Termination of trial of streptokinase in severe acute ischaemic stroke

1,283

759

Background and Purpose-The National Institutes of Health (NIH) estimates that stroke costs now exceed $45 billion per year.Stroke is the third leading cause of death and one of the leading causes of adult disability in North America, Europe, and Asia. A number of well-designed randomized stroke trials and case series have now been reported in the literature to evaluate the safety and efficacy of thrombolytic therapy for the treatment of acute ischemic stroke. These stroke trials have included intravenous studies, intra-arterial studies, and combinations of both, as well as use of mechanical devices for removal of thromboemboli and of neuroprotectant drugs, alone or in combination with thrombolytic therapy. At this time, the only therapy demonstrated to improve outcomes from an acute stroke is thrombolysis of the clot responsible for the ischemic event.There is room for improvement in stroke lysis studies. Divergent criteria, with disparate reporting standards and definitions, have made direct comparisons between stroke trials difficult to compare and contrast in terms of overall patient outcomes and efficacy of treatment. There is a need for more uniform definitions of multiple variables such as collateral flow, degree of recanalization, assessment of perfusion, and infarct size.In addition, there are multiple unanswered questions that require further investigation, in particular, questions as to which patients are best treated with thrombolysis. One of the most important predictors of clinical success is time to treatment, with early treatment of Ͻ3 hours for intravenous tissue plasminogen activator and Ͻ6 hours for intra-arterial thrombolysis demonstrating significant improvement in terms of 90-day clinical outcome and reduced cerebral hemorrhage. It is possible that improved imaging that identifies the ischemic penumbra and distinguishes it from irreversibly infarcted tissue will more accurately select patients for therapy than duration of symptoms. There are additional problems in the assessment of patients eligible for thrombolysis. These include being able to predict whether a particular site of occlusion can be successfully revascularized, predict an individual patient's prognosis and outcome after revascularization, and in particular, to predict the development of intracerebral hemorrhage, with and without clinical deterioration. It is not clear to assume that achieving immediate flow restoration due to thrombolytic therapy implies clinical success and improved outcome. There is no simple correlation between recanalization and observed clinical benefit in all ischemic stroke patients, because other interactive variables, such as collateral circulation, the ischemic penumbra, lesion location and extent, time to treatment, and hemorrhagic conversion, are all interrelated to outcome. Methods-This article was written under the auspices of the Technology Assessment Committees for both the AmericanSociety of Interventional and Therapeutic Neuroradiology and the Society of Interventional Radiology. The purpose ...

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confidence: 99%

Trial Design and Reporting Standards for Intra-Arterial Cerebral Thrombolysis for Acute Ischemic Stroke

Higashida

Furlan

Roberts

et al. 2003

1,283

759

“…[515][516][517][518] Other intravenously administered fibrinolytic agents, including reteplase, urokinase, anistreplase, and staphylokinase, have not been tested extensively. Tenecteplase is a modified tissue plasminogen activator with a longer half-life and higher fibrin specificity than alteplase and appears promising as an effective fibrinolytic, with greater reperfusion and major vessel recanalization with fewer bleeding complications than alteplase in pilot studies.…”

Section: Other Fibrinolytic Agentsmentioning

confidence: 99%

Guidelines for the Early Management of Patients With Acute Ischemic Stroke

Jauch¹,

Saver²,

Adams³

et al. 2013

5,336

1,801

Background and Purpose-The authors present an overview of the current evidence and management recommendations for evaluation and treatment of adults with acute ischemic stroke. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators responsible for the care of acute ischemic stroke patients within the first 48 hours from stroke onset. These guidelines supersede the prior 2007 guidelines and 2009 updates. Methods-Members of the writing committee were appointed by the American Stroke Association Stroke Council's Scientific Statement Oversight Committee, representing various areas of medical expertise. Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Panel members were assigned topics relevant to their areas of expertise, reviewed the stroke literature with emphasis on publications since the prior guidelines, and drafted recommendations in accordance with the American Heart Association Stroke Council's Level of Evidence grading algorithm. Results-The goal of these guidelines is to limit the morbidity and mortality associated with stroke. The guidelines support the overarching concept of stroke systems of care and detail aspects of stroke care from patient recognition; emergency medical services activation, transport, and triage; through the initial hours in the emergency department and stroke unit. The guideline discusses early stroke evaluation and general medical care, as well as ischemic stroke, specific interventions such as reperfusion strategies, and general physiological optimization for cerebral resuscitation. The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. Guidelines for the Early Management of PatientsThis statement was approved by the American Heart Association Science Advisory and Coordinating Committee on December 12, 2012. A copy of the document is available at http://my.americanheart.org/statements by selecting either the "By Topic" link or the "By Publication Date" link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com.The Executive Summary is available as an online-only Data Supplement with this article at http://stroke.ahajournals.org/lookup/suppl/ doi:10.1161/STR.0b013e318284056a/-/DC1.The American Heart Association requests that this document be cited as follows: Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan PW Jr, Qureshi AI, Rosenfield K, Scott PA, Summers DR, Wang DZ, Wintermark M, Yonas H; on behalf of the American Heart Association Stroke Council, Council on Cardio...

“…Furthermore, even if reperfusion can be achieved with recombinant tissue plasminogen activator or other thrombolytic agents, the reperfusion itself can precipitate further cerebral injury. 3 A number of studies have established the role of leukocyte adhesion receptors in cerebral reperfusion injury. In a murine model of stroke, neutrophil-depleted wild-type, homozygous null intercellular adhesion molecule-1 (ICAM-1)-deficient, and homozygous P-selectin null animals have smaller strokes, reduced microvascular failure, and improved functional outcomes.…”

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confidence: 99%

Postischemic Cerebrovascular E-Selectin Expression Mediates Tissue Injury in Murine Stroke

Huang

Choudhri

Winfree

et al. 2000

147

116

Background and Purpose-Although the deleterious role of several proinflammatory mediators, including P-selectin, in reperfused stroke is well established, the role of E-selectin has not been fully characterized. Methods-E-selectin mRNA expression was studied at 4, 10, and 24 hours after reperfusion with reverse transcription and polymerase chain reaction in mice (nϭ18) subjected to transient intraluminal middle cerebral artery occlusion (MCAO).Mice received intravenous injection with anti-E-selectin monoclonal antibody (10, 35, or 50 g), nonimmune IgG, or vehicle immediately before MCAO and 90 minutes later (nϭ85). Others received anti-E-selectin antibody 3 or 6 hours after MCAO (nϭ32). Myeloperoxidase activity was measured in sham-operated mice and after 10 hours of reperfusion in saline-, nonimmune IgG-, or anti-E-selectin IgG-treated cohorts (nϭ17). Serial cerebral blood flow was measured with laser-Doppler flowmetry, and outcomes were assessed by neurological deficits and infarct volumes with the use of planimetric analysis of triphenyltetrazolium chloride-stained sections. Results-Upregulated E-selectin expression occurred in the ischemic cerebral vasculature within 4 hours of reperfusion and persisted for 24 hours. Anti-E-selectin antibody increased ischemic cortical cerebral blood flow up to 2.6-fold (PϽ0.05). In addition to dose-dependent reductions in neurological deficits (PϽ0.05), mortality, and infarct volumes (PϽ0.01 for 35 and 50 g), anti-E-selectin treatment reduced cerebral neutrophil accumulation (PϽ0.05) and was neuroprotective even if delayed until 3 hours after ischemia (PϽ0.05). Conclusions-These findings establish a functional role for E-selectin in the pathogenesis of tissue injury after cerebral ischemia and reperfusion and suggest that E-selectin blockade may be clinically useful in the treatment of reperfused stroke. (Stroke. 2000;31:3047-3053.)