The Need for New Therapies for Acute Ischaemic Stroke

Stroke creates the fourth highest burden of disease worldwide, and is the leading cause of adult long-term disability in developed countries. These factors mean that stroke has a high associated cost for healthcare systems, and a potentially devastating effect on family and carers. One of the main reasons why patients have such a poor prognosis is a lack of treatment options. Recombinant tissue plasminogen activator (rt-PA) is the only treatment currently licensed to treat selected patients with acute ischaemic stroke. However, only 1–8.5% of hospitalised patients receive treatment with rt-PA due to the short time window for administration (within 3 h of symptom onset), risk of intracerebral haemorrhage, need for a computed tomography scan, and exclusions due to other specific criteria. For acute ischaemic stroke, well-tolerated treatments that offer an extended therapeutic window are urgently needed to decrease disability, aid neurological recovery and improve patient prognosis. Neuroprotective agents potentially offer benefit to stroke patients without the associated haemorrhagic risk of thrombolytic therapy. Such agents target the ischaemic penumbra and aim to reduce the risk of brain injury and long-term disability by disrupting the cellular, biochemical, and metabolic consequences of infarction following exposure to ischaemia. Future directions should involve developing a neuroprotective compound that is safe, well tolerated and effective in a broad range of patients.

[1]  Fernando Vinuela,et al.  MERCI 1: A Phase 1 Study of Mechanical Embolus Removal in Cerebral Ischemia , 2004, Stroke.

[2]  M. Fisher.  Recommendations for Advancing Development of Acute Stroke Therapies: Stroke Therapy Academic Industry Roundtable 3 , 2003, Stroke.

[3]  M. Moskowitz,et al.  Pathobiology of ischaemic stroke: an integrated view , 1999, Trends in Neurosciences.

[4]  P. Amarenco,et al.  Costs of Stroke Care according to Handicap Levels and Stroke Subtypes , 2003, Cerebrovascular Diseases.

[5]  A. Furlan,et al.  Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. , 2000, JAMA.

[6]  California Acute Stroke Pilot Registry Investigators.  Prioritizing interventions to improve rates of thrombolysis for ischemic stroke , 2005 .

[7]  G. Rosenberg,et al.  Closure of the Blood-Brain Barrier by Matrix Metalloproteinase Inhibition Reduces rtPA-Mediated Mortality in Cerebral Ischemia With Delayed Reperfusion , 2003, Stroke.

[8]  L. Lisabeth,et al.  Survey of emergency physicians about recombinant tissue plasminogen activator for acute ischemic stroke. , 2005, Annals of emergency medicine.

[9]  E. Lo,et al.  Blood-Brain Barrier Disruption and Matrix Metalloproteinase-9 Expression During Reperfusion Injury: Mechanical Versus Embolic Focal Ischemia in Spontaneously Hypertensive Rats , 2002, Stroke.

[10]  Joseph P. Broderick,et al.  Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. , 1995 .

[11]  Joseph P Broderick,et al.  Eligibility for Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke: A Population-Based Study , 2004, Stroke.

[12]  G. Hankey,et al.  Management of acute ischaemic stroke: new guidelines from the American Stroke Association and European Stroke Initiative , 2003, The Lancet Neurology.

[13]  Marc Fisher,et al.  The Ischemic Penumbra: Identification, Evolution and Treatment Concepts , 2003, Cerebrovascular Diseases.

[14]  Eng H. Lo,et al.  The Neurotoxicity of Tissue Plasminogen Activator? , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[15]  R. Medcalf,et al.  Vampire Bat Salivary Plasminogen Activator (Desmoteplase): A Unique Fibrinolytic Enzyme That Does Not Promote Neurodegeneration , 2003, Stroke.

[16]  G. D. Graham,et al.  Tissue Plasminogen Activator for Acute Ischemic Stroke in Clinical Practice: A Meta-Analysis of Safety Data , 2003, Stroke.

[17]  W. Schleuning,et al.  Structural Features Mediating Fibrin Selectivity of Vampire Bat Plasminogen Activators (*) , 1995, The Journal of Biological Chemistry.

[18]  A. Dobson,et al.  Disease impact number and population impact number: population perspectives to measures of risk and benefit. , 2000, BMJ : British Medical Journal.

[19]  G Schlaug,et al.  Why are stroke patients excluded from tPA therapy? An analysis of patient eligibility , 2001, Neurology.

[20]  Scott Hamilton,et al.  Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials , 2004, The Lancet.

[21]  J. Grotta,et al.  Neuroprotective Therapy , 1998, Seminars in neurology.

[22]  J. Lynch,et al.  Vampire bat salivary plasminogen activator promotes rapid and sustained reperfusion without concomitant systemic plasminogen activation in a canine model of arterial thrombosis. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[23]  Michael D Hill,et al.  Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. , 2004, The New England journal of medicine.

[24]  J. Gijn.  From randomised trials to rational practice. , 2005 .

[25]  M. Alberts,et al.  Analysis of the Safety and Efficacy of Intra-Arterial Thrombolytic Therapy in Ischemic Stroke , 2002, Stroke.

[26]  W. Hacke,et al.  Thrombolysis in acute ischemic stroke: controlled trials and clinical experience. , 1999, Neurology.

[27]  A. Furlan,et al.  Community use of intravenous tissue plasminogen activator for acute stroke: results of the brain matters stroke management survey. , 2001, Stroke.

[28]  J. Grotta,et al.  Clinical Deterioration Following Improvement in the NINDS rt-PA Stroke Trial , 2001, Stroke.

[29]  S. Warach,et al.  The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): A Phase II MRI-Based 9-Hour Window Acute Stroke Thrombolysis Trial With Intravenous Desmoteplase , 2005, Stroke.

[30]  Inke R König,et al.  Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA , 2005, Neurology.

[31]  J. M. Wardlaw,et al.  Thrombolytic Therapy With Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke: Where Do We Go From Here? A Cumulative Meta-Analysis , 2003, Stroke.

[32]  A. Alexandrov,et al.  Ischemic Stunning of the Brain: Early Recanalization Without Immediate Clinical Improvement in Acute Ischemic Stroke , 2004, Stroke.

[33]  L. Goldstein.  Neuroprotective therapy for acute ischaemic stroke: down, but not out , 2004, The Lancet.

[34]  J. Martí-Fàbregas,et al.  Reasons for exclusion from thrombolytic therapy following acute ischemic stroke. , 2005, Neurology.

[35]  A. Werner.  Prioritizing interventions to improve rates of thrombolysis for ischemic stroke , 2005, Neurology.

[36]  Peter E. Hilsenrath,et al.  The World Health Report 2000 , 2002 .

[37]  E. Tournier-Lasserve.  CACNA1A mutations , 1999, Neurology.

[38]  E. Ennis,et al.  Stroke: Awareness of the Signs, Symptoms and Risk Factors – A Population-Based Survey , 2003, Cerebrovascular Diseases.

[39]  Nirds,et al.  Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group , 1995 .

[40]  P. Heuschmann,et al.  Frequency of Thrombolytic Therapy in Patients With Acute Ischemic Stroke and the Risk of In-Hospital Mortality: The German Stroke Registers Study Group , 2003, Stroke.

[41]  Joseph P Broderick,et al.  Acute Stroke Care in the US: Results from 4 Pilot Prototypes of the Paul Coverdell National Acute Stroke Registry , 2005, Stroke.

[42]  S. Cramer,et al.  Treatment With Tissue Plasminogen Activator and Inpatient Mortality Rates for Patients With Ischemic Stroke Treated in Community Hospitals , 2001, Stroke.

[43]  Jeffry R Alger,et al.  Late secondary ischemic injury in patients receiving intraarterial thrombolysis , 2002, Annals of neurology.

[44]  M. Moskowitz,et al.  tPA and proteolysis in the neurovascular unit. , 2004, Stroke.