When acute ischemic stroke occurs, the patient’s outcome depends on rapid clearance of the thrombus. Two of the primary treatments for stroke are IV thrombolysis with alteplase (rt-PA) and thrombectomy via endovascular therapy (EVT). Time is brain. What do you choose?
What are the latest guidelines on the time window for IV thrombolysis with rt-PA?
What are the inclusion and exclusion criteria for administering rt-PA?
Is the patient’s age a factor in deciding whether to administer rt-PA?
What are the two major complications from IV thrombolysis, and how should you manage them?
Can you perform EVT on a patient who has been given rt-PA? Should you?
What are the circumstances when thrombectomy is a better choice than IV thrombolysis?
How has the evidence for EVT evolved?
What are the best uses of CT angiography and CT perfusion in assessing patients with acute ischemic stroke?
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Part 1: Intravenous Thrombolysis in Acute Ischemic Stroke
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Part 2: Endovascular Therapy in Acute Ischemic Stroke
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Abbreviation List
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Abbreviations of Clinical Trials
Part 1: Intravenous Thrombolysis in Acute Ischemic Stroke
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Introduction
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Inclusion and Exclusion of Intravenous Thrombolysis: A Changing Landscape
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Hematologic Disorders and Previous Antithrombotic Treatment
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Seizures
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Minor Stroke
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Cerebral Microbleeds
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Glucose Disorders
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Myocardial Infarction and Other Cardiological Disorders
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Additional Recommendations
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Intravenous Thrombolysis in Clinical Practice
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Intravenous Thrombolysis Complications
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Hemorrhagic Transformation
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Radiological Classification
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Clinical Implications of Hemorrhagic Transformation
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Orolingual Angioedema
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“Wake-up” Stroke – Changing the Paradigm
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New Thrombolysis Agents and Techniques
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Conclusion
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Tables and Figures
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Table 1. Eligibility Criteria and Exclusion Criteria for Intravenous Thrombolysis
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Table 2. American Heart Association Definitions of Classification of Recommendations
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Table 3. Management of Orolingual Angioedema Post Intravenous Thrombolysis
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Figure 1. Types of Hemorrhagic Transformation
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References
Introduction
Stroke is the fifth leading cause of death in the United States and an important cause of long-term disability.1 Approximately 795,000 people suffer from stroke each year (610,000 primary strokes and 185,000 recurrent strokes),1 with ischemic stroke representing the vast majority of all stroke types (87%).2 The cornerstone of acute ischemic stroke treatment relies on rapid clearance of an offending thrombus in the cerebrovascular system.3 Advanced neuroimaging and clinical trials, together with continuous adjustments of inclusion/exclusion criteria, have helped emergency clinicians to rapidly and more accurately identify the patients who will benefit from acute stroke treatment.
Alteplase (recombinant tissue plasminogen activator [rt-PA]) was the first drug approved by the United States Food and Drug Administration (FDA) for treatment of acute ischemic stroke. rt-PA is a protease derived by recombinant DNA technology that activates fibrin-bound plasminogen, leading to plasmin formation and the disintegration of fibrin clots.4,5 In 1995, the National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator trial showed that patients suffering from ischemic stroke who received intravenous (IV) rt-PA in a dose of 0.9 mg/kg within 3 hours of symptom onset had a more favorable outcome at 3 months than those who received placebo (odds ratio [OR] 1.7; 95% confidence interval [CI], 1.2 to 2.6; P = .008).6 Since then, other studies and randomized controlled trials have confirmed the safety and efficacy of IV thrombolysis (IVT).7-12
In 2008, the ECASS III study13 showed a statistically significant benefit in selected patients treated with IV rt-PA between 3 hours and 4.5 hours from symptom onset. Additional studies have supported the use of IVT in a time window as late as 4.5 hours after symptom onset.14-16 The IST-3 trial attempted to extend the time window for IVT administration beyond the 4.5-hour time window, but was unable to show a meaningful improvement in outcome beyond that time point.17 However, the recently published EXTEND trial reveals promising results for extending the time window up to 9 hours, in selected populations.18 The benefit of IVT in favorable neurologic outcome has been demonstrated to persist at both 3 and 12 months after stroke occurrence.6,19
Tables and Figures
References
Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.
To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available.
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Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67-e492. (Guidelines)
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Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation. 2011;123(4):e18-e209. (Guidelines)
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Bivard A, Lin L, Parsonsb MW. Review of stroke thrombolytics. J Stroke. 2013;15(2):90-98. (Systematic review)
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Collen D, Dewerchin M, Rapold HJ, et al. Thrombolytic and pharma-cokinetic properties of a conjugate of recombinant single-chain urokinase-type plasminogen activator with a monoclonal antibody specific for cross-linked fibrin in a baboon venous thrombosis model. Circulation. 1990;82(5):1744-1753. (Basic research)
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Marder VJ, Novokhatny V. Direct fibrinolytic agents: biochemical attributes, preclinical foundation and clinical potential. J Thromb Haemost. 2010;8(3):433-444. (Systematic review)
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The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke N Engl J Med. 1995;333(24):1581-1587. (Randomized double-blind trial; Part 1: 291 patients, Part 2: 333 patients)
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Saver JL. Number needed to treat estimates incorporating effects over the entire range of clinical outcomes: novel derivation method and application to thrombolytic therapy for acute stroke. Arch Neurol. 2004;61(7):1066-1070. (Randomized controlled trial)
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Wardlaw JM, Murray V, Berge E, et al. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2014(7):CD000213. (Cochrane review; 27 trials, 10,187 patients)
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Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363(9411):768-774. (Pooled analysis; 3 trials)
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Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet. 2012;379(9834):2364-2372. (Systematic review and meta-analysis; 12 trials, 7012 patients)
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Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007;369(9558):275-282. (Observational study; 6483 patients)
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Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274(13):1017-1025. (Randomized double-blind placebo-controlled clinical trial; 109 patients)
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Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317- 1329. (Randomized double-blind controlled trial; 821 patients)
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Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet. 2008;372(9646):1303-1309. (Prospective study; 12,529 patients)
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Bluhmki E, Chamorro A, Davalos A, et al. Stroke treatment with al-teplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol. 2009;8(12):1095-1102. (Randomized double-blind controlled trial; 418 patients)
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Ahmed N, Wahlgren N, Grond M, et al. Implementation and outcome of thrombolysis with alteplase 3-4.5 h after an acute stroke: an updated analysis from SITS-ISTR. Lancet Neurol. 2010;9(9):866-874. (Observational study; 23,942 patients)
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IST Collaborative Group, Sandercock P, Wardlaw JM, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the Third International Stroke Trial [IST-3]): a randomised controlled trial. Lancet. 2012;379(9834):2352-2363. (Multicenter randomized open-treatment trial; 3035 patients)
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Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019;380(19):1795-1803. (Multicenter randomized placebo-controlled trial; 225 patients)
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Fischer U, Mono ML, Zwahlen M, et al. Impact of thrombolysis on stroke outcome at 12 months in a population: the Bern stroke project. Stroke. 2012;43(4):1039-1045. (Prospective study; 807 patients)
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Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2018;49(3):e46-e110. (Guidelines)
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Wechsler LR. Intravenous thrombolytic therapy for acute ischemic stroke. N Engl J Med. 2011;364(22):2138-2146. (Systematic review)
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Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early man-agement of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947. (Guidelines)
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Tsivgoulis G, Katsanos AH, Mavridis D, et al. Intravenous thrombolysis for ischemic stroke patients on dual antiplatelets. Ann Neurol. 2018;84(1):89-97. (Retrospective analysis of prospectively collected data; 2086 patients)
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De Silva DA, Manzano JJ, Chang HM, et al. Reconsidering recent myocardial infarction as a contraindication for IV stroke thrombolysis. Neurology. 2011;76(21):1838-1840. (Systematic review)
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Patel MR, Meine TJ, Lindblad L, et al. Cardiac tamponade in the fibrinolytic era: analysis of >100,000 patients with ST-segment elevation myocardial infarction. Am Heart J. 2006;151(2):316-322. (Meta-analysis; 102,060 patients)
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Kremen SA, Wu MN, Ovbiagele B. Hemopericardium following intravenous thrombolysis for acute ischemic stroke. Cerebrovasc Dis. 2005;20(6):478-479. (Case report)
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Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;384(9958):1929-1935. (Meta-analysis; 9 trials, 6756 patients)
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Meretoja A, Strbian D, Mustanoja S, et al. Reducing in-hospital delay to 20 minutes in stroke thrombolysis. Neurology. 2012;79(4):306-313. (Retrospective analysis of prospectively collected data; 1860 patients)
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Meretoja A, Weir L, Ugalde M, et al. Helsinki model cut stroke throm-bolysis delays to 25 minutes in Melbourne in only 4 months. Neurology. 2013;81(12):1071-1076. (Retrospective analysis of prospectively collected data; 48 patients)
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White-Bateman SR, Schumacher HC, Sacco RL, et al. Consent for intravenous thrombolysis in acute stroke: review and future directions. Arch Neurol. 2007;64(6):785-792. (Systematic review)
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Larrue V, von Kummer RR, Muller A, et al. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European- Australasian Acute Stroke Study (ECASS II). Stroke. 2001;32(2):438-441. (Secondary analysis of randomized controlled trial; 450 patients)
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Paciaroni M, Agnelli G, Corea F, et al. Early hemorrhagic transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results of a prospective multicenter study. Stroke. 2008;39(8):2249-2256. (Prospective multicenter study; 1125 patients)
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Thomalla G, Sobesky J, Kohrmann M, et al. Two tales: hemorrhagic transformation but not parenchymal hemorrhage after thrombolysis is related to severity and duration of ischemia: MRI study of acute stroke patients treated with intravenous tissue plasminogen activator within 6 hours. Stroke. 2007;38(2):313-318. (Retrospective analysis of prospectively collected data; 152 patients)
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Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet. 2000;355(9216):1670-1674. (Prospective study; 203 patients)
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Demchuk AM, Hill MD, Barber PA, et al. Importance of early ischemic computed tomography changes using ASPECTS in NINDS rt-PA Stroke Study. Stroke. 2005;36(10):2110-2115. (Prospective study; 608 CT scans)
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Lou M, Safdar A, Mehdiratta M, et al. The HAT score: a simple grading scale for predicting hemorrhage after thrombolysis. Neurology. 2008;71(18):1417-1423. (Grading scale development)
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Strbian D, Engelter S, Michel P, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. Ann Neurol. 2012;71(5):634-641. (Grading scale development; 974 patients)
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Mazya M, Egido JA, Ford GA, et al. Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: safe Implementation of Treatments in Stroke (SITS) symptomatic intracerebral hemorrhage risk score. Stroke. 2012;43(6):1524- 1531. (Prospective study; 31,627 patients)
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Asuzu D, Nystrom K, Amin H, et al. TURN: a simple predictor of symptomatic intracerebral hemorrhage after IV thrombolysis. Neurocrit Care. 2015;23(2):166-171. (Retrospective analysis of prospectively collected data; 1336 patients, validation cohort 983 patients)
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Strbian D, Michel P, Seiffge DJ, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: comparison of prediction scores. Stroke. 2014;45(3):752-758. (Retrospective analysis of prospectively collected data; 3012 patients)
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Anderson CS, Robinson T, Lindley RI, et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N Engl J Med. 2016;374(24):2313-2323. (Randomized controlled trial; 1607 patients)
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Goldstein JN, Marrero M, Masrur S, et al. Management of thrombol-ysis-associated symptomatic intracerebral hemorrhage. Arch Neurol. 2010;67(8):965-969. (Retrospective analysis of prospectively collected data; 311 patients)
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French KF, White J, Hoesch RE. Treatment of intracerebral hemorrhage with tranexamic acid after thrombolysis with tissue plasminogen activator. Neurocrit Care. 2012;17(1):107-111. (Case report)
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Yaghi S, Eisenberger A, Willey JZ. Symptomatic intracerebral hemorrhage in acute ischemic stroke after thrombolysis with intravenous recombinant tissue plasminogen activator: a review of natural history and treatment. JAMA Neurol. 2014;71(9):1181-1185. (Systematic review)
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Albers GW, Bates VE, Clark WM, et al. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. 2000;283(9):1145-1150. (Prospective mulitcenter study; 389 patients)
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Engelter ST, Fluri F, Buitrago-Tellez C, et al. Life-threatening orolingual angioedema during thrombolysis in acute ischemic stroke. J Neurol. 2005;252(10):1167-1170. (Observational study; 120 patients)
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Hill MD, Lye T, Moss H, et al. Hemi-orolingual angioedema and ACE in-hibition after alteplase treatment of stroke. Neurology. 2003;60(9):1525- 1527. (Prospective study; 176 patients)
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Myslimi F, Caparros F, Dequatre-Ponchelle N, et al. Orolingual angioedema during or after thrombolysis for cerebral ischemia. Stroke. 2016;47(7):1825-1830. (Prospective study; 923 patients)
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Pahs L, Droege C, Kneale H, et al. A novel approach to the treatment of orolingual angioedema after tissue plasminogen activator adminis-tration. Ann Emerg Med. 2016;68(3):345-348. (Case report)
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Mackey J, Kleindorfer D, Sucharew H, et al. Population-based study of wake-up strokes. Neurology. 2011;76(19):1662-1667. (Population-based study; 1854 patients)
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Fink JN, Kumar S, Horkan C, et al. The stroke patient who woke up: clinical and radiological features, including diffusion and perfusion MRI. Stroke. 2002;33(4):988-993. (Prospective study; 364 patients)
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Michel P, Ntaios G, Reichhart M, et al. Perfusion-CT guided intravenous thrombolysis in patients with unknown-onset stroke: a randomized, double-blind, placebo-controlled, pilot feasibility trial. Neuroradiol-ogy. 2012;54(6):579-588. (Randomized double-blind pilot trial; 12 patients)
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Michel P, Odier C, Rutgers M, et al. The Acute STroke Registry and Analysis of Lausanne (ASTRAL): design and baseline analysis of an ischemic stroke registry including acute multimodal imaging. Stroke. 2010;41(11):2491-2498. (Registry design; 1633 patients)
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Nogueira RG, Gupta R, Jovin TG, et al. Predictors and clinical relevance of hemorrhagic transformation after endovascular therapy for anterior circulation large vessel occlusion strokes: a multicenter retrospective analysis of 1122 patients. J Neurointerv Surg. 2015;7(1):16-21. (Retrospective analysis; 1122 patients)
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Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708-718. (Multicenter randomized open-label trial with blinded outcome assessment; 182 patients)
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Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379(7):611- 622. (Randomized controlled trial; 503 patients)
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Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study. Lancet Neurol. 2015;14(4):368-376. (Randomized open-label blinded endpoint study; 104 patients)
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Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366(12):1099-1107. (Randomized phase 2 trial; 75 patients)
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Haley EC, Jr, Thompson JL, Grotta JC, et al. Phase IIB/III trial of te-necteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke. 2010;41(4):707-711. (Randomized double-blind controlled phase 2B/3 trial; 112 patients)
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Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017;16(10):781-788. (Randomized open-label blinded endpoint study; 1100 patients)
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Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med. 2018;378(17):1573-1582. (Randomized open-label, blinded outcome study; 202 patients)
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No authors listed. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial--Italy (MAST-I) Group. Lancet. 1995;346(8989):1509-1514. (Randomized controlled trial; 662 patients)
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Multicenter Acute Stroke Trial--Europe Study Group, Hommel M, Cornu C, et al. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med. 1996;335(3):145-150. (Randomized controlled trial; 310 patients)
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Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA. 1996;276(12):961-966. (Randomized double-blind placebo-controlled trial; 340 patients)
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Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009;8(2):141-150. (Randomized double-blind placebo-controlled trial; 186 patients)
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Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Isch-emic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36(1):66-73. (Randomized double-blind placebo-controlled phase 2 trial; 104 patients)
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von Kummer R, Mori E, Truelsen T, et al. Desmoteplase 3 to 9 hours after major artery occlusion stroke: the DIAS-4 Trial (efficacy and safety study of desmoteplase to treat acute ischemic stroke). Stroke. 2016;47(12):2880-2887. (Randomized double-blind placebo-controlled phase 3 trial; 270 patients)
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Albers GW, von Kummer R, Truelsen T, et al. Safety and efficacy of desmoteplase given 3-9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet Neurol. 2015;14(6):575-584. (Randomized double-blind placebo-controlled phase 3 trial; 492 patients)
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Pancioli AM, Broderick J, Brott T, et al. The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: the CLEAR stroke trial. Stroke. 2008;39(12):3268-3276. (Randomized double-blind dose escalation and safety study; 94 patients)
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Nacu A, Kvistad CE, Naess H, et al. NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study): randomized controlled contrast-enhanced sonothrombolysis in an unselected acute ischemic stroke population. Stroke. 2017;48(2):335-341. (Randomized double-blind controlled trial; 183 patients)
Part 2: Endovascular Therapy in Acute Ischemic Stroke
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The Evolution of Medical and Endovascular Management of Acute Ischemic Stroke
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Current Evidence for Endovascular Thrombectomy
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Patient Selection
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Age
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Duration of Symptoms
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Stroke Severity
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Premorbid Functional Status
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Occlusion Location
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Imaging
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Computed Tomography
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Computed Tomographic Angiography
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Computed Tomographic Perfusion
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Magnetic Resonance Imaging
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rt-PA Status
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Technique
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Vascular Access
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Catheter System Setup
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Balloon Guide Catheters
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Thrombectomy Devices
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Future Directions and Systems of Care
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Figures
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Figure 1. Application of CT Perfusion in Management of a Patient With Acute Stroke
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Figure 2. Distal Anterior Cerebral Artery Thrombectomy
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Figure 3. Evaluation of Ischemic Changes on Brain CT Scan
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Figure 4. CT Perfusion Modalities and Their Interpretation in Acute Stroke
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Figure 5. Trans-Radial Approach for Acute Thrombectomy
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Figure 6. Challenging Arterial Anatomy for Thrombectomy in a Patient With Acute Stroke
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References
The Evolution of Medical and Endovascular Management of Acute Ischemic Stroke
The studies that heralded the 1996 United States Food and Drug Administration (FDA) approval of recombinant tissue plasminogen activator (rt-PA; also known as alteplase) as the first medication for the treatment of acute ischemic stroke set the stage for a new age of hyperacute stroke interventions.1,2 In spite of the impact of intravenous (IV) rt-PA on the treatment of acute ischemic stroke, some patients do not respond to the drug, particularly those patients who harbor an embolus lodged in a vessel that is too large for the medication to lyse. There are studies showing that large-vessel occlusions may respond to rt-PA in only some patients.1 In addition, many patients are ineligible for IV rt-PA because treatment requires that the patient receive the drug within 3 hours from the time of stroke onset (4.5 hours in selected patients).2 Many patients are excluded from IV rt-PA due to medical and surgical exclusion criteria.
The first trial of intra-arterial thrombolytic treatment was published in 1998 when the PROACT I study demonstrated the safety and efficacy of intra-arterial (IA) prourokinase (pro-UK) in the treatment of patients with a large-vessel occlusion of the middle cerebral artery (MCA).3 In this study, patients were randomized to treatment with either a continuous infusion of IV heparin alone or heparin plus treatment with pro-UK, infused intra-arterially via an endovascularly placed catheter. Patients in the pro-UK arm were found to have higher recanalization rates compared with the control group, although in patients treated with pro-UK, there was a non–statistically significant trend toward a higher rate of intracerebral hemorrhage.
One of the earliest mechanical devices aimed at endovascular lysis of a cerebrovascular clot was the EKOS MicroLysis® Micro-infusion (EKOS corporation, Bothell, WA), which implemented a combination of mechanical disruption and ultrasound for clot lysis.4 Another early device, the MERCI® Retriever (Concentric Medical, CA) is a corkscrew-like device that engages and retrieves the target clot.5 Penumbra (Penumbra, Inc., Alameda, CA) introduced its first separator aspiration-based systems in 2007, which break down the clot locally by mechanical disruption, then aspirate the fragments via large-bore catheters.6 Each of these devices has been evaluated in single-arm studies that have shown modest recanalization rates and better functional outcomes compared to their nonrandomized matched patients from the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA study.4,5,7,8
In 2013, IMS-III, SYNTHESIS, and MR RESCUE, 3 long-anticipated randomized controlled trials of endovascular management of stroke, were published and demonstrated no additional benefit of endovascular therapy (EVT) over medical treatment.9-11 In hindsight, there were many factors that contributed to the failure of these studies to demonstrate a benefit for EVT in the treatment of large-vessel occlusion. By the time of the conclusion of IMS-III, the majority of the devices used in it were considered obsolete by practice standards of the day.
Retrievable stents, also known as stent-retrievers or stentrievers (eg, Solitaire [ev3/Covidien, Irvine, CA, USA] and Trevo [Stryker, Kalamazoo, MI, USA]) and large-bore aspiration catheters (eg, Penumbra aspiration system [Penumbra, Inc., Alameda, CA]) have demonstrated superiority in achieving vessel recanalization in head-to-head trials with older devices such as EKOS and the Penumbra separator.12 Broussalis et al demonstrated that the rates of successful recanalization in patients treated with stentrievers was 82% compared with only 62% in patients treated with MERCI retrievers (P = .016).12 A major critique of the IMS-III trial was poor patient selection, because patients were enrolled on the basis of clinical stroke severity rather than on direct confirmation of the presence of a large-vessel occlusion using noninvasive computed tomographic (CT) angiography imaging. The most critical lesson learned from those trials is that clinical benefit is highly dependent on timely recanalization. In the IMS-I and IMS-II populations, every 30-minute delay in recanalization was associated with a 10% decrease in the chance of functional independence (defined as a modified Rankin scale [mRS] score of ≤ 2).
Figures
References
Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.
To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available.
-
Linfante I, Llinas RH, Selim M, et al. Clinical and vascular outcome in internal carotid artery versus middle cerebral artery occlusions after intravenous tissue plasminogen activator. Stroke. 2002;33(8):2066-2071. (Retrospective; 36 patients)
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Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317- 1329. (Randomized double-blind controlled trial; 821 patients)
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del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29(1):4-11. (Prospective randomized controlled trial; 46 patients)
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The Interventional Management of Stroke (IMS) II study. Stroke. 2007;38(7):2127-2135. (Prospective randomized trial; 81 patients)
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Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005;36(7):1432-1438. (Prospective randomized controlled trial; 151 patients)
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The Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40(8):2761-2768. (Prospective randomized controlled trial; 125 patients)
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IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke. 2004;35(4):904-911. (Prospective randomized trial; 80 patients)
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Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008;39(4):1205-1212. (Prospective randomized controlled trial; 164 patients)
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Ciccone A, Valvassori L. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368(25):2433-2434. (Prospective randomized controlled trial; 362 patients)
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Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914-923. (Prospective randomized controlled trial; 118 patients)
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Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893-903. (Prospective randomized controlled trial; 656 patients)
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Broussalis E, Trinka E, Hitzl W, et al. Comparison of stent-retriever devices versus the MERCI retriever for endovascular treatment of acute stroke. AJNR Am J Neuroradiol. 2013;34(2):366-372. (Prospective ran-domized controlled trial; 122 patients)
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Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11-20. (Prospective randomized trial; 500 patients)
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Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285-2295. (Prospective randomized controlled trial; 196 patients)
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Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372(24):2296-2306. (Prospective randomized controlled trial; 206 patients)
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Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009-1018. (Prospective randomized controlled trial; 70 patients)
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Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019-1030. (Prospective randomized controlled trial; 316 patients)
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Mocco J, Zaidat OO, von Kummer R, et al. Aspiration thrombectomy after intravenous alteplase versus intravenous alteplase alone. Stroke. 2016;47(9):2331-2338. (Prospective randomized controlled trial; 105 patients)
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Bracard S, Ducrocq X, Mas JL, et al. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Lancet Neurol. 2016;15(11):1138-1147. (Prospective randomized controlled trial; 414 patients)
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Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723-1731. (Meta-analysis; 1287 patients)
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Powers WJ, Derdeyn CP, Biller J, et al. 2015 American Heart Associa-tion/American Stroke Association focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(10):3020-3035. (Systematic review)
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Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708-718. (Multicenter randomized, open-label trial with blinded outcome assessment; 182 patients)
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Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11-21. (Prospective randomized controlled trial; 206 patients)
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Albers GW. Late window paradox. Stroke. 2018;49(3):768-771. (Literature review)
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Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2018;49(3):e46-e110. (Guidelines)
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Nagel S, Bouslama M, Krause LU, et al. Mechanical thrombectomy in patients with milder strokes and large vessel occlusions. Stroke. 2018;49(10):2391-2397. (Retrospective cohort study; 300 patients)
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Ohta T, Morimoto M, Okada K, et al. Mechanical thrombectomy in anterior circulation occlusion could be more effective than medical management even in low DWI-ASPECTS patients. Neurol Med Chir (Tokyo). 2018;58(4):156-163. (Retrospective cohort study; 83 patients)
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Grossberg JA, Rebello LC, Haussen DC, et al. Beyond large vessel occlusion strokes: distal occlusion thrombectomy. Stroke. 2018;49(7):1662-1668. (Retrospective cohort study; 949 patients)
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Alawieh A, Starke RM, Chatterjee AR, et al. Outcomes of endovascular thrombectomy in the elderly: a ‘real-world’ multicenter study. J Neurointerv Surg. 2018. (Prospective randomized controlled trial; 560 patients)
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Hilditch CA, Nicholson P, Murad MH, et al. Endovascular management of acute stroke in the elderly: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2018;39(5):887-891. (Systematic review and meta-analysis; 860 patients)
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Fonarow GC, Reeves MJ, Zhao X, et al. Age-related differences in characteristics, performance measures, treatment trends, and outcomes in patients with ischemic stroke. Circulation. 2010;121(7):879-891. (Systematic review)
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Cobb MIH, Laarakker AS, Gonzalez LF, et al. Endovascular therapies for acute ischemic stroke in children. Stroke. 2017;48(7):2026-2030. (Literature review)
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Kim JT, Park MS, Chang J, et al. Proximal arterial occlusion in acute ischemic stroke with low NIHSS scores should not be considered as mild stroke. PLoS One. 2013;8(8):e70996. (Systematic review and meta-analysis)
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Heldner MR, Jung S, Zubler C, et al. Outcome of patients with occlusions of the internal carotid artery or the main stem of the middle cerebral artery with NIHSS score of less than 5: comparison between thrombolysed and non-thrombolysed patients. J Neurol Neurosurg Psychiatry. 2015;86(7):755-760. (Systematic review and meta-analysis; 5312 patients)
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Messer MP, Schonenberger S, Mohlenbruch MA, et al. Minor stroke syndromes in large-vessel occlusions: mechanical thrombectomy or thrombolysis only? AJNR Am J Neuroradiol. 2017;38(6):1177-1179. (Case series; 2213 patients)
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Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J. 1957;2(5):200-215. (Case series; 252 patients)
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Bonita R, Beaglehole R. Recovery of motor function after stroke. Stroke. 1988;19(12):1497-1500. (Prospective; 680 patients)
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van der Hoeven EJ, Schonewille WJ, Vos JA, et al. The Basilar Artery International Cooperation Study (BASICS): study protocol for a randomised controlled trial. Trials. 2013;14:200. (Prospective randomized controlled trial; 750 patients)
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Rubiera M, Ribo M, Delgado-Mederos R, et al. Tandem internal carotid artery/middle cerebral artery occlusion: an independent predictor of poor outcome after systemic thrombolysis. Stroke. 2006;37(9):2301- 2305. (Prospective randomized controlled trial; 156 patients)
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Heck DV, Brown MD. Carotid stenting and intracranial thrombectomy for treatment of acute stroke due to tandem occlusions with aggressive antiplatelet therapy may be associated with a high incidence of intracranial hemorrhage. J Neurointerv Surg. 2015;7(3):170-175. (Prospective randomized controlled trial; 221 patients)
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Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibi-tion with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368(14):1303-1313. (Prospective; 11,145 patients)
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Rangel-Castilla L, Rajah GB, Shakir HJ, et al. Management of acute ischemic stroke due to tandem occlusion: should endovascular recana-lization of the extracranial or intracranial occlusive lesion be done first? Neurosurg Focus. 2017;42(4):E16. (Prospective randomized controlled trial; 45 patients)
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Yang D, Shi Z, Lin M, et al. Endovascular retrograde approach may be a better option for acute tandem occlusions stroke. Interv Neuroradiol. 2019;25(2):194-201. (Retrospective; 60 patients)
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Roman LS, Menon BK, Blasco J, et al. Imaging features and safety and efficacy of endovascular stroke treatment: a meta-analysis of individual patient-level data. Lancet Neurol. 2018;17(10):895-904. (Systematic review)
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Lee DH, Sung JH, Kim SU, et al. Effective use of balloon guide catheters in reducing incidence of mechanical thrombectomy related distal embolization. Acta Neurochir (Wien). 2017;159(9):1671-1677. (Retrospective; 139 patients)
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Gory B, Lapergue B, Blanc R, et al. Contact aspiration versus stent retriever in patients with acute ischemic stroke with M2 occlusion in the ASTER randomized trial (contact aspiration versus stent retriever for successful revascularization). Stroke. 2018;49(2):461-464. (Prospective randomized controlled trial; 79 patients)
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Turk AS, Siddiqui AH, Mocco J. A comparison of direct aspiration versus stent retriever as a first approach (‘COMPASS’): protocol. J Neurointerv Surg. 2018;10(10):953-957. (Literature review)
Abbreviation List
ADAPT |
A direct aspiration first-pass technique (thrombectomy) |
AHA |
American Heart Association |
aPTT |
Activated prothrombin time |
ASPECTS |
Alberta Stroke Program early CT score |
BGC |
Balloon guide catheter |
CBC |
Complete blood cell (count) |
CBF |
Cerebral blood flow |
CBV |
Cerebral blood volume |
CMB |
Cerebral microbleed |
CI |
Confidence interval |
CT |
Computed tomography |
CTA |
Computed tomographic angiography |
DBP |
Diastolic blood pressure |
END |
Early neurological deterioration |
EVT |
Endovascular therapy |
FDA |
United States Food and Drug Administration |
HI |
Hemorrhagic infarct |
ICA |
Internal carotid artery |
IV |
Intravenous |
IVT |
Intravenous thrombolysis |
MCA |
Middle cerebral artery |
MERCI Retriever |
Mechanical Embolus Removal in Cerebral Ischemia |
MRI |
Magnetic resonance imaging |
mRS |
Modified Rankin Scale |
MTT |
Mean transit time |
NIHSS |
National Institutes of Health Stroke Scale |
NINDS |
National Institute of Neurological Disorders and Stroke |
OR |
Odds ratio |
PH |
Parenchymal hemorrhage |
Pro-UK |
Prourokinase |
rt-PA |
Recombinant tissue plasminogen activator |
SBP |
Systolic blood pressure |
TICI |
Thrombolysis in cerebral infarction |
TTP |
Time to peak |
Abbreviations of Clinical Trials
ASTER |
Contact Aspiration vs Stent Retriever for Successful Revascularization (NCT03290885) |
BASICS |
Basilar Artery International Cooperation Study (NCT01717755) |
DAWN |
Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo (NCT02142283) |
DEFUSE 3 |
Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (NCT02586415) |
ECASS |
European Cooperative Acute Stroke Study (NCT00153036) |
ESCAPE |
Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times (NCT01778335) |
EXTEND |
Extending the Time for Thrombolysis in Emergency Neurological Deficits (NCT00887328, NCT01580839) |
EXTEND-IA |
Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke (NCT02388061) |
HERMES |
Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials |
IMS-III |
Interventional Management of Stroke (NCT00359424) |
IST-3 |
Third International Stroke Trial |
MR CLEAN |
Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands |
MR RESCUE |
Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (NCT00389467) |
PROACT |
Prolyse in Acute Cerebral Thromboembolism |
REVASCAT |
Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours (NCT01692379) |
SITS-MOST |
Safe Implementation of Thrombolysis in Stroke-Monitoring Study (NCT02229812) |
SWIFT PRIME |
Solitaire™ With the Intention For Thrombectomy as PRIMary Endovascular Treatment (NCT01657461) |
SYNTHESIS |
Local Versus Systemic Thrombolysis for Acute Ischemic Stroke (NCT00540527) |
THERAPY |
The Randomized, Concurrent Controlled Trial to Assess the Penumbra System’s Safety and Effectiveness in the Treatment of Acute Stroke (NCT01429350) |
THRACE |
Mechanical Thrombectomy After Intravenous Alteplase Versus Alteplase Alone After Stroke (NCT01062698) |
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The NIHSS is used to quantify the severity of ischemic stroke. The modified Rankin Scale (mRS) for neurologic disability measures the degree of disability or dependence in the daily activities of people who have suffered a stroke. The Alberta Stroke Program Early CT Score (ASPECTS) assesses the severity of middle cerebral artery stroke using available computed tomography data. The tPA dosing for stroke calculator indicates the weight-based dose of tPA for stroke patients.
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National Institutes of Health Stroke Scale (NIHSS)
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Modified Rankin Scale (mRS) for Neurologic Disability
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Alberta Stroke Program Early CT Score (ASPECTS)
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tPA (Tissue Plasminogen Activator) Dosing for Stroke Calculator
National Institutes of Health Stroke Scale (NIHSS)
Introduction
The NIHSS is used to quantify the severity of ischemic stroke.
Points & Pearls
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The National Institutes of Health Stroke Scale (NIHSS) was developed to help clinicians objectively rate the severity of ischemic strokes.
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Increasing NIHSS scores indicate a more severe stroke and have been shown to correlate with the size of the infarction as measured by both computed tomography and magnetic resonance imaging.
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When assessed within the first 48 hours following a stroke, NIHSS scores have been shown to correlate with clinical outcomes at the 3-month and 1-year marks.
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Patients who have a total NIHSS score ≤ 4 generally have favorable clinical outcomes and a high likelihood of functional independence regardless of treatment.
Points to keep in mind:
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Many guidelines and protocols warn that administration of tissue plasminogen activator (tPA) in patients with an NIHSS score > 22 is associated with an increased risk of hemorrhagic conversion; however, these patients are also the most severely debilitated and dependent from their strokes.
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Some components of the NIHSS have lower interrater reliability (eg, facial movement, limb ataxia, neglect, level of consciousness, and dysarthria), and some may be quite limited (eg, due to altered mental status).
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A simpler, modified version of the NIHSS has been found to have greater interrater reliability with equivalent clinical performance, although it has not been adopted as widely as the original NIHSS.
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A patient with a large-territory posterior circulation stroke syndrome may have a low or normal NIHSS score, which highlights an important limitation of the scale.
Why and When to Use, Rules for Scoring, Next Steps and Advice
Why to Use
The NIHSS can be used to help clinicians determine the severity of a stroke and predict clinical outcomes.
When to Use
The NIHSS is used in patients presenting with stroke in the acute setting.
Rules for Scoring
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Score what you see, not what you think.
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Score the first response, not the best response (except for item 9, “Best Language”).
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Don’t coach.
Next Steps
In patients who present with symptoms that are concerning for ischemic stroke, the following actions are generally considered to be standard practice:
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Obtain a neurology consult.
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Determine the onset of stroke symptoms or the time the patient last felt or was observed as normal.
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Obtain a stat CT scan of the head to rule out hemorrhagic stroke.
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In appropriate circumstances and in consultation with both the neurologist and the patient, consider intravenous thrombolysis for ischemic stroke in patients who have no contraindications.
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Always consider stroke mimics in the differential diagnosis, especially in cases with atypical features (eg, age, risk factors, history, physical examination), including:
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Recrudescence of a previous stroke due to metabolic or infectious stress
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Todd paralysis after seizure
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Complex migraine
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Pseudoseizure or conversion disorder
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Consider ordering further imaging studies, including CT, CT angiography, and MRI/MRA.
Instructions
The NIHSS has many caveats buried within it. If a patient has prior known neurologic deficits (eg, prior weakness, hemiplegia or quadriplegia, blindness), is intubated, has a language barrier, or has other limitations, assessment of the score becomes especially complicated. In those cases, clinicians should consult the NIHSS website. The score calculator discussed and linked to in this article attempts to clarify many of the caveats to the NIHSS but is not to be substituted for the official protocol.
Abbreviations: CT, computed tomography; MRA, magnetic resonance angiogram; MRI, magnetic resonance imaging; NIHSS, National Institutes of Health Stroke Scale.
Calculator Review Authors
Daniel Runde, MD
Department of Emergency Medicine, University of Iowa
Hospitals and Clinics, Iowa City, IA
Critical Actions
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The NIHSS is broadly predictive of clinical outcomes, but individual case outcomes will vary and management decisions must be made in consultation with the patient whenever possible.
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Patients who have an NIHSS score ≤ 4 are highly likely to have good clinical outcomes.
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Whenever possible, patients with acute stroke should be transferred to a stroke center for initial evaluation and treatment, as holistic care (medical optimization, early initiation of physical and occupational therapies, patient and family education, and discharge planning) is associated with improved clinical outcomes; some experts argue that most of the gains in reduction of stroke morbidity and mortality are due to these improvements in stroke care.
Evidence Appraisal
The first iteration of the NIHSS was created in a pilot study of 10 patients who were evaluated within 3 weeks of having an ischemic stroke. The study applied the Toronto Stroke Scale, the Oxbury Initial Severity Scale, and the Cincinnati Stroke Scale to these patients, then analyzed the results and created a composite scale, which was intended for use in a trial of naloxone for stroke (Brott 1989). The scale was modified later by Lyden et al (1994) for use in the National Institute of Neurological Disorders and Stroke (NINDS) study on tPA in patients with ischemic stroke (NINDS tPA Stroke Study Group 1995).
A retrospective review of 1281 patients with ischemic stroke found that each 1-point increase in the NIHSS score decreased the likelihood of an excellent outcome by 24% at 7 days and by 17% at 3 months (Adams 1999). In 2003, Schlegel et al conducted a trial of 94 patients and found that when the NIHSS score was assessed within 24 hours of stroke, each 1-point increase in the score correlated with a decreased likelihood of the patient being discharged.
A study of 893 patients found that the initial NIHSS score, if assessed within 72 hours of the ischemic event, was predictive of whether the patient would need to be placed in either a nursing home or a rehabilitation facility following discharge. Patients with moderate (defined as 6-13 points) or severe (≥ 14 points) NIHSS scores had a threefold increased risk of being placed in a nursing home after discharge and an eightfold increased risk of requiring inpatient rehabilitation therapy (Rundek 2000).
In a 2004 study of 377 patients, Appelros et al found that NIHSS scores that were assessed 24 to 48 hours after an ischemic stroke were broadly predictive of group outcomes at 1 year, with 75% of patients who had scores ≤ 4 being functionally independent at the 1-year mark. The median score in this study was 6, and 33% of patients died within the first year after their stroke event.
A prospective trial of 54 patients found that combining diffusion-weighted magnetic resonance imaging with the NIHSS score was more predictive of clinical outcomes at 3 months (70% of outcomes predicted) than the score or imaging alone (43% and 54%, respectively) (Yoo 2010).
An analysis of 312 patients with acute ischemic stroke who were treated with tPA found that an NIHSS score ≥ 20 was associated with a 17% rate of intracerebral hemorrhage, while a score < 10 was associated with a 3% rate (NINDS t-PA Stroke Study Group 1997).
Calculator Creator
Patrick D. Lyden, MD
References
Original/Primary Reference
Validation References
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Johnston KC, Connors AF Jr, Wagner DP, et al. Predicting outcome in ischemic stroke: external validation of predictive risk models. Stroke. 2003;34(1):200-202.
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Adams HP Jr, Davis PH, Leira EC, et al. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology. 1999;53(1):126-131.
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Schlegel D, Kolb SJ, Luciano JM, et al. Utility of the NIH Stroke Scale as a predictor of hospital disposition. Stroke. 2003;34(1):134-137.
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Rundek T, Mast H, Hartmann A, et al. Predictors of resource use after acute hospitalization: the Northern Manhattan Stroke Study. Neurology. 2000;55(8):1180-1187.
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Appelros P, Terént A. Characteristics of the National Institute of Health Stroke Scale: results from a population-based stroke cohort at baseline and after one year. Cerebrovasc Dis. 2004;17(1):21-27.
Other References
Modified Rankin Scale (mRS) for Neurologic Disability
Introduction
The modified Rankin Scale (mRS) for neurologic disability measures the degree of disability or dependence in the daily activities of people who have suffered a stroke.
Points & Pearls
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The modified Rankin Scale (mRS) assesses disability in patients who have suffered a stroke. The mRS score is compared over time to check for recovery and degree of continued disability. A score of 0 indicates no disability, a score of 5 indicates disability requiring constant care for all needs, and a score of 6 indicates death.
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The mRS has been used in clinical research for more than 30 years and is a common standard for assessing functional outcomes in patients with stroke.
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Multiple studies have shown that the mRS correlates with physiological indicators such as stroke type, lesion size, and neurological impairment as assessed by other stroke evaluation scales.
Points to keep in mind:
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There has been criticism that the mRS contains subject components that result in variability and bias that can lower the score’s reliability.
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The use of structured interviews when assessing the mRS appears to result in improved interrater reliability, although the evidence for this effect is not completely consistent.
Why and When to Use, Next Steps and Suggested Management
Why to Use
The mRS is widely used to measure the functional outcomes for patients who have suffered a stroke. It can also provide a common language for describing the degree of disability for these patients.
When to Use
The mRS can be used to help determine the degree of disability in patients who have suffered a stroke.
Next Steps
Decisions about further medical management, the need for physical and/or occupational therapy, and the degree of care that a patient requires can be partially informed by the mRS, but final determinations should be made on an individual basis.
Abbreviation: mRS, modified Rankin Scale.
Calculator Review Authors
Daniel Runde, MD
Department of Emergency Medicine, University of Iowa
Hospitals and Clinics, Iowa City, IA
Critical Action
The mRS is used to evaluate the degree of disability in patients who have suffered a stroke, but individual quality of life and independence are influenced by a wide variety of factors, including the presence of comorbidities and socioeconomic status.
Evidence Appraisal
The original Rankin Scale was introduced in 1957 by Dr. John Rankin. It was changed to the current modified Rankin Scale form for use in the UK-TIA (United Kingdom transient ischaemic attack) study (van Swieten 1988). The interrater reliability of the mRS was first assessed in a trial of 100 stroke patients who each participated in 2 separate interviews that were conducted by pairs of raters drawn from a group of 10 staff neurologists and 24 neurology residents. The overall kappa was 0.56 with a weighted kappa of 0.91.
A trial of 63 stroke patients evaluated by 2 raters found that the use of structured interviews to conduct the mRS improved reliability and decreased variability and bias (Wilson 2002). A similar trial of 113 patients assessed by 2 trained raters found that overall agreement between the raters was 43% without a structured interview (kappa = 0.25), while agreement improved markedly (81%, kappa = 0.74) when a structured interview was used (Wilson 2005). In 2007, Banks et al conducted a literature review and systematic analysis of 50 trials and found an overall moderate interrater reliability for the mRS (kappa = 0.56) that improved when structured interviews were used (kappa = 0.78).
In a study of 50 patients assessed using a simplified mRS questionnaire, paired raters had good agreement (kappa = 0.72) and the average time to administer the simplified mRS was 1 minute and 40 seconds versus an average of 5 minutes for the standard mRS (Bruno 2010).
A systematic review that included 10 trials found wide variability in interrater reliability for the mRS (kappa = 0.25-0.95) and only moderate reliability overall (kappa = 0.46) (Quinn 2009). A study assessing the reliability of prestroke function as described by the mRS found 56% agreement for the standard mRS (weighted kappa = 0.55; 95% confidence interval [CI], 0.39-0.71) and 70% agreement for prestroke mRS (weighted kappa = 0.70; 95% CI, 0.53-0.87). The poor correlation of prestroke mRS with certain markers of function raised concerns about the validity of the mRS as a measure of prestroke function and introduced the possibility of bias in trial samples (Fearon 2012).
A 2015 trial compared mRS assessments completed by local evaluators to assessments completed by central evaluators who used either phone or video interviews. The study found that video assessment had higher agreement rates (weighted kappa = 0.92; 95% CI, 0.88-0.96) than phone assessment (weighted kappa = 0.77; 95% CI, 0.72-0.83), demonstrating the potential utility of video interviews for mRS assessment (López- Cancio 2015).
Calculator Creator
John van Swieten, MD, PhD
References
Original/Primary Reference
Validation References
Other References
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Wilson JT, Hareendran A, Grant M, et al. Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin Scale. Stroke. 2002;33(9):2243-2266.
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Wilson JT, Hareendran A, Hendry A, et al. Reliability of the modified Rankin Scale across multiple raters: benefits of a structured interview. Stroke. 2005;36(4):777-781.
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Bruno A, Shah N, Lin C, et al. Improving modified Rankin Scale assessment with a simplified questionnaire. Stroke. 2010;41(5):1048-1050.
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Farrell B, Godwin J, Richards S, et al. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991;54(12):1044-1054.
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Quinn TJ, Dawson J, Walters MR, et al. Reliability of the modified Rankin Scale: a systematic review. Stroke. 2009;40(10):3393-3395.
Alberta Stroke Program Early CT Score (ASPECTS)
Introduction
The Alberta Stroke Program Early CT Score (ASPECTS) assesses the severity of middle cerebral artery stroke using available computed tomography data.
Points & Pearls
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The Alberta Stroke Program Early CT Score (ASPECTS) quantifies computed tomography (CT) changes in early middle cerebral artery stroke. More early changes seen on CT suggest a poorer outcome from stroke.
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Patients with ASPECTS ≥ 8 points have a better chance for an independent outcome.
Points to keep in mind:
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ASPECTS does not predict treatment response or intracranial hemorrhage consistently, nor does it offer nuanced prognostic information.
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The score has been studied primarily in patients treated with or eligible for stroke reperfusion therapy, but many stroke patients do not qualify for that therapy.
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More recent studies have evaluated ASPECTS on the basis of the entire scale, as well as dichotomous (< 8 vs ≥ 8 points) or trichotomous (0-4 points, 5-7 points, and 8-10 points) divisions, but few robust prospective trials have been published.
Why and When to Use, Next Steps and Advice
Why to Use
Identification of patients who have a greater likelihood of poor functional outcome following middle cerebral artery stroke may be helpful in the early stages of care for supporting transfer or therapy decisions.
When to Use
ASPECTS can be used for patients presenting within the first minutes and hours of a stroke, when there is clinical suspicion for middle cerebral artery occlusion.
Next Steps
In patients who present with symptoms that are concerning for ischemic stroke, the following actions are generally considered to be standard practice:
-
Obtain a neurology consult.
-
Determine the onset of stroke symptoms or the time the patient last felt or was observed as normal.
-
Obtain a stat CT scan of the head to rule out hemorrhagic stroke.
-
In appropriate circumstances and in consultation with both the neurologist and the patient, consider intravenous thrombolysis for ischemic stroke in patients who have no contraindications.
-
Always consider stroke mimics in the differential diagnosis, especially in cases with atypical features (eg, age, risk factors, history, physical examination), including:
-
Recrudescence of a previous stroke due to metabolic or infectious stress
-
Todd paralysis after seizure
-
Complex migraine
-
Pseudoseizure or conversion disorder
Advice
Using the traditional cutoff scores (< 8 vs ≥ 8 points) as a rough estimate for predicting independence may help inform decisions. Some ASPECTS studies suggest that early CT changes in stroke may be a harbinger of poor outcomes.
Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; CT, computed tomography.
Calculator Review Authors
Daniel Runde, MD
Department of Emergency Medicine, University of Iowa
Hospitals and Clinics, Iowa City, IA
Critical Action
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ASPECTS relies on subtle CT findings and thus requires interpretation by an experienced radiologist. Its only validated use is as a binary variable (< 8 vs ≥ 8 points) for general outcome prediction in those patients who are eligible for reperfusion therapy.
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For patients being considered for intra-arterial tissue plasminogen activator administration, ASPECTS may be useful to exclude patients who are not likely to do well in terms of functional independence (ie, patients for whom intra-arterial treatment is likely to be futile) (Yoo 2014).
Evidence Appraisal
There appears to be a lack of consistency in studies evaluating the interrater reliability of ASPECTS. A trial using ASPECTS assessments of 43 patients by a senior radiology resident, a neuroradiology fellow, and 2 senior neuroradiologists found that agreement varied from 0.486 to 0.678 in Cohen's kappa coefficient when comparing the fellow to the neuroradiology staff, and 0.198 to 0.491 when comparing the radiology resident to the neuroradi-ology staff (Kobkitsuksakul 2018).
Using the binary outcome, a study of 34 cases found only 42% observer agreement for ASPECTS (kappa = 0.34) (Mak 2003). In contrast, a trial of 214 patients using the binary outcome compared CT scans read for ASPECTS in real time by the treating physician with later readings by an expert assessor, showing substantial agreement (weighted kappa = 0.69) (Coutts 2004).
Calculator Creator
Phillip A. Barber, MD
References
Original/Primary Reference
Validation Reference
Other References
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Aviv RI, Mandelcorn J, Chakraborty S et al. Alberta Stroke Program Early CT Scoring of CT perfusion in early stroke visualization and assessment. AJNR Am J Neuroradiol. 2007;28(10): 1975-1980.
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Puetz V, Dzialowski I, Hill MD et al. The Alberta Stroke Program Early CT Score in clinical practice: what have we learned?. Int J Stroke. 2009;4(5):354-364.
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Yoo AJ, Zaidat OO, Chaudhry ZA, et al. Impact of pretreatment noncontrast CT Alberta Stroke Program Early CT Score on clinical outcome after intra-arterial stroke therapy. Stroke. 2014;45(3):746-751.
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Kobkitsuksakul C, Tritanon O, Suraratdecha V. Interobserver agreement between senior radiology resident, neuroradiology fellow, and experienced neuroradiologist in the rating of Alberta Stroke Program Early Computed Tomography Score (ASPECTS). Diagn Interv Radiol. 2018;24(2):104-107.
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Mak HK, Yau KK, Khong PL, et al. Hypodensity of >1/3 middle cerebral artery territory versus Alberta Stroke Programme Early CT Score (ASPECTS): comparison of two methods of quantitative evaluation of early CT changes in hyperacute ischemic stroke in the community setting. Stroke. 2003;34(5):1194-1196.
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Coutts SB, Demchuk AM, Barber PA, et al. Interobserver variation of ASPECTS in real time. Stroke. 2004;35(5):e103-e105.
tPA (Tissue Plasminogen Activator) Dosing for Stroke Calculator
Introduction
The tPA dosing for stroke calculator indicates the weight-based dose of tPA for stroke patients.
Points & Pearls
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There are strict protocols concerning the appropriate administration of intravenous (IV) tissue plasminogen activator (tPA) in patients with ischemic stroke.
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For patients within the 3-hour window who meet the inclusion criteria and have no contraindications, earlier administration of tPA was associated with improved outcomes in 1 randomized trial (NINDS t-PA Stroke Study Group 1997).
Points to keep in mind:
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Administration of IV tPA for patients with acute ischemic stroke is associated with a significant increase in symptomatic intracranial hemorrhage, so it is essential to adhere to accepted protocols and to engage in shared decision-making with the patient and/or the family when considering treatment with tPA.
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The evidence and strength of recommendations for administration of tPA within the 3- to 4.5-hour window from symptom onset is less robust than for giving thrombolytics inside the 3-hour window.
Why and When to Use, Next Steps and Advice
Why to Use
Because of the time-sensitive and high-stress nature of cases involving administration of IV tPA to patients with ischemic stroke, there is a risk for medication error. Using a calculator to double-check dosing prior to administration can reduce this risk.
When to Use
This calculator is intended solely for calculating the IV tPA (also known as alteplase) dose for ischemic stroke. It does not apply to dosing for acute coronary syndromes or pulmonary embolism.
Next Steps
In patients who present with symptoms that are concerning for ischemic stroke, the following actions are generally considered to be standard practice:
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Obtain a neurology consult.
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Determine the onset of stroke symptoms or the time the patient last felt or was observed as normal.
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Obtain a stat CT scan of the head to rule out hemorrhagic stroke.
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Administer tPA when indicated. The American Heart Association/American Stroke Association guidelines for administration of IV tPA include these criteria:
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Patient was last known well within the previous 3 hours.
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Age ≥ 18 years
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Blood pressure is < 185/110 mm Hg (or blood pressure can be lowered safely to < 185/110 mm Hg)
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Blood glucose level > 50 mg/dL
Individual institutions may have different absolute and relative contraindications for tPA administration.
Abbreviation: CT, computed tomography; IV, intravenous; tPA, tissue plasminogen activator.
Calculator Review Authors
Bryan D. Hayes, PharmD
Department of Emergency Medicine and Toxicology,
Massachusetts General Hospital, Boston, MA
Critical Action
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Patients presenting with a potential acute ischemic stroke should have a noncontrast computed tomography scan of the head performed as soon as is safely possible.
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Any patient who is a candidate for IV thrombolysis with tPA should be evaluated carefully for any absolute or relative contraindications.
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The patient should be assessed using the National Institutes of Health Stroke Scale (NIHSS) as part of the evaluation. The assessment should be completed by an NIHSS-certified provider if one is available.
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While a high NIHSS score (> 22) is not an absolute contraindication to tPA within the 3-hour window, the rate of symptomatic or fatal intracranial hem-orrhage is higher among this cohort.
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If the patient has an elevated blood pressure (systolic blood pressure > 185 mm Hg or diastolic blood pressure > 110 mm Hg) as the only contraindication to receiving tPA, consider using parenteral medication to lower the patient’s blood pressure to an acceptable level. If the blood pressure can be adequately controlled, the patient may be given tPA if the other inclusion criteria are met and there are no other contraindications.
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When considering administration of tPA in the extended window (3-4.5 hours), clinicians should remember that an NIHSS score > 25 is generally considered a contraindication to thrombolysis.
Instructions
Use the tPA Dosing for Stroke Calculator only for ischemic stroke patients. Do NOT use this calculator for patients with acute coronary syndromes or pulmonary embolism.
References
Original/Primary Reference
Genentech, Inc. Activase® (alteplase) product insert. Accessed on July 1, 2019.
Validation Reference
The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke. 1997;28(11):2109-2118.
To Read The Companion Article:
To Read The Companion Article:
To Read The Companion Article: