345-3
Library of Congress Control Number: 2016955837
© Springer International Publishing Switzerland 2017
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Preface
This is a very timely compilation of cutting-edge aspects of neuroprotective therapy for ischaemic stroke in a myriad of clinical and experimental situations. It was assembled by basic and clinical scientists at a time well after the dust had settled on the subject, following the difficulties of translating neuroprotection from bench to bedside. However, we are still mystified as to why this translational gap persists although numerous possible explanations have been given, in what now must be thousands of review articles. The book is logically and easily divided into four sections, ranging from the historical aspects of neuroprotection right through to the very latest aspects of clinical trial design.
Several positives have come from the difficulties experienced in translation of neuroprotective therapies, and these are all brought out nicely in this volume. First, there is now a vastly increased rigour in preclinical trial design which led to the STAIR (Stroke Treatment Academic Industry Roundtable) series of recommendations. These have provided valuable benchmarks for all those now conducting research in this area. Second, the idea of aggregating preclinical animal model data using meta-analysis techniques as used in the clinical sphere was pioneered by the Melbourne and Edinburgh groups led by Malcolm McLeod and David Howells, which later exposed problems with sample sizes, publication bias and lack of blinding as only some of the issues that need to be addressed to improve the quality of the preclinical research data. These findings have increased the likelihood of translation into the clinic. The Melbourne and Edinburgh groups have formalised their efforts in this area with the CAMARADES (Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies) collaboration which acts as a preclinical form of the Cochrane Collaboration. The groups have also published guidelines for experimental design in a number of journals; indeed the movement has become so influential that other research disciplines are rapidly following suit. Third, translational failures are stimulating the search for new therapeutic targets such as autophagy as well as existing pathways and processes such as uric acid metabolism and the immune system.
An important component of the book is the recognition that modern endovascular treatment and its ischaemic consequences play an important part in the neuroprotection story. Indeed, the entirety of Sect. 4 is dedicated to combination therapies. Clearly, the outstanding success of recanalisation approaches with devices has re-energised the debate about reperfusion injury. There already existed an extensive experimental background well before these interventions were shown to be so clinically successful. On balance, the likelihood that an effective form of neuroprotection of clinical importance would arise from this type of research would seem to be quite high. Time will tell.
The compilation of such a complete range of aspects of neuroprotection raises the question as to whom the readership should be directed and who would most benefit. It certainly would be an ideal reference for any current researcher in any aspect of neuroprotection, either experienced or just beginning. It would also be a useful compendium for interested students, clinicians or scientists from other disciplines who’d like to dip into its rich matrix.
The quality of the information assembled shines through the experiences of the authors who are clearly leaders in their field. This alone makes this volume one that anyone would be proud to have on their bookshelf or, as is often the case today, readily accessible on their laptop.
Melbourne, VIC, Australia
Geoffrey A. Donnan 2016
1
Paul A. Lapchak and Paul D. Boitano
2
3
4
Sarah K. McCann, Emily S. Sena, Gillian L. Currie, Malcolm R. Macleod, and David W. Howells
Donald J. DeGracia, Doaa Taha, Fika Tri Anggraini, and Zhi-Feng Huang
7
Ali Razmara and Steven C. Cramer
Linda M. Haugaard-Kedström, Eduardo F.A. Fernandes, and Kristian Strømgaard
Zhong-Ping Feng and Hong-Shuo
22 Targeting Pericytes and the Microcirculation for Ischemic Stroke Therapy..................................................................
Ain A. Neuhaus, Brad A. Sutherland, and Alastair M. Buchan Part III Thrombolysis and Embolectomy
23 Thrombolytic and Endovascular Therapies for Acute Ischemic Stroke ...................................................................... 559
Hormozd Bozorgchami and Helmi L. Lutsep
24 Sonothrombolysis for Acute Ischemic Stroke: A Critical Appraisal ................................................................................
Georgios Tsivgoulis, Apostolos Safouris, and Andrei V. Alexandrov
25 Combination Therapy with Thrombolysis
Burak Yulug and Wolf-Rüdiger Schäbitz
26 Oxygen Carriers: Are they Enough for Cellular Support? 621
Jennifer L.H. Johnson
27 A New Paradigm in Protecting Ischemic Brain: Preserving the Neurovascular Unit Before Reperfusion 641
Natacha Le Moan, Philberta Y. Leung, Natalia Rost, Jonathan A. Winger, Ana Krtolica, and Stephen P. Cary Part IV Stroke Models and Clinical Trial Considerations
28 The Right Rodent for the Job: Infarct Variability Between Strains and Its Impact on Logistics of Experimental Animal Studies 667
Sarah Rewell and David W. Howells
29 Rabbit Spinal Cord Ischemia Model for the Development of Neuroprotective Treatments 689
Daisy Chou, Anja Muehle, Paul A. Lapchak, and Ali Khoynezhad
30 Stroke Sex Differences: From Basic Research to Clinical Trials
Claire L. Gibson, Philip M.W. Bath, and Raeed Altaee
31 Unpuzzling the Comorbid Type 2 Diabetes and Hypertension-Related Cognitive Dysfunction and Stroke ........... 711 I. Sebastião, E. Candeias, M.S. Santos, C.R. Oliveira, Paula I. Moreira, and Ana I. Duarte
32 Sex-Specific Factors in Stroke ................................................................
Anjali Chauhan, Hope Moser, and Louise D. McCullough
Jenny P. Tsai and Gregory W. Albers
Contributors
Todd A. Abruzzo, M.D. Department of Neurosurgery, College of Medicine, University of Cincinnati (UC), Cincinnati, OH, USA
Comprehensive Stroke Center at UC Neuroscience Institute, Cincinnati, OH, USA
Mayfield Clinic, Cincinnati, OH, USA
Gregory W. Albers Department of Neurology, Stanford University, Stanford, CA, USA
Alberto Alcázar Department of Investigation, Hospital Ramón y Cajal, IRYCIS, Madrid, Spain
Andrei V. Alexandrov, M.D. Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA
Stroke Unit, Metropolitan Hospital, Piraeus, Greece
Carine Ali Normandie Université, UNICAEN, INSERM UMR-S U919 “Serine Proteases and Pathophysiology of the Neurovascular Unit”, Caen, France
Raeed Altaee Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK
Diana Amantea, Ph.D. Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Calabria, Italy
Sergio Amaro, M.D., Ph.D. Hospital Clinic of Barcelona Neurosciences Institute, Functional Unit of Cerebrovascular Diseases, Hospital Clínic of Barcelona, Barcelona, Spain
Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
Fika Tri Anggraini Department of Physiology, Wayne State University, Detroit, MI, USA
Anders Bach, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Giacinto Bagetta, Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Calabria, Italy
Taura L. Barr, Ph.D., R.N., F.A.H.A. CereDx Inc., Eight Medical Center Drive, Morgantown, WV, USA
Philip M.W. Bath, Stroke, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK
Paul D. Boitano, B.Sc. Department of Neurology and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Hormozd Bozorgchami, Oregon Health & Science University, Portland, OR, USA
Alastair M. Buchan, D.Sc. (Oxon), L.L.D. (Hon), F.R.C.P., F.R.C.P.Ed. Acute Stroke Programme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Medical Sciences Division, University of Oxford, Oxford, Oxfordshire, UK
Acute Vascular Imaging Centre, University of Oxford, Oxford University Hospitals, Oxford, UK
E. Candeias, CNC—Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Pólo 1, 1st Floor), University of Coimbra, Coimbra, Portugal
Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal
Stephen P. Cary, Omniox Inc., San Carlos, CA, USA
Ángel Chamorro, M.D., Ph.D. Functional Unit of Cerebrovascular Diseases, Clínic Institute of Neurosciences (ICN), Hospital Clínic de Barcelona, Barcelona, Spain
Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
Medical Department, School of Medicine, University of Barcelona, Barcelona, Spain
Anjali Chauhan, Ph.D. McGovern Medical School—The University of Texas Health Science Center at Houston, Houston, TX, USA
Mourad Chioua, Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry (CSIC), Madrid, Spain
Daisy Chou, M.D. Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Steven C. Cramer, M.D., M.M.Sc. Department of Neurology, University of California, Irvine, Orange, CA, USA Contributors
Gillian L. Currie, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
Donald J. DeGracia, Department of Physiology, Wayne State University, Detroit, MI, USA
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
Ana I. Duarte, CNC—Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Pólo 1, 1st Floor), University of Coimbra, Coimbra, Portugal
Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal
Alejandro Escobar-Peso, Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry (CSIC), Madrid, Spain
Chizoba J. Ezepue, M.D. Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, USA
Zhong-Ping Feng, Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Eduardo F.A. Fernandes, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
Federica Ferrari, B.Sc., M.Sc., Ph.D., A.C.C.P. Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
Mark Fisher, M.D. Departments of Neurology, Anatomy & Neurobiology, and Pathology & Laboratory Medicine, University of California Irvine, Irvine, CA, USA Department of Neurology, UC Irvine Medical Center, Orange, CA, USA
Valerio Frezza, Department of Investigation, Hospital Ramón y Cajal, IRYCIS, Madrid, Spain
Claire L. Gibson, Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK
R. Giersch, CereDx Inc., Eight Medical Center Drive, Morgantown, WV, USA
V. Gionis, CereDx Inc., Eight Medical Center Drive
Steven L. Gogela, M.D. Department of Neurosurgery, College of Medicine, University of Cincinnati (UC), Cincinnati, OH, USA
Rosaria Greco, Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, “C. Mondino” National Neurological Institute, Pavia, Italy Contributors
Linda M. Haugaard-Kedström, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
David C. Hess, M.D. Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, USA
David W. Howells, Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia
Faculty of Health, School of Medicine, University of Tasmania, Medical Science Precinct, Hobart, TAS, Australia
Zhi-Feng Huang, Department of Physics and Astronomy, Wayne State University, Detroit, MI, USA
Jennifer L.H. Johnson, Ph.D. Thayer Medical Corporation, Tucson, AZ, USA
Ali Khoynezhad, M.D., Ph.D., F.A.C.S. Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Ana Krtolica, Omniox Inc., San Carlos, CA, USA
Paul A. Lapchak, Ph.D., F.A.H.A. Department of Neurology and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
JungSeok Lee, M.D., Ph.D. Department of Neurology, JeJu National University School of Medicine, Jeju, South Korea
Department of Neurology, University of California Irvine, Irvine, CA, USA
Eloise Lemarchand, Normandie Université, UNICAEN, INSERM UMR-S U919
“Serine Proteases and Pathophysiology of the Neurovascular Unit”, Caen, France
Philberta Y. Leung, Omniox Inc., San Carlos, CA, USA
Morgane Louessard, Normandie Université, UNICAEN, INSERM UMR-S U919
“Serine Proteases and Pathophysiology of the Neurovascular Unit”, Caen, France
Helmi L. Lutsep, Oregon Health & Science University, Portland, OR, USA
Malcolm R. Macleod, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
José Marco-Contelles, Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry (CSIC), Madrid, Spain
Emma Martínez-Alonso, Department of Investigation, Hospital Ramón y Cajal, IRYCIS, Madrid, Spain
Sarah K. McCann, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
Louise D. McCullough, M.D., Ph.D. McGovern Medical School—The University of Texas Health Science Center at Houston, Houston, TX, USA
Memorial Hermann Hospital—Texas Medical Center, Houston, TX, USA
Natacha Le Moan, Ph.D. Omniox Inc., San Carlos, CA, USA
Paula I. Moreira, CNC—Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Pólo 1, 1st Floor), University of Coimbra, Coimbra, Portugal
Institute of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Antonio Moretti, D.Pharm., Ph.D. Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
Hope Moser, R.N., D.N.P. Memorial Hermann Hospital—Texas Medical Center, Houston, TX, USA
Anja Muehle, M.D. Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Ain A. Neuhaus, M.A. Acute Stroke Programme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Victoria E. O’Collins, Florey Neuroscience Institutes, Parkville, VIC, Australia
C.R. Oliveira, CNC—Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Pólo 1, 1st Floor), University of Coimbra, Coimbra, Portugal
Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Roy Poblete, M.D. Department of Neurology, Keck Hospital of the University of Southern California, Los Angeles, CA, USA
Ali Razmara, M.D., Ph.D. Department of Neurology, University of California, Irvine, Orange, CA, USA
Sarah Rewell, Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia
Natalia Rost, J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
Benoit Denis Roussel, Normandie Université, UNICAEN, INSERM UMR-S U919 “Serine Proteases and Pathophysiology of the Neurovascular Unit”, Caen, France
Apostolos Safouris, M.D. Second Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
Stroke Unit, Metropolitan Hospital, Piraeus, Greece
M.S. Santos, CNC—Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Pólo 1, 1st Floor), University of Coimbra, Coimbra, Portugal
Life Sciences Department, University of Coimbra, Coimbra, Portugal
Wolf-Rüdiger Schäbitz, Department of Neurology, Bethel-EvKB, University of Münster, Bielefeld, Germany
I. Sebastião, CNC—Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Pólo 1, 1st Floor), University of Coimbra, Coimbra, Portugal
Emily S. Sena, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
Kristian Strømgaard, Ph.D. in Medicinal Chemistry Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
Hong-Shuo Sun, M.D., M.Sc., Ph.D. Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Gene Sung, M.D., M.P.H. Department of Neurology, University of Southern California, Los Angeles, CA, USA
Brad A. Sutherland, Ph.D. Acute Stroke Programme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
School of Medicine, University of Tasmania, Hobart, Australia
Doaa Taha, Department of Physics and Astronomy, Wayne State University, Detroit, MI, USA
Cristina Tassorelli, Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, “C. Mondino” National Neurological Institute, Pavia, Italy
Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
George Trendelenburg, Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
Kreiskrankenhaus Freiberg gGmbH, Freiberg, Germany
Jenny P. Tsai, Department of Neurology, Stanford University, Stanford, CA, USA
Georgios Tsivgoulis, M.D. Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA
Second Department of Neurology, National and Kapodistrian University of Athens, School of medicine, Athens, Greece
Department of Neurology, Attikon Hospital, Athens, Greece
Contributors
Xabier Urra, M.D., Ph.D. Hospital Clinic of Barcelona Neurosciences Institute, Functional Unit of Cerebrovascular Diseases, Hospital Clínic of Barcelona, Barcelona, Spain
Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
Victor V. Uteshev, Ph.D. Institute for Healthy Aging, Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, TX, USA
Roberto Federico Villa, D.Sc., M.D., Ph.D., A.C.C.P. Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
Denis Vivien, Normandie Université, UNICAEN, INSERM UMR-S U919 “Serine Proteases and Pathophysiology of the Neurovascular Unit”, Caen, France
Jonathan A. Winger, Omniox Inc., San Carlos, CA, USA
Burak Yulug, Department of Neurology and Regenerative and Restorative Medical Research Center, Experimental Neurology Laboratory, University of IstanbulMedipol, Istanbul, Turkey
Mario Zuccarello, M.D. Department of Neurosurgery, College of Medicine, University of Cincinnati (UC), Cincinnati, OH, USA
Comprehensive Stroke Center at UC Neuroscience Institute, Cincinnati, OH, USA
Mayfield Clinic, Cincinnati, OH, USA
Chapter 1 Reflections on Neuroprotection Research and the Path Toward Clinical Success
Paul A. Lapchak and Paul D. Boitano
“Hubris and science are incompatible”
Douglas J. Preston
(American Author, novelist, journalist, 1956-)
Abstract Translational neuroprotection research is currently undergoing a rebirth, a much needed revival, in part due to the efficacy of both thrombolytic and endovascular procedures in subpopulations of ischemic stroke patients. Stroke is currently treated with the Food and Drug administration (FDA)-approved thrombolytic, tissue plasminogen activator (rt-PA), and can be treated with endovascular approaches using the MERCI stent retriever or the Solitaire FR stent retriever, with the application of thrombolytic (i.e., rt-PA or urokinase) prior to embolectomy for rt-PA eligible patients. Moreover, from retrospective analysis in rt-PA ineligible stroke patients, embolectomy alone has proven safe and beneficial if completed within 6 h. Despite many decades of research into the identification and translational development of neuroprotective compounds, only few strategies have progressed into appropriately designed unbiased, randomized, placebo-controlled clinical trials. The FDA has still not been able to afford approval to a neuroprotectant to treat ischemic disease, primarily because of exaggerated overestimation of efficacy in rodent models that did not translate into efficacy in humans. During the process of
P.A. Lapchak, Ph.D., F.A.H.A. (*) • P.D. Boitano, B.Sc.
Department of Neurology and Neurosurgery, Cedars-Sinai Medical Center, Advanced Health Sciences Pavilion, Suite 8305, 127S. San Vicente Blvd,, Los Angeles, CA 90048, USA
e-mail: Paul.Lapchak@cshs.org
© Springer International Publishing Switzerland 2017
P.A. Lapchak, J.H. Zhang (eds.), Neuroprotective Therapy for Stroke and Ischemic Disease, Springer Series in Translational Stroke Research, DOI 10.1007/978-3-319-45345-3_1
P.A. Lapchak and P.D. Boitano
developing neuroprotective compounds to treat ischemic diseases, stroke in particular, numerous problems have emerged including the absolute failure to translate preclinical animal efficacy into efficacy in stroke victims, and in some cases, both significant adverse events and unforeseen toxicities have hindered drug development and approval. This chapter describes successes and failures in the stroke neuroprotection research, provides a comprehensive tabulated assessment of select neuroprotectants that have been tested in clinical trials, and proposes recommendations and essential checklists to both guide and improve the quality of science being conducted in preclinical and translational laboratories worldwide. The ultimate goal is to reap the benefits of a worldwide concerted neuroprotection research effort to provide superior care to stroke victims.
Keywords Translational • Neuroprotection • Neuroprotective • Cytoprotective • Brain • Stroke • Hemorrhage • SAH • ICH • Clinical trial • NIHSS • STAIR • RIGOR • Transparency • Rodin • Penumbra
1 Introduction: A Brief Chronological History of Stroke
Stroke, or a condition referred to as apoplexy, or the sudden onset of paralysis was first “reported” by Hippocrates between 460 and 370BC and can be found documented in Hippocratic transcripts [1]. In 1658, Wepfer redescribed apoplexy or apoplectic seizure which formed the basis for stroke classification into cerebral infarction and hemorrhagic stroke [2]. The interesting account by Wepfer, discussed in detail by Gurdjian and Gurdjian [3] communicates the idea that bodyderived “natural spirits” also known as “vital spirits” are transported into brain via the carotid and vertebral arteries and a network of arteries at the base of the brain. Wepfer hypothesized that oxygenated blood was transported into the brain as a vital factor, as a source of nutrition and thereafter Willis suggested that the “cerebrovascular system” included a network of arteries, including the “circle of Willis, which he described in 1664 [4]. In autopsy records from the 1700s there was confirmation of two types of apoplexy; the first suggested to be apoplexia serosa defined as serous apoplexy and the second apoplexia sanguinea defined as sanguineous apoplexy (i.e., ischemic stroke and hemorrhagic stroke, respectively). In 1856, Virchow [5] was the first physician to recognize that an “embolus” could result in a thromboembolism, and coined both terms related to the pathogenesis of ischemic stroke. The 1866 Dictionnaire Encyclopédique des Sciences Médicales of Dechambre summarized over 150 apoplexy references [6] documented from the 1600 to 1800s. More recently, but still of historical significance, Bramwell and Symonds published scientific articles in 1886 [7] and 1924 [8] that described “spontaneous” meningeal and subarachnoid hemorrhage (SAH). It is currently estimated that brain hemorrhage categorized into SAH, intracerebral hemorrhage
(ICH), and intraventricular hemorrhage (IVH) occurs in approximately 17–20 % of all stroke victims [9–11]; hemorrhage is usually associated with a higher mortality rate than ischemic stroke and a rapid decline after vessel rupture. The 30-day mortality rate for ischemic stroke is estimated to be 8–12 %, whereas hemorrhagic stroke is estimated to be 50 % [12–15].
1.1 Of Neurons and Time
The term neuroprotection has been in use for more than 50 years [see [16–19]]. The first pharmacological “modern” approach to therapeutic neuroprotection, or method to prevent neuronal death was the application of barbiturate drugs, which were neuroprotective and thought to target and reduce oedema (edema), free radicals, altered fatty acid metabolism, and even stabilize membranes [18]. Currently, “neuroprotection” is used interchangeably with “cytoprotection,” especially when applied to the treatment of stroke where there has been the realization that the neurovascular unit (neurons, glial cells, and vascular connectivity) requires protection after an ischemic event [20–23].
1.1.1 Extrapolated Stroke and Cerebrovascular Disease Incidence
We all agree that there is a critical need for new neuroprotective or cytoprotective strategies to reduce the morbidity and mortality incidence related to ischemic stroke, and to ultimately improve stroke victim quality of life, not just select clinical measures routinely used for 30- and 90-day evaluation, but every day “quality” for all victims. Until recently, stroke has been described as the fifth leading cause of mortality and leading cause of adult morbidity in the United States and it is estimated that 0.8 million people suffer a stroke in the USA [24], and 15 million people worldwide [9]. In the United Kingdom, stroke is the 4th largest cause of death with an annual incidence of 152,000 and 12.5 % of stroke victims die within 30 days.
The societal impact of stroke becomes even more devastating and overwhelming if we consider the updated definition of stroke from the American Heart Association (AHA)/American Stroke Association (ASA) [25], which now includes “central nervous system infarction of brain, spinal cord or retinal cell death attributable to ischemia.” The AHA study authors also suggest that nonsymptomatic silent infarcts should be included in the statistical analysis of cerebrovascular disease. With silent infarcts included, 15–20 % of the US population would have some form of cerebrovascular disease that eventually becomes apparent as cognitive impairment, dementia, and Alzheimer’s disease [25]. With a current worldwide population of 7.4 billion people [26], the estimated population with cerebrovascular disease escalates to 1.4 billon.
P.A. Lapchak and P.D. Boitano
Endovascular Procedures (with thrombolysis)
Endovascular Procedures (without thrombolysis)
Endo GP 185 (116-315) rt-PA 110 (80-142)
Endo GP 210 (166-251) rt-PA 127 (93-162)
Endo GP 260 (210-313) rt-PA 85 (67-110)
Endo GP 269 (201-340) rt-PA 117.5 (90-150)
Endo GP 224 (165-275) rt-PA 110.5 (85-156)
(inclusive of 360)
DTGPT-door to groin puncture time (median); rt-PA-initiation of thrombolytic administration
1.1.2 Time–brain matters!
Time is of the essence according to Saver [27], Holscher et al. [28], and Lapchak [29], among others, all researchers who have emphasized that an ischemic event is devastating to the brain, and that rapid treatment is essential. It is estimated that two million neurons die in the human brain per minute after hypoxia, the majority of which are located in the “penumbra” the primary and possibly only target of neuroprotectants, and 14 billion synapses are lost every minute following an ischemic event. As shown in Table 1.1, there is no correlation between time to treatment efficacious outcome, and estimated cellular loss in a select few recently conducted clinical trials. Within the current clinically recommended door-to-needle-time (DTNT) for rt-PA, it can be estimated that a stroke patient loses 120 × 106 neurons if treated with 60 min. The losses escalate to fraction of billions, to billions of lost neurons in many other recent clinical trials, when the initiation of treatment is delayed to hours. This is particularly important when one considers that recent reperfusion therapies including endovascular procedures demonstrated considerable efficacy up to 6 h following a stroke, but even a classical neuroprotection trial attempt (i.e., FAST-MAG) was ineffective even when drug administration starting as soon as 45 min following a stroke.
• Is this in any way related to choice of drug/device, target, or patient population selection?
All of these questions remain to be answered and can only be answered when there is conclusive evidence that a neuroprotective therapy is efficacious in stroke victims.
2 Limited Benefit Treatment Options for Acute Ischemic Stroke Victims: Successes!
This section will provide an overview of currently accepted and utilized treatments for acute ischemic stroke. They can both be categorized as reperfusion therapies: (1) thrombolysis with rt-PA or other proteins with similar activity [30, 45, 46], and (2) endovascular procedures (thrombectomy or embolectomy) in combination with thrombolysis [31–35] or without rt-PA administration [36].
2.1 Thrombolysis: Thrombolytic Therapy
The thrombolytic, rt-PA (Alteplase™) was first approved by the FDA in 1996 and is now widely accepted as a standard of care, but drastically underutilized in almost all communities worldwide. Alteplase has been shown to be effective up to 4.5 h after a stroke [45, 46], but it is currently FDA approved for use within a 3-h therapeutic window. It has been difficult to estimate the actual use and application of rt-PA in eligible stroke victims, but it has been suggested that less than 7–10 % of stroke patients are being treated with rt-PA in the United States [47–49] despite the fact that rt-PA may be beneficial in up to 50 % of patients provided the drug as a treatment option [30].
Clua-Espuny and colleagues have recently reported an important gender difference in survival response after a stroke that was correlated with benefit when rt-PA was provided after a first stroke [50]. Based upon a 1272 patient cohort, the authors analyzed survival outcome in male and females with first strokes in Spain and found that thrombolysis increased survival in both groups, but there was a pronounced survival effect in women that was not observed in men over an 8-year period. Clearly, rt-PA should be provided to both genders if they are eligible at time of admission.
Cost analysis of rt-PA utilization within 3–4.5 h after stroke onset clearly shows incremental benefit in patients with National Institutes of Health Stroke Scale (NIHSS) scores of 0–19, compared to no treatment [51]. This translates into qualityadjusted life-years (QALY) benefit for the stroke victim [51]. While rt-PA is beneficial, it does have a few shortcomings, primarily a significant risk of hemorrhagic transformation (HT) or intracerebral hemorrhage (ICH) in up to 6 % of patients treated within 3–4.5 h of a stroke [52], an increase in the odds ratio for mortality rate after 4 h [52], and minimal [53, 54] or lack of neuroprotective activities, or possibly detrimental biological properties and adverse effects under some circumstances [55].
P.A. Lapchak and P.D. Boitano
Table 1.2 Thrombolysis trials—efficacy analysis: mRS 90 day outcome
mRS: modified Rankin scale (%); OHS: Oxford Handicap Scale
Highlighted Boxes indicate mRS/OHS 0-2 functional independence.
Of importance to the topic of this Springer volume of Neuroprotection is the measure commonly referred to as DTNT. In the literature, the recommended DTNT for standard rt-PA thrombolytic therapy is less than 60 min [56–58]. However, according to a recent Cochrane review article, rt-PA is being administered in a time frame in great excess of that recommendation [59]. In the original National Institute of Neurological Disorders and Stroke (NINDS) rt-PA clinical trial [30], the administration time was stratified between 0–90 and 91–180 min. Subsequent clinical trials [European Cooperative Acute Stroke Study (ECASS trials)] determined whether rt-PA would be efficacious with an expanded therapeutic window [45, 60], rather than reduce time to treatment, and rt-PA was shown to retain efficacy in specific patient populations.
Table 1.2 summarizes the historical efficacy data from the original NINDS rt-PA clinical trial [30], and ECASS III [45, 61, 62], directly comparing 90-day outcome on the modified Rankin scale (mRS). In ECASS III [45, 61, 62], the safety and efficacy of rt-PA was studied in patients when administered up to 4.5 h following an ischemic stroke. The trial showed that there was a significant shift in the mRS score 0–3 in 66.5 % of rt-PA-treated patients compared to 61.5 % in the control group. This represented an absolute change of 5 %. As recently described by the Stroke Thrombolysis Trialists Group [63], administration of a thrombolytic is most efficacious when provided within 3 h of a stroke. An additional eight intravenous rt-PA clinical trials enrolling 6729 patients also provided data that thrombolysis can promote significant improvement in patients when administered up to 6 h following a stroke. Since time is brain, all efforts should be made to administer therapy as soon as possible.
It has now been a milestone 20 years since the FDA approval of rt-PA; somewhat of a platinum anniversary, and the treatment is still underutilized worldwide [47, 49], but there has been some improvement in DTNT [64, 65]. A leader in the field of
stroke clinical trials, Dr. Saver (UCLA, Los Angeles) has published on an extensive data analysis set collected using more than 58,000 stroke patients receiving rt-PA within 4.5 h of symptom onset. The analysis of onset to time of treatment provided some evidence for a direct correlation between the rapidity of “thrombolytic” treatment and benefit on measures important to the patient that included increased functional independence and increase time of discharge from the hospital, in addition to reduced hemorrhage incidence and mortality. The argument can then be made that Time is Brain and the faster reperfusion therapy is administered, the greater benefit to the patient [27, 29, 66–69].
Nothing is a waste of time if you use the experience wisely Francois-Auguste-Rene Rodin
(French born sculptor and progenitor of modern sculpture. 1840–1917)
2.2 Endovascular Procedures and Thrombolysis
The great ESCAPE, EXTEND-IA, MR CLEAN, REVASCAT, and SWIFT PRIME endovascular trials demonstrated that a specific well defined, but heterogeneous population of acute ischemic stroke patient with a large vessel occlusion (LVO) can now be offered additional therapy to successfully improve functional independence. Endovascular procedures with clot retrievers can promote functional independence at 90 days as indicated by a significant shift in modified Rankin Scale score (mRS) 0–2 (common odds ratio range of 1.7–3.1) in 13.5–31 % of patients undergoing the endovascular procedure. Moreover, the procedure has now been shown to be safe in patients with LVOS, salvageable brain tissue (i.e., large penumbra) with small infarct areas ASPECTS score 7–10, and median NINDS score of 16–17; therapy was neither age, nor gender specific. This section will review salient aspects of the efficacy and safety results from the trials, discuss enrollment criteria, and propose future stroke development strategies incorporating neuroprotection.
Until recently, the use of mechanical embolectomy in patients with documented LVO was complicated by lack of efficacy [70–75], either due to clinical trial design flaws, patient selection, inadequate device design, or possibly due to methodological problems arising from interpretation of recanalization success rates [76]. In previous embolectomy trials, the procedure was performed more than 6 h after stroke onset and did not appear to provide benefit to patients [77–79]. However, with the introduction and use of new devices including the Mechanical Embolus Removal in Cerebral Ischemia (MERCI retriever; Concentric Medical Inc., Mountain View, CA, USA) and Solitaire FR Revascularization Device (Ev3/Covidien, Paris France) retrievable stent, patients had substantial benefit when recanalization was initiated within 6 h of stroke onset. Now, use of mechanical embolectomy, with or without thrombolysis, is considered the newest form of standard of care therapy in patients with a documented LVO [31–36]. 1 Reflections
P.A. Lapchak and P.D. Boitano
Table 1.3 ESCAPE-embolectomy–thrombolysis enrollment—end point analysis
ESCAPE(32) N=316 (238 received intravenous rt-PA) 120 patients 118 patients
Patient population selection: Small infarct core (ASPECTS 6-10), an occluded proximal artery in the anterior circulation (middle cerebral artery trunk and immediate branches with or without internal carotid artery occlusion), and moderate-to-good collateral circulation (filling of 50% or more of the middle cerebral artery pial artery circulation).
% Achieving Reperfusion
Age range (yrs): NIHSS range interquartile range (median)]
60-81 (71) 13-20 (16)
60-81 (70) 12-20 (17)
Time-to-Treat [range (median)] minEndo GP 185 (116315) rt-PA 110 (80-142) rt-PA 125 (89-183)
Median Time to Reperfusion following stroke (min) 241 (176-359)
Symptomatic Intracerebral Hemorrhage % 3.62.7
Serious Adverse Event Excluding death % (SAE definiton for ESCAPE- resulting in a prolonged hospital stay, readmission, were severe or life threatening (large or malignant MCAO stroke, he matoma at access site, perforation of the MCA)
Mortality Rate % (90 days)
2.2.1 ESCAPE [32]: Table 1.3
The Canadian-based ESCAPE trial supported by Covidien enrolled a total of 316 patients with a proximal intracranial occlusion in the anterior circulation (ICA and M1 middle cerebral artery, or M1 or M2 middle cerebral artery segments, and moderate-to-good collateral circulation. Importantly, as a measure of a small ischemic core and large penumbra, median ASPECTS on CT was 9, interquartile range of 8–10 in the embolectomy arm and 8–10 in the rt-PA arm. Patients were enrolled up to 12 h after symptom onset; 238 patients received rt-PA (120 in the embolectomy plus IV rt-PA arm and 118 in the rt-PA control group) within a median time of 110 min for the embolectomy arm and 125 min for the rt-PA control arm. The median time from CT head to the first noted reperfusion was 84 min for embolectomy (65–115 interquartile range), defined as the first visualization of reflow in the middle cerebral artery, which in most patients was coincident with the deployment of a retrievable stent. For embolectomy, the median time from symptom onset to groin puncture was 51 min (39–68 interquartile range) in the intervention group,
and rt-PA was initiated within 110 min (80–142 interquartile range). In the control group, IV rt-PA was administered within 125 min (89–183 interquartile range) from stroke onset. The median time of stroke onset to first reperfusion was 241 min (176–359 range) in the embolectomy arm. The trial used retrievable stents or balloon catheters for suction clot removal. Notably, both groups included 87.3 % of white race patients, and 52.1–52.7 % of females. In both groups, the majority of patients had hypertension (63.6–72 %), a minority were diabetic (20–26 %) and had atrial fibrillation (37–40 %).
In the combination treatment group, 53 % of patients achieved mRS of 0–2 (90 days) compared to only 29.3 % in the rt-PA group, showing greater benefit of embolectomy plus rt-PA compared to rt-PA alone at 90 days. This benefit could be associated with a greater population of patients achieving reperfusion in the embolectomy/ rt-PA group 72.4 % (Thrombolysis in Cerebral Infarction [TICI] scale score of 2b or 3) compared to 31.2 % (modified arterial occlusive lesion [mAOL] score of 2 or 3) in the control group. Both genders, male and female responded equally to treatment with a common odds ratio (95 % Cl) of 2.5 (1.4–4.5 male), to 2.6 (1.5–4.4 female) favoring embolectomy/rt-PA. While symptomatic intracranial hemorrhage (sICH) rates specifically defined as a new intracranial hemorrhage associated with evidence of clinical worsening, in which the hemorrhage is judged to be the most important cause of clinical worsening, were not significantly different between groups (P = 0.75), and were lower (by 50 %) than reported for the NINDS-rt-PA trial [30], mortality was greatly reduced by embolectomy/rt-PA compared to rt-PA 10.4 % vs. 19 % control (P = 0.04). The rate ratio for sICH and mortality was 1.4; 95 % CI, 0.4–4.7 and 0.5; 95 % CI, 0.3–1.0; P = 0.04, respectively.
2.2.2 EXTEND-IA [33]: Table 1.4
The Australian-based EXTEND-IA clinical trial was a small 70 patient trial, with patients receiving rt-PA within 4.5 h of stroke symptom onset. Inclusion criteria included occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 mL on CT perfusion imaging. Endovascular therapy had to be initiated via groin puncture within 6 h of stroke onset and completed within 8 h of onset. The trial demonstrated significant efficacy after enrolling 35 patients in each of the two treatment groups. The trial enrolled 49 % male/51 % female in both groups, and there was also a history of hypertension (rt-PA 66; embolectomy 60 %), diabetes (23 % rt-PA; 6 % embolectomy), and atrial fibrillation (31 % rt-PA; 34 % embolectomy). Thus, the trial was stopped at interim analysis because of significant benefit in the endovascular therapy arm and publication of MR CLEAN trial with similar efficacy (see Sect. 2.2.3). Patients were treated with the Solitaire FR retrievable stent within a median time of 248 min from stroke onset to modified TICI2b or 3 or completion of the procedure (interquartile range 204–277) for endovascular therapy in combination with rt-PA (within 127 min median) compared to a median time of 145 min for rt-PA. The median time from stroke to groin puncture was 210 min (166–251 min) and 74 min from initiation of rt-PA to groin puncture. 1 Reflections
P.A. Lapchak and P.D. Boitano
Table 1.4 EXTEND-IA embolectomy–thrombolysis enrollment—end point analysis
Trial
EXTEND-IA (33) N=70
Embolectomy
+ Thrombolysis Thrombolysis
35 patients
35 patients
Patient population selection: Occlusion in the proximal anterior circulation (middle cerebral artery or internal carotid artery) with evidence of salvageable brain tissue and small ischemic core (<70ml on CT).
% Achieving Reperfusion
% Achieving Recanalization @24hrs
89 (reperfusion >90% without SICH) 94
34 (reperfusion >90% without SICH) [p< 0.001] 42
% Achieving mRS 0-2 (90 days) 71 40 [p=0.01]
Age range (yrs): NIHSS range interquartile range (median)]
68.6 ±12.3 13-20 (17)
70.2 ±11.8 9-19 (13)
Time-to-Treat range (median) minEndo GP 210 (166251) rt-PA 127 (93-162) rt-PA 145 (105-180)
Median Time to Reperfusion following stroke (min) 248 (204-277)
Symptomatic Intracerebral Hemorrhage % 06
Serious Adverse Event %
(SAE definiton for EXTEND-IAparenchymal hematoma) 11 9
Mortality Rate % 920
In the endovascular therapy arm, 94 % of patients achieved recanalization at 24 h, 89 % had >90 % reperfusion at 24 h and were without symptomatic intracerebral hemorrhage, and 71 % of patients achieved mRS of 0–2 at 90 days compared to 40 % in control arm. This is compared to 34 % of rt-PA patients having extensive reperfusion at 24 h and a lower recanalization rate at the same time point (43 % vs. 94 % in the endovascular group). As shown in Table 1.4, there were no significant differences in sICH rate (sICH defined as a large parenchymal hematoma where blood occupied >30 % of the infarct volume with mass effect, and an increase of 4 points or more in the NIHSS score) or mortality between the groups. The patients included in the study were randomized 70 min sooner (30 vs. 100 min) and time from stroke onset to groin puncture was faster compared to MR CLEAN (210 vs. 260 min. see later).
2.2.3 MR CLEAN [31]: Table 1.5
The Netherlands-based MR CLEAN trial enrolled 500 patients with a proximal artery occlusion in the anterior cerebral circulation within 6 h after symptom onset: 233 enrolled in the intra-arterial treatment arm (mechanical embolectomy and thrombolytic) and 267 receiving thrombolytic treatment (either rt-PA maximum dose of 90 mg or 1.2 million IU of urokinase with a median time to treatment of 85 min for the embolectomy arm and 87 min for the rt-PA/urokinase arm.
1.5
Trial
MR CLEAN(31) N=500
Embolectomy + Thrombolysis
233 patients
Thrombolysis
267 patients
Patient population: Occlusion of the distal intracranial carotid artery, middle cerebral artery (M1 or M2) or anterior cerebral artery (A1 or A2) and small ischemic cores ASPECTS (7-10).
% Achieving Reperfusion
% Achieving Recanalization @ 24hour s
% Achieving mRS 0-2 (90 days)
Age range (yrs)
NIHSS range interquartile range (median)] 54.5-76 (65.8) 14-21 (17) 55.5-76.4 (65.7) 14-22 (18)
Time-to-Treat [range (median)] minEndo GP 260 (210313) rt-PA 85 (67-110) rt-PA 87 (65-116)
Median Time to groin puncture following stroke (min) 260 (210-313)
Symptomatic Intracerebral Hemorrhage % 7.76.4
Serious Adverse Event Excluding Death % 25.3 18.0
Mortality Rate % (30 days) 18.9 18.4
Importantly, as a measure of a small ischemic core and large penumbra, median ASPECTS on CT was 9, interquartile range of 7–10 in the embolectomy arm and 8–10 in the rt-PA arm. Like the ESCAPE and EXTEND-IA trials, the patient population was diverse with certain common comorbidities including diabetes mellitus (rt-PA 12.7; embolectomy 14.6 %), hypertension (42.1–48.3 %), and atrial fibrillation (rt-PA 28.3: embolectomy 25.8). The trial was funded and supported in part by Covidien/ev3, Medac/Lamepro, and Penumbra.
This comparison study used mechanical treatment in 83.7 % of patients: retrievable stents were used in 81.5 % of patients and other devices were used in 2.1 % patients assigned to the intra-arterial treatment. There was no difference in the proportion of patients achieving reperfusion between the two groups: 58.7 % (TICI score of 2b or 3) vs. 57.5 % (mAOL score of 2 or 3), but there was a statistically significant difference in the rate of functional independence (mRS 0–2) in favor of combined intervention (32.6 % vs. 19.1 %), an absolute difference of 13.5 %. Interestingly, in the intervention group, 75.4 % of patients showed an absence of residual occlusion of the target site compared to only 32.9 % in rt-PA patients.
Treatment effect favored endovascular intervention for both age groups >80 and <80, and surprisingly, patients in the >80 age group did much better on the endovascular intervention adjusted conditional odds ratio (acOR) 95 % CI 3.24 vs. 1.6). The number of serious adverse events in this trial was high for both groups (42.3–47.2 %), but sICH defined as type 1—one or more blood clots in 30 % or less of the infarcted area with a mild space-occupying effect, or type-2 blood clots in more than 30 % of the infarcted area with a clinically significant space-occupying effect,
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