BackgroundandPurpose Thepurposeoftheseguidelinesistoprovideanup-to-datecomprehensivesetofrecommendations in a single document for clinicians caring for adult patients with acute arterial ischemic stroke. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators. These guidelines supersede the 2013 Acute Ischemic Stroke (AIS) Guidelines and are an update of the 2018 AIS Guidelines. Methods Members of the writing group were appointed by the American Heart Association (AHA) Stroke Council s Scientific Statements Oversight Committee, representing various areas of medical expertise. Members were not allowed to participate in discussions or to vote on topics relevant to their relations with industry. An update of the 2013 AIS Guidelines was originally published in January 2018. This guideline was approved by the AHA Science Advisory and Coordinating Committee and the AHA Executive Committee. In April 2018, a revision to these guidelines, deleting some recommendations, was published online by the AHA. The writing group was asked review the original document and revise if appropriate. In June 2018, the writing group submitted a document with minor changes and with inclusion of important newly published randomized controlled trials with >100 participants and clinical outcomes at least 90 days after AIS. The document was sent to 14 peer reviewers. The writing group evaluated the peer reviewers comments and revised TheAmerican HeartAssociation 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. This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on September 12, 2019, and the American Heart Association Executive Committee on October 3, 2019. A copy of the document is available at https://professional.heart.org/statements by using either Search for Guidelines & Statements or the Browse by Topic area. To purchase additional reprints, call 843-216-2533 or email kelle. ramsay@wolterskluwer.com. The online-only Data Supplements are available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STR.0000000000000211. The American Heart Association requests that this document be cited as follows: Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL; on behalf of the American Heart Association Stroke Council. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50:e344 e418 doi: 10.1161/STR.0000000000000211. The expert peer review of AHA-commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit https://professional.heart.org/statements. Select the Guidelines & Statements drop-down menu, then click Publication Development. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at https://www.heart.org/permissions. A link to the Copyright Permissions Request Form appears in the second paragraph (https://www.heart.org/en/about-us/statements-and-policies/copyright-request-form). Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association Endorsed by the Society for Academic Emergency Medicine and The Neurocritical Care Society Reviewed for evidence-based integrity and endorsed by the American Association of Neurological Surgeons and Congress of Neurological Surgeons. William J. Powers, MD, FAHA, Chair; Alejandro A. Rabinstein, MD, FAHA, Vice Chair; Teri Ackerson, BSN, RN; Opeolu M. Adeoye, MD, MS, FAHA; Nicholas C. Bambakidis, MD, FAHA; Kyra Becker, MD, FAHA; Jos Biller, MD, FAHA; Michael Brown, MD, MSc; Bart M. Demaerschalk, MD, MSc, FAHA; Brian Hoh, MD, FAHA; Edward C. Jauch, MD, MS, FAHA; Chelsea S. Kidwell, MD, FAHA; Thabele M. Leslie-Mazwi, MD; Bruce Ovbiagele, MD, MSc, MAS, MBA, FAHA; Phillip A. Scott, MD, MBA, FAHA; Kevin N. Sheth, MD, FAHA; Andrew M. Southerland, MD, MSc, FAHA; Deborah V. Summers, MSN, RN, FAHA; David L. Tirschwell, MD, MSc, FAHA; on behalf of the American Heart Association Stroke Council 2019 American Heart Association, Inc. Stroke is available at https://www.ahajournals.org/journal/str AHA/ASA Guideline Powers et al 2019 Guidelines for Management of AIS e345 when appropriate. The current final document was approved by all members of the writing group except when relationships with industry precluded members from voting and by the governing bodies of theAHA. These guidelines use theAmerican College of Cardiology/AHA 2015 Class of Recommendations and Level of Evidence and the new AHA guidelines format. Results These guidelines detail prehospital care, urgent and emergency evaluation and treatment with intravenous and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are appropriately instituted within the first 2 weeks. The guidelines support the overarching concept of stroke systems of care in both the prehospital and hospital settings. Conclusions These guidelines provide general recommendations based on the currently available evidence to guide clinicians caring for adult patients with acute arterial ischemic stroke. In many instances, however, only limited data exist demonstrating the urgent need for continued research on treatment of acute ischemic stroke. (Stroke. 2019;50:e344 e418. Key Words: AHA Scientific Statements critical care disease management emergency medical services secondary prevention stroke therapeutics See related article, p 3331 New high-quality evidence has produced major changes in the evidence-based treatment of acute ischemic stroke (AIS) since the publication of the guidelines for the early management of patients with acute ischemic stroke in 2013.1 Much of this new evidence has been incorporated into American Heart Association (AHA) focused updates, guidelines, or scientific statements on specific topics relating to the management of patients with AIS since 2013. The purpose of these guidelines is to provide an up- to-date comprehensive set of recommendations for clinicians caring for adult patients with acute arterial ischemic stroke in a single document. These guidelines address prehospital care, ur- gent and emergency evaluation and treatment with intravenous (IV) and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are often begun during the initial hospitalization. We have restricted our recom- mendations to adults and to secondary prevention measures that are appropriately instituted within the first 2 weeks. We have not included recommendations for cerebral venous sinus thrombosis because these were covered in a 2011 scientific statement and there is no new evidence that would change those conclusions.2 An independent Evidence Review Committee was com- missioned to perform a systematic review of a limited number of clinical questions identified in conjunction with the writ- ing group, the results of which were considered by the writing group for incorporation into the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke (2018 and this 2019 update. The systematic reviews for the 2018 AIS Guidelines have been previously published.3,4 These guidelines use the American College of Cardiology (ACC)/AHA Class of Recommendations (COR) and Level of Evidence (LOE) format shown in Table 1. New or revised recom- mendations that supersede previous guideline recommendations are accompanied by 250-word knowledge bytes and data sup- plement tables summarizing the key studies supporting the rec- ommendations in place of extensive text. These data supplement tables can be found in Data Supplement 1 and literature search information for all data supplement tables can be found in Data Supplement 2. Because this guideline represents an update of the 2018AIS Guidelines, the term New Recommendation refers to recommendations that are new to either the 2018 AIS Guidelines or to this 2019 update. Existing recommendations that are un- changed are reiterated with reference to the previous publication. These previous publications and their abbreviations used in this document are listed in Table 2. When there is no new pertinent evidence for these unchanged recommendations, no knowledge byte or data supplement is provided. For some unchanged recom- mendations, there are new pertinent data that support the existing recommendation, and these are provided. Additional abbrevia- tions used in this guideline are listed in Table 3. Members of the writing committee were appointed by the AHA Stroke Council s Scientific Statements Oversight Committee,representingvariousareasofmedicalexpertise.Strict adherence to the AHA conflict-of-interest policy was maintained throughout the writing and consensus process. Members were not allowed to participate in discussions or to vote on topics relevant to their relations with industry. Writing group members accepted topics relevant to their areas of expertise, reviewed the stroke literature with emphasis on publications since the prior guide- lines, and drafted recommendations. Draft recommendations and supporting evidence were discussed by the writing group, and the revised recommendations for each topic were reviewed by a designated writing group member. The full writing group then evaluated the complete guidelines. The members of the writing group unanimously approved all recommendations except when relations with industry precluded members voting. Prerelease review of the draft 2018 guidelines was performed by 4 expert peer reviewers and by the members of the Stroke Council s Scientific Statements Oversight Committee and Stroke Council Leadership Committee. The 2018AIS Guidelines were approved by the AHA Science Advisory and Coordinating Committee on November 29, 2017, and by the AHA Executive Committee on December 11, 2017. It was published online January 24, 2018. On April 18, 2018, the AHA published a revision to the AIS Guidelines online, deleting 7 specific recommendations and all of Section 6, In-Hospital Institution of Secondary Prevention. The writing group was asked to review the entire guideline, in- cluding the deleted recommendations. In June 2018, the writing group submitted a document with minor changes and with inclu- sion of important newly published randomized controlled trials (RCTs) with >100 participants and clinical outcomes at least 90 days after AIS. The document was sent out to 14 peer reviewers. The writing group evaluated the peer reviewers comments and revised when appropriate. This revised document was reviewed by Stroke Council s Scientific Statements Oversight Committee and theAHA ScienceAdvisory and Coordinating Committee. To allow these guidelines to be as timely as possible, RCTs address- ing AIS published between November 2018 and April 2019 were reviewed by the writing group. Modifications of Section Table 1. Applying ACC/AHA Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015) Section 3.7.2., Recommendation 2 resulted. To allow these modi- fications to be incorporated, the standard peer review process was abbreviated, with review provided by the members of the Stroke Council s Scientific Statements Oversight Committee and by liaisons from the endorsing organizations listed on the masthead. The list of these reviewers is provided at the end of the guideline. The final document was approved by theAHA ScienceAdvisory and Coordinating Committee and Executive Committee. These guidelines provide general recommendations based on the currently available evidence to guide clinicians caring for adult patients with acute arterial ischemic stroke. They will not be applicable to all patients. Local resources and expertise, specific clinical circumstances and patient preferences, and evidence published since the issuance of these guidelines are some of the additional factors that should be considered when making individual patient care decisions. In many instances, only limited data exist demonstrating the urgent need for con- tinued research on treatment of AIS. A focused update addressing data from additional relevant recent RCTs is in process. Powers et al 2019 Guidelines for Management of AIS e347 Table 2. Guidelines, Policies, and Statements Relevant to the Management of AIS Document Title Year Published Abbreviation Used in This Document Recommendations for the Implementation of Telemedicine Within Stroke Systems of Care: A Policy Statement From the American Heart Association 5 Diagnosis and Management of Cerebral Venous Thrombosis: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association 2 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association 1 Interactions Within Stroke Systems of Care: A Policy Statement From the American Heart Association/American of Care 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Recommendations for the Management of Cerebral and Cerebellar Infarction With Swelling: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association 8 Palliative and End-of-Life Care in Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association 9 Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association 10 Prevention Clinical Performance Measures for Adults Hospitalized With Acute Ischemic Stroke: Performance Measures for Healthcare Professionals From the American Heart Association/American Stroke Association 11 Part 15: First Aid: 2015 American Heart Association and American Red Cross Guidelines Update for First Aid 12 2015 American Heart Association/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 13 Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association 14 Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association 15 Poststroke Depression: A Scientific Statement for Healthcare Professionals From the American Heart Association/ American Stroke Association 16 Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplase in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines 18 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Guidelines AACVPR indicates American Association of Cardiovascular and Pulmonary Rehabilitation; AAPA, American Academy of Physician Assistants; ABC, Association of Black Cardiologists; ACC, American College of Cardiology; ACPM, American College of Preventive Medicine; ADA, American Diabetes Association; AGS, American Geriatrics Society; AHA, American Heart Association; AIS, acute ischemic stroke; APhA, American Pharmacists Association; ASH, American Society of Hypertension; ASPC, American Society for Preventive Cardiology; CPR, cardiopulmonary resuscitation; ECC, emergency cardiovascular care; HRS, Heart Rhythm Society; IV, intravenous; N/A, not applicable; NLA, National Lipid Association; NMA, National Medical Association; and PCNA, Preventive Cardiovascular Nurses Association. Table 3. Abbreviations in This Guideline ACC American College of Cardiology AHA American Heart Association AIS Acute ischemic stroke ARD Absolute risk difference ASA American Stroke Association ASCVD Atherosclerotic cardiovascular disease ASPECTS Alberta Stroke Program Early Computed Tomography Score BP Blood pressure CEA Carotid endarterectomy CeAD Cervical artery dissection CMB Cerebral microbleed COR Class of recommendation CPAP Continuous positive airway pressure CS Conscious sedation CT Computed tomography CTA Computed tomographic angiography CTP Computed tomographic perfusion DTN Door-to-needle DVT Deep vein thrombosis DW-MRI Diffusion-weighted magnetic resonance imaging ED Emergency department EMS Emergency medical services EVT Endovascular therapy GA General anesthesia GWTG Get With The Guidelines HBO Hyperbaric oxygen HR Hazard ratio HT Hemorrhagic transformation ICH Intracerebral hemorrhage IPC Intermittent pneumatic compression IV Intravenous LDL-C Low-density lipoprotein cholesterol LMWH Low-molecular-weight heparin LOE Level of evidence LVO Large vessel occlusion M1 Middle cerebral artery segment 1 M2 Middle cerebral artery segment 2 M3 Middle cerebral artery segment 3 MCA Middle cerebral artery MI Myocardial infarction MR Magnetic resonance MRA Magnetic resonance angiography MRI Magnetic resonance imaging mRS Modified Rankin Scale mTICI Modified Thrombolysis in Cerebral Infarction NCCT Noncontrast computed tomography NIHSS National Institutes of Health Stroke Scale NINDS National Institute of Neurological Disorders and Stroke OR Odds ratio OSA Obstructive sleep apnea PFO Patent foramen ovale RCT Randomized clinical trial RR Relative risk rt-PA Recombinant tissue-type plasminogen activator SBP Systolic blood pressure sICH Symptomatic intracerebral hemorrhage TIA Transient ischemic attack UFH Unfractionated heparin Table 3. Continued (Continued) Powers et al 2019 Guidelines for Management of AIS e349 1. Prehospital Stroke Management and Systems of Care 1.1. Prehospital Systems 1.2. EMS Assessment and Management 1.2. EMS Assessment and Management COR LOE New, Revised, or Unchanged The use of a stroke assessment tool by first aid providers, including EMS dispatch personnel, is recommended. I B-NR Recommendation reworded for clarity from 2015 CPR/ECC. COR and LOE unchanged. See Table XCV in online Data Supplement 1 for original wording. In 1 study, the positive predictive value for a hospital discharge diagnosis of stroke/transient ischemic attack (TIA) among 900 cases for which EMS dispatch suspected stroke was 51% (95% CI, 47 54), and the positive predictive value for ambulance personnel impression of stroke was 58% (95% CI, 52 64).23 In another study of 21760 dispatches for stroke, the positive predictive value of the dispatch stroke/TIA symptoms identification was 34.3% In both cases, use of a prehospital tool for stroke screening improved stroke identification, but better stroke identification tools are needed in the prehospital setting. See Table I in online Data Supplement 1. EMS personnel should provide prehospital notification to the receiving hospital that a suspected stroke patient is en route so that the appropriate hospital resources may be mobilized before patient arrival. I B-NR Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. In the AHA Get With The Guidelines (GWTG) registry, EMS personnel provided prearrival notification to the destination ED for 67% of transported stroke patients. EMS prenotification was associated with increased likelihood of alteplase treatment within 3 hours (82.8% versus 79.2%), shorter door-to-imaging times (26 minutes versus 31 minutes), shorter DTN times (78 minutes versus 80 minutes), and shorter symptom onset-to-needle times (141 minutes versus See Table I in online Data Supplement 1. 1.1. Prehospital Systems COR LOE New, Revised, or Unchanged Public health leaders, along with medical professionals and others, should design and implement public education programs focused on stroke systems and the need to seek emergency care (by calling 9-1-1) in a rapid manner. These programs should be sustained over time and designed to reach racially/ ethnically, age, and sex diverse populations. I B-NR Recommendation revised from 2013 Stroke Systems of Care. COR and LOE added. Such educational programs should be designed to specifically target the public, physicians, hospital personnel, and emergency medical services (EMS) personnel to increase use of the 9-1-1 EMS system, to decrease stroke onset to emergency department (ED) arrival times, and to increase timely use of thrombolysis and thrombectomy. I C-EO New recommendation. Early stroke symptom recognition is essential for seeking timely care. Unfortunately, knowledge of stroke warning signs and risk factors in the United States remains poor. Blacks and Hispanics particularly have lower stroke awareness than the general population and are at increased risk of prehospital delays in seeking care.20 These factors may contribute to the disparities in stroke outcomes. Available evidence suggests that public awareness interventions are variably effective by age, sex, and racial/ethnic minority status.21 Thus, stroke education campaigns should be designed in a targeted manner to optimize their effectiveness.21 See Tables I and II in online Data Supplement 1. Activation of the 9-1-1 system by patients or other members of the public is strongly recommended. 9-1-1 dispatchers should make stroke a priority dispatch, and transport times should be minimized. I B-NR Recommendation and COR unchanged from 2013 AIS Guidelines. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. EMS use by stroke patients has been independently associated with earlier ED arrival (onset-to-door time 3 hours; adjusted odds ratio [OR], 2.00 [95% CI, 1.93 2.08]), quicker ED evaluation (more patients with door-to-imaging time 25 minutes; OR, 1.89 [95% CI, 1.78 2.00]), more rapid treatment (more patients with door-to-needle [DTN] time 60 minutes; OR, 1.44 [95% CI, 1.28 1.63]), and more eligible patients being treated with alteplase if onset is yet only 60% of all stroke patients use EMS.22 Men, blacks, and Hispanics are less likely to use EMS.20,22 Thus, persistent efforts to ensure activation of the 9-1-1 or similar emergency system by patients or other members of the public in the case of a suspected stroke are warranted. See Table I in online Data Supplement 1. 1.3. EMS Systems 1.3. EMS Systems COR LOE New, Revised, or Unchanged Regional systems of stroke care should be developed. These should consist of the following: (a) healthcare facilities that provide initial emergency care, including administration of IV alteplase, and (b) centers capable of performing endovascular stroke treatment with comprehensive periprocedural care to which rapid transport can be arranged when appropriate. I A Recommendation reworded for clarity from 2015 Endovascular. COR and LOE unchanged. See Table XCV in online Data Supplement 1 for original wording. EMS leaders, in coordination with local, regional, and state agencies and in consultation with medical authorities and local experts, should develop triage paradigms and protocols to ensure that patients with a known or suspected stroke are rapidly identified and assessed by use of a validated and standardized tool for stroke screening. I B-NR Recommendation reworded for clarity from 2013 Stroke Systems of Care. COR and LOE added to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Multiple stroke screening tools have been developed for prehospital evaluation of suspected stroke. A 2016 systematic review assessed the performance of 7 tools.26 Those with the highest number of subjects in whom the tool had been applied included Cincinnati Prehospital Stroke Scale (CPSS),27 Los Angeles Prehospital Stroke Screen Recognition of Stroke in the Emergency Room (ROSIER),29 and FAST (Face, Arm, Speech, Time).30 CPSS and FAST performed similarly with regard to sensitivity (range, 44% 95% for CPSS, 79% 97% for FAST) but both had poor specificity (range, 24% 79% for CPSS, 13% 88% for FAST). More complex tools such as LAPSS had improved specificity (range, 48% 97%) but at the cost of sensitivity (range, 59% 91%). All tools inadequately accounted for false-negative cases, thereby likely artificially boosting performance. The review concluded that no strong recommendation could be made for use of one tool over another. See Tables III and IV in online Data Supplement 1. Patients with a positive stroke screen or who are strongly suspected to have a stroke should be transported rapidly to the closest healthcare facilities that are able to administer IV alteplase. I B-NR Recommendation reworded for clarity from 2013 AIS Guidelines. See Table XCV in online Data Supplement 1 for original wording. The 2013 recommendation referred to initial emergency care as described elsewhere in the guidelines, which specified administration of IV alteplase as part of this care. The current recommendation is unchanged in intent but reworded to make this clear. When several IV alteplase capable hospital options exist within a defined geographic region, the benefit of bypassing the closest to bring the patient to one that offers a higher level of stroke care, including mechanical thrombectomy, is uncertain. IIb B-NR New recommendation. Effective prehospital procedures to identify patients who are ineligible for IV thrombolysis and have a strong probability of large vessel occlusion (LVO) stroke should be developed to facilitate rapid transport of patients potentially eligible for thrombectomy to the closest healthcare facilities that are able to perform mechanical thrombectomy. IIb C-EO New recommendation. At least 6 stroke severity scales targeted at recognition of LVO in the prehospital setting to facilitate transfer to endovascular centers have been published.31 36 The 2018 AHA systematic review on the accuracy of prediction instruments for diagnosing LVO in patients with suspected stroke concluded that No scale predicted LVO with both high sensitivity and high specificity. 4 Specifically, the probability of LVO with a positive LVO prediction test was thought to be only 50% to 60%, whereas >10% of those with a negative test may have an LVO. Thus, more effective tools are needed to identify suspected stroke patients with a strong probability of LVO. All the scales were initially derived from data sets of confirmed stroke cases or selected prehospital cases, and there has been only limited study of their performance in the prehospital setting.37 39 For prehospital patients with suspected LVO by a stroke severity scale, the Mission: Lifeline Severity based Stroke Triage Algorithm for EMS40 recommends direct transport to a comprehensive stroke center if the travel time to the comprehensive stroke center is <15 additional minutes compared with the travel time to the closest primary stroke center or acute stroke-ready hospital. However, at this time, there is insufficient evidence to recommend 1 scale over the other or a specific threshold of additional travel time for which bypass of a primary stroke center or acute stroke-ready hospital is justifiable. Given the known impact of delays to IV alteplase on outcomes,41 the known impact of delays to mechanical thrombectomy on outcome,42 and the anticipated delays in transport for mechanical thrombectomy in eligible patients originally triaged to a nonendovascular center, the Mission: Lifeline algorithm may be a reasonable guideline in some circumstances. Customization of the guideline to optimize patient outcomes will be needed to account for local and regional factors, including the availability of endovascular centers, door in door out times for nonendovascular stroke centers, interhospital transport times, and DTN and door-to-puncture times. Rapid, protected, collaborative, regional quality review, including EMS agencies and hospitals, is recommended for operationalized bypass algorithms. Further research is needed. See Table III in online Data Supplement 1. Powers et al 2019 Guidelines for Management of AIS e351 1.4. Hospital Stroke Capabilities 1.4. Hospital Stroke Capabilities COR LOE New, Revised, or Unchanged Certification of stroke centers by an independent external body, such as Center for Improvement in Healthcare Quality, Det Norske Veritas, Healthcare Facilities Accreditation Program, and The Joint Commission (TJC),* or designation by a state health department, is recommended. *AHA has a cobranded, revenue-generating stroke certification with TJC. I B-NR Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Data support the development of stroke centers to improve patient care and outcomes.43 Differences in stroke quality of care are associated with differences in certifying organization. Between 2010 and 2012, an analysis of 477297 AIS admissions from 977 certified primary stroke centers (73.8% TJC, 3.7% Det Norske Veritas, 1.2% Healthcare Facilities Accreditation Program, and 21.3% state based) participating in AHA GWTG-Stroke was conducted. Composite care quality was generally similar among the 4 groups of hospitals, although state-certified primary stroke centers underperformed TJC-certified primary stroke centers in a few key measures. The rates of alteplase use were higher in TJC- and Det Norske Veritas (9.0% and 9.8%) and lower in state- and Healthcare Facilities Accreditation Program certified hospitals (7.1% and 5.9%; P<0.0001). DTN times were significantly longer in Healthcare Facilities Accreditation Program hospitals. State primary stroke centers had higher in-hospital risk-adjusted mortality (OR, 1.23 [95% CI, 1.07 1.41]) compared with TJC-certified primary stroke centers.44 See Table V in online Data Supplement 1. 1.5. Hospital Stroke Teams 1.5. Hospital Stroke Teams COR LOE New, Revised, or Unchanged An organized protocol for the emergency evaluation of patients with suspected stroke is recommended. I B-NR Recommendation and COR unchanged from 2013 AIS Guidelines. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. Designation of an acute stroke team that includes physicians, nurses, and laboratory/radiology personnel is recommended. Patients with stroke should have a careful clinical assessment, including neurological examination. I B-NR Recommendation wording modified from 2013 AIS Guidelines to match COR I stratifications. COR unchanged. LOE added to conform with ACC/AHA 2015 Recommendation Classification System. Multicomponent quality improvement initiatives, which include ED education and multidisciplinary teams with access to neurological expertise, are recommended to safely increase IV fibrinolytic treatment. I A New recommendation. Multicomponent quality improvement programs to improve stroke care demonstrate clear utility in safely increasing alteplase use in the community hospital setting in multiple settings. The US cluster-randomized INSTINCT trial (Increasing Stroke Treatment Through Interventional Change Tactics) demonstrated increased rates of alteplase use among all stroke patients. In the intervention group hospitals, alteplase use increased from 59 of 5882 (1.00%) before intervention to 191 of 7288 (2.62%) after intervention. This compared favorably with the change in the control group hospitals from 65 of 5957 (1.09%) to 120 of 6989 (1.72%), with a relative risk (RR) of 1.68 (95% CI, 1.09 2.57; P=0.02). Safety was also demonstrated with symptomatic intracranial hemorrhage (within 36 In the PRACTISE trial (Penumbra and Recanalisation Acute Computed Tomography in Ischaemic Stroke Evaluation), a multilevel intervention was conducted in a sample of 12 Dutch hospitals. After implementation of an intensive stroke treatment strategy, intervention hospitals treated 393 patients with IV alteplase (13.1% of all patients with acute stroke) versus 308 (12.2%) at control hospitals (adjusted OR, 1.25 The AVC (Impact of a Training Program and Organization on the Management of Stroke in the Acute Phase) II trial identified a similar magnitude of improvement (adjusted OR, 1.39 [95% CI, 1.01 2.02]) for overall fibrinolytic delivery between intervention and control groups) among 18 emergency units in France using a See Tables VI and VII in online Data Supplement 1. It is recommended that stroke systems of care be developed so that fibrinolytic-eligible patients and mechanical thrombectomy-eligible patients receive treatment in the fastest achievable onset-to-treatment time. I A Recommendation revised from 2013 AIS Guidelines. Treatment of AIS with IV tissue-type plasminogen activator is of proven benefit for select patients given up to 4.5 hours after symptom onset.48,49 Pooled data from RCTs indicate the benefit is greatest when treatment occurs early after stroke onset and declines with time.50 Registry data from AHA GWTG-Stroke hospitals confirm this temporal relationship. In an analysis of 58353 alteplase-treated patients, treatment started more rapidly (evaluated in 15-minute increments) was associated with reduced in-hospital mortality (OR, 0.96 [95% CI, 0.95 0.98]; P<0.001), reduced symptomatic intracerebral hemorrhage (sICH) (OR, 0.96 [95% CI, 0.95 0.98]; P<0.001), increased independent ambulation at discharge (OR, 1.04 [95% CI, 1.03 1.05]; P<0.001), and increased discharge to home (OR, 1.03 [95% CI, 1.02 1.04]; P<0.001). Patient factors most strongly associated with shorter onset-to-treatment times include greater stroke severity, arrival by ambulance, and arrival during regular hours.41 With respect to endovascular treatment, a pooled analysis of 5 randomized trials comparing endovascular therapy (EVT) with medical therapy alone in which the majority of the patients were treated within 6 hours found that the odds of improved disability outcomes at 90 days (as measured by the modified Rankin Scale [mRS] distribution) declined with longer time from symptom onset to arterial puncture.42 The 6- to 16- and 6- to 24-hour treatment windows trials, which used advanced imaging to identify a relatively uniform patient group, showed limited variability of treatment effect with time in these highly The absence of detailed screening logs in these trials limits estimations of the true impact of time in this population. To ensure that the highest proportion of eligible patients presenting in the 6- to 24-hour window have access to mechanical thrombectomy, evaluation and treatment should be as rapid as possible. See Table VIII in online Data Supplement 1. Establishing and monitoring target time goals for ED door-to-treatment IV fibrinolysis time can be beneficial to monitor and enhance system performance. I B-NR New recommendation. In AHA GWTG-Stroke hospitals, median DTN time for IV alteplase administration decreased from 77 minutes (interquartile range, 60 98 minutes) during the 2003 to 2009 preintervention period to 67 minutes (interquartile range, 51 87 minutes) during the 2010 to 2013 postintervention period (P<0.001). The percentage of alteplase-treated patients having DTN times of 60 minutes increased from 26.5% (95% CI, 26.0 27.1) to 41.3% (95% CI, 40.8 41.7; P<0.001). Comparing the quarter immediately before the intervention (quarter 4 of 2009) and the final postintervention quarter (quarter 3 of 2013) showed that DTN times of 60 minutes increased from 29.6% (95% CI, 27.8 31.5) to In a subsequent study evaluating a cohort of hospitals from 2014 to 2015, 59.3% of patients received IV alteplase within a DTN time of 60 minutes.54 See Table IX in online Data Supplement 1. 1.6. Telemedicine COR LOE New, Revised, or Unchanged For sites without in-house imaging interpretation expertise, teleradiology systems approved by the US Food and Drug Administration are recommended for timely review of brain imaging in patients with suspected acute stroke. I A Recommendation revised from 2013 AIS Guidelines. When implemented within a telestroke network, teleradiology systems approved by the US Food and Drug Administration are effective in supporting rapid imaging interpretation in time for IV alteplase administration decision making. I A Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE revised. See Table XCV in online Data Supplement 1 for original wording. Studies of teleradiology to read brain imaging in acute stroke have successfully assessed feasibility; agreement between telestroke neurologists, radiologists, and neuroradiologists over the presence or absence of radiological contraindications to IV alteplase; and reliability of telestroke radiological evaluations. Further support for this unchanged recommendation from the 2013 AIS Guidelines with LOE upgraded to A is provided by 3 additional studies published since the 2013 Guidelines.55 57 See Table X in online Data Supplement 1. The use of telemedicine/telestroke resources and systems should be supported by healthcare institutions, governments, payers, and vendors as one method to ensure adequate 24/7 coverage and care of acute stroke patients in a variety of settings. I C-EO Recommendation reworded for clarity from 2013 Stroke Systems of Care. COR and LOE added to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Telestroke/teleradiology evaluations of AIS patients can be effective for correct IV alteplase eligibility decision making. IIa B-R New recommendation. The STRokEDOC (Stroke Team Remote Evaluation Using a Digital Observation Camera) pooled analysis supported the hypothesis that telemedicine consultations, which included teleradiology, compared with telephone-only resulted in statistically significantly more accurate IV alteplase eligibility decision-making for patients exhibiting symptoms and signs of an acute stroke syndrome in EDs.58 See Table XI in online Data Supplement 1. 1.5. Hospital Stroke Teams (Continued) COR LOE New, Revised, or Unchanged Powers et al 2019 Guidelines for Management of AIS e353 Administration of IV alteplase guided by telestroke consultation for patients with AIS can be beneficial. IIa B-NR New recommendation. A systematic review and meta-analysis was performed to evaluate the safety and efficacy of IV alteplase delivered through telestroke networks in patients with AIS. sICH rates were similar between patients subjected to telemedicine- guided IV alteplase and those receiving IV alteplase at stroke centers. There was no difference in mortality or in functional independence at 3 months between telestroke-guided and stroke center managed patients. The findings indicate that IV alteplase delivery through telestroke networks is safe and effective in the 3-hour time window.59 See Table XII in online Data Supplement 1. Telestroke networks may be reasonable for triaging patients with AIS who may be eligible for interfacility transfer in order to be considered for emergency mechanical thrombectomy. IIb B-NR New recommendation. An observational study compared clinical outcomes of EVT between patients with anterior circulation stroke transferred after teleconsultation and those directly admitted to a tertiary stroke center. The study evaluated 151 patients who underwent emergency EVT for anterior circulation stroke. Of these, 48 patients (31.8%) were transferred after teleconsultation, and 103 (68.2%) were admitted primarily through an ED. Transferred patients were younger, received IV alteplase more frequently, had prolonged time from stroke onset to EVT initiation, and tended to have lower rates of symptomatic intracranial hemorrhage and mortality than directly admitted patients. Similar rates of reperfusion and favorable functional outcomes were observed in patients treated by telestroke and those who were directly admitted. Telestroke networks may enable the triage and the delivery of EVT to selected ischemic stroke patients transferred from remote hospitals.60 See Table XII in online Data Supplement 1. Providing alteplase decision-making support via telephone consultation to community physicians is feasible and safe and may be considered when a hospital has access to neither an in-person stroke team nor a telestroke system. IIb C-LD New recommendation. The advantages of telephone consultations for patients with acute stroke syndromes are feasibility, history of use, simplicity, availability, portability, short consultation time, and facile implementation.61 See Table XIII in online Data Supplement 1. 1.7. Organization and Integration of Components 1.7. Organization and Integration of Components COR LOE New, Revised, or Unchanged All hospitals caring for stroke patients within a stroke system of care should develop, adopt, and adhere to care protocols that reflect current care guidelines as established by national and international professional organizations and state and federal agencies and laws. I C-EO Recommendation unchanged from 2013 Stroke Systems of Care. COR and LOE added to conform with ACC/AHA 2015 Recommendation Classification System. Different services within a hospital that may be transferring patients through a continuum of care, as well as different hospitals that may be transferring patients to other facilities, should establish hand-off and transfer protocols and procedures that ensure safe and efficient patient care within and between facilities. Protocols for interhospital transfer of patients should be established and approved beforehand so that efficient patient transfers can be accomplished at all hours of the day and night. I C-EO Recommendation unchanged from 2013 Stroke Systems of Care. COR and LOE added to conform with ACC/AHA 2015 Recommendation Classification System. Mechanical thrombectomy requires the patient to be at an experienced stroke center with rapid access to cerebral angiography, qualified neurointerventionalists, and a comprehensive periprocedural care team. Systems should be designed, executed, and monitored to emphasize expeditious assessment and treatment. Outcomes for all patients should be tracked. Facilities are encouraged to consider preestablished criteria that can be used to credential individuals who can perform safe and timely intra-arterial revascularization procedures such as those agreed on by the Committee for Advanced Subspecialty Training of the Society of Neurological Surgeons in conjunction with other professional societies.61a I C-EO Recommendation reworded for clarity from 2015 Endovascular. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. It may be useful for primary stroke centers and other healthcare facilities that provide initial emergency care, including administration of IV alteplase, to develop the capability of performing emergency noninvasive intracranial vascular imaging to most appropriately select patients for transfer for mechanical thrombectomy and to reduce the time to mechanical thrombectomy. IIb C-LD Recommendation reworded for clarity from 2015 Endovascular. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Between 2006 and 2010, the proportion of ischemic strokes undergoing computed tomographic angiography (CTA) increased from 3.8% to 9.1% (P<0.0001). Computed tomography perfusion (CTP) increased from 0.05% to 2.9% over the same period (P<0.0001). Reperfusion treatment was more common among those who were imaged with CTA (13.0%) and CTP (17.6%) compared with those with computed tomography (CT) of the head alone (4.0%; P<0.0001).62 However, when considering implementation of multimodal CT imaging at small or remote-access hospitals, resource availability and realistic expectations for gains in efficiency should be taken into account. 1.6. Telemedicine (Continued) COR LOE New, Revised, or Unchanged It may be useful for government agencies and third-party payers to develop and implement reimbursement schedules for patients with acute stroke that reflect the demanding care and expertise that such patients require to achieve an optimal outcome, regardless of whether they receive a specific medication or procedure. IIb C-EO Recommendation revised from 2013 Stroke Systems of Care. Multiple studies evaluating fibrinolytic therapy and mechanical thrombectomy, alone or in combination, have demonstrated substantial societal economic value for acute stroke treatment across multiple countries. Pre mechanical thrombectomy era data demonstrate that, in the United States, cost savings of approximately US $30 million would be realized if the proportion of all ischemic stroke patients receiving IV alteplase was increased to 8%. This excludes any gain from increased quality-adjusted life-years gained, a source of tremendous additional economic and patient value. Before the implementation of Centers for Medicare & Medicaid Services Diagnosis-Related Group 559 payment in 2005, treatment of acute stroke was economically discouraged at a hospital level because of a high hospital cost-reimbursement ratio. Diagnosis-Related Group 559 favorably altered the cost-reimbursement ratio for stroke care. In a single-hospital study, this ratio decreased from 1.41 (95% CI, 0.98 2.28) before Diagnosis-Related Group 559 to 0.82 (95% CI, 0.66 0.97) after Diagnosis-Related Group 559. The subsequent years corresponded to a period of rapid growth in the number of primary stroke centers and increasing total stroke treatment cases. Addressing economic barriers to treatment is important as acute stroke care complexity evolves.63 68 1.8. Establishment of Data Repositories 1.8. Establishment of Data Repositories COR LOE New, Revised, or Unchanged Participation in a stroke data repository is recommended to promote consistent adherence to current treatment guidelines, to allow continuous quality improvement, and to improve patient outcomes. I B-NR Recommendation reworded for clarity from 2013 AIS Guidelines. COR and LOE added to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Participation in a stroke data repository as one part of a quality improvement process was associated with improved IV alteplase administration after AIS,68a,68b lower in-hospital mortality68b,68c and intracranial hemorrhage rates, and an increase in the percentage of patients discharged home.53,69,69a See Table XIV in online Data Supplement 1. 1.9. Stroke System Care Quality Improvement Process 1.9. Stroke System Care Quality Improvement Process COR LOE New, Revised, or Unchanged Healthcare institutions should organize a multidisciplinary quality improvement committee to review and monitor stroke care quality benchmarks, indicators, evidence-based practices, and outcomes. The formation of a clinical process improvement team and the use of a stroke care registry are helpful for such quality of care assurances. The data repository can be used to identify the gaps or disparities in quality stroke care. Once the gaps have been identified, specific interventions can be initiated to address these gaps or disparities. I B-NR Recommendation reworded for clarity from 2013 AIS Guidelines. COR and LOE added where missing in part of recommendation. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. A multidisciplinary quality improvement committee, as 1 part of a quality improvement process, was associated with improved timeliness of IV alteplase administration after AIS, lower in-hospital mortality and intracranial hemorrhage rates, and an increase in the percentage of patients discharged home.53,69 Identification of stroke treatment barriers with targeted interventions has demonstrated benefit in improving stroke treatment in community hospitals.45 See Tables VI, VII, and XIV in online Data Supplement 1. 2. Stroke outcome measures should include adjustments for baseline severity. I B-NR Recommendation revised from 2013 Stroke Systems of Care. COR and LOE added to conform with ACC/AHA 2015 Recommendation Classification System. Continuous quality improvement processes, implemented by each major element of a stroke system of care and the system as a whole, can be useful in improving patient care or outcomes. IIa B-NR Recommendation revised from 2013 Stroke Systems of Care. COR and LOE added to conform with ACC/AHA 2015 Recommendation Classification System. Data indicate that continuous quality improvement efforts along the stroke spectrum of care, from initial patient identification to EMS activation, ED evaluation, stroke team activation, and poststroke care, can be useful in improving Stroke outcome measures are strongly influenced by baseline stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS).70 73 Other identified predictors of poor outcomes include age, blood glucose, and infarct on imaging.73 Quality improvement efforts should recognize these predictors in order to have meaningful comparisons between stroke care systems. See Tables VI, VII, XIV, and XV in online Data Supplement 1. 1.7. Organization and Integration of Components (Continued) COR LOE New, Revised, or Unchanged Powers et al 2019 Guidelines for Management of AIS e355 2. Emergency Evaluation and Treatment 2.1. Stroke Scales 2.1. Stroke Scales COR LOE New, Revised, or Unchanged The use of a stroke severity rating scale, preferably the NIHSS, is recommended. I B-NR Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Formal stroke scores or scales such as the NIHSS (Table 4) may be performed rapidly, have demonstrated utility, and may be administered by a broad spectrum of healthcare providers with accuracy and reliability.75,76 Use of a standardized scale quantifies the degree of neurological deficit, facilitates communication, helps identify patients for fibrinolytic or mechanical intervention, allows objective measurement of changing clinical status, and identifies those at higher risk for complications such as intracerebral hemorrhage (ICH).71 73,77 See Table XV in online Data Supplement 1. Table 4. National Institutes of Health Stroke Scale Tested Item Title Responses and Scores 1A Level of consciousness 0 Answers both correctly 2 Answers neither correctly 1C Response to 0 Performs both tasks correctly movements 1 Partial gaze palsy 2 Complete gaze palsy 3 Visual fields 0 No visual field defect 1 Minor facial weakness 2 Partial facial weakness 3 Complete unilateral palsy 5 Motor function (arm) a. Left 1 Drift before 10 s b. Right 2 Falls before 10 s 3 No effort against gravity 6 Motor function (leg) 0 No drift a. Left 1 Drift before 5 s b. Right 2 Falls before 5 s 3 No effort against gravity 7 Limb ataxia 0 No ataxia 8 Sensory 0 No sensory loss 1 Mild sensory loss 2 Severe sensory loss 3 Mute or global aphasia 11 Extinction or inattention modality lost) lost) Adapted from Lyden et al.74 Copyright 1994, American Heart Association, Inc. Table 4. Continued Tested Item Title Responses and Scores 2.2. Head and Neck Imaging 2.2.1. Initial Imaging COR LOE New, Revised, or Unchanged All patients with suspected acute stroke should receive emergency brain imaging evaluation on first arrival to a hospital before initiating any specific therapy to treat AIS. I A Recommendation reworded for clarity from 2013 AIS Guidelines. COR and LOE unchanged. See Table XCV in online Data Supplement 1 for original wording. Systems should be established so that brain imaging studies can be performed as quickly as possible in patients who may be candidates for IV fibrinolysis or mechanical thrombectomy or both. I B-NR New recommendation. The benefit of IV alteplase is time dependent, with earlier treatment within the therapeutic window leading to bigger A brain imaging study to exclude ICH is recommended as part of the initial evaluation of patients who are potentially eligible for these therapies. With respect to endovascular treatment, a pooled analysis of 5 randomized trials comparing EVT with medical therapy alone in which the majority of the patients were treated within 6 hours found that the odds of improved disability outcomes at 90 days (as measured by the mRS score distribution) declined with longer time from symptom onset to arterial puncture.42 treatment windows trials, which used advanced imaging to identify a relatively uniform patient group, showed limited variability of treatment effect with time in these highly selected patients.51,52 The absence of detailed screening logs in these trials limits estimations of the true impact of time in this population. To ensure that the highest proportion of eligible patients presenting in the 6- to 24-hour window have access to mechanical thrombectomy, evaluation and treatment should be as rapid as possible. Reducing the time interval from ED presentation to initial brain imaging can help to reduce the time to treatment initiation. Studies have shown that median or mean door-to-imaging times of 20 minutes can be achieved in a variety of different hospital settings.79 81 See Tables XVI and XVII in online Data Supplement 1. Noncontrast CT (NCCT) is effective to exclude ICH before IV alteplase administration. I A Recommendation revised from 2013 AIS Guidelines. Magnetic resonance (MR) imaging (MRI) is effective to exclude ICH before IV alteplase administration. I B-NR Recommendation revised from 2013 AIS Guidelines. CTA with CTP or MR angiography (MRA) with diffusion-weighted magnetic resonance imaging (DW-MRI) with or without MR perfusion is recommended for certain patients. I A New recommendation. In many patients, the diagnosis of ischemic stroke can be made accurately on the basis of the clinical presentation and either a negative NCCT or one showing early ischemic changes, which can be detected in the majority of patients with careful attention.82,83 NCCT scanning of patients with acute stroke is effective for the rapid detection of acute ICH. NCCT was the only neuroimaging modality used in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA (Recombinant Tissue-Type Plasminogen Activator) trials and in ECASS (European Cooperative Acute Stroke Study) III and is therefore sufficient neuroimaging for decisions about IV alteplase in most patients.48,49 Immediate CT scanning provides high value for patients with acute stroke.84,85 MRI was as accurate as NCCT in detecting hyperacute intraparenchymal hemorrhage in patients presenting with stroke symptoms within 6 hours of onset when gradient echo sequences were used.86,87 In patients who awake with stroke or have unclear time of onset >4.5 hours from baseline or last known well, MRI to identify diffusion-positive fluid-attenuated inversion recovery (FLAIR) negative lesions can be useful for selecting those who can benefit from IV alteplase administration within 4.5 hours of stroke symptom CTA with CTP or MRA with DW-MRI with or without MR perfusion is useful for selecting candidates for mechanical thrombectomy between 6 and 24 hours after last known well.51,52 See specific recommendations below. See Tables XVII through XX in online Data Supplement 1. 2.2.2. IV Alteplase Eligibility COR LOE New, Revised, or Unchanged Administration of IV alteplase in eligible patients without first obtaining MRI to exclude cerebral microbleeds (CMBs) is recommended. I B-NR New recommendation. CMBs are common in patients receiving IV alteplase, occurring in 15% to 27%.89 94 Such patients were undoubtedly included in the pivotal NINDS and ECASS III trials that established the benefits of IV alteplase treatment.48,49 Two meta- analyses of the association of baseline CMBs and the risk of sICH after IV alteplase reported that sICH is more common in patients with baseline CMBs, whereas 2 other meta-analyses and 1 multicenter study did not.89 93 In 2 studies using ECASS II sICH criteria, the rates in patients with CMBs were 5.8% and 6.5% compared with 5.3% in ECASS III.49,90,91 One study analyzing the risk of sICH in patients with CMBs detected after IV alteplase treatment reported sICH of 5% using the NINDS criteria compared with 6.4% in the NINDS tPA trials.48,94 The risk of sICH in patients with >10 CMBs (30% 47%) is consistently reported as significantly greater than in those with no CMBs (1% 4.4%). However, these data are based on <50 patients, constituting <2% of these series.90,91,93,94 No RCTs of IV alteplase in AIS with baseline MRI to identify CMBs have been conducted, so no determination of the effect of baseline CMB on the treatment effect of alteplase with CMB is available. In the absence of direct evidence that IV alteplase provides no benefit or produces harm in eligible patients with CMBs, withholding treatment on the basis of the presence of CMBs could lead to the exclusion of patients who would benefit from treatment. See Table XXI in online Data Supplement 1. Powers et al 2019 Guidelines for Management of AIS e357 In patients eligible for IV alteplase, because benefit of therapy is time dependent, treatment should be initiated as quickly as possible and not delayed for additional multimodal neuroimaging, such as CT and MRI perfusion imaging. I B-NR New recommendation. NCCT was the only neuroimaging modality used in the NINDS rt-PA trial and in ECASS III and is therefore sufficient neuroimaging for decisions about IV alteplase in most patients.48,49 Multimodal CT and MRI, including diffusion and perfusion imaging, are not necessary when the diagnosis of ischemic stroke is very likely, and their performance may delay time-sensitive administration of IV alteplase. In some cases, particularly when there is substantial diagnostic uncertainty, advanced imaging may be beneficial. See Table XX in online Data Supplement 1. In patients with AIS who awake with stroke symptoms or have unclear time of onset > 4.5 hours from last known well or at baseline state, MRI to identify diffusion-positive FLAIR-negative lesions can be useful for selecting those who can benefit from IV alteplase administration within 4.5 hours of stroke symptom recognition. IIa B-R New recommendation. The WAKE-UP trial (Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke) randomized 503 patients with AIS who awoke with stroke or had unclear time of onset >4.5 hours from last known well and could be treated with IV alteplase within 4.5 hours of stroke symptom recognition. Eligibility required MRI mismatch between abnormal signal on DW-MRI and no visible signal change on FLAIR. DW-MRI lesions larger than one-third of the territory of the middle cerebral artery (MCA), NIHSS score >25, contraindication to treatment with alteplase, or planned thrombectomy were all exclusions. The trial was terminated early for lack of funding before the designated 800 patients were randomized. Ninety-four percent were wake-up strokes. Median NIHSS score was 6. Median time from last known well was slightly over 10 hours. At baseline, one-third of the patients had vessel occlusion on time-of-flight MRA, and three-quarters of the FLAIR lesions were <9 mL. The end point of an mRS score of 0 to 1 at 90 days was achieved in 53.3% of the IV alteplase group and in 41.8% of the placebo group (P=0.02).88 See Table XIX in online Data Supplement 2.2.3. Mechanical Thrombectomy Eligibility Vessel Imaging COR LOE New, Revised, or Unchanged For patients who otherwise meet criteria for mechanical thrombectomy, noninvasive vessel imaging of the intracranial arteries is recommended during the initial imaging evaluation. I A Recommendation reworded for clarity from 2015 Endovascular. COR and LOE unchanged. See Table XCV in online Data Supplement 1 for original wording. For patients with suspected LVO who have not had noninvasive vessel imaging as part of their initial imaging assessment for stroke, noninvasive vessel imaging should then be obtained as quickly as possible (eg, during alteplase infusion if feasible). I A Recommendation revised from 2015 Endovascular. COR and LOE unchanged. A recent systematic review evaluated the accuracy of prediction instruments for diagnosing LVO.4 In the setting where confirmed ischemic stroke patients would be assessed by a neurologist or emergency physician in the ED, the authors suggested that the NIHSS score is the best of the LVO prediction instruments. According to their meta-analysis, a threshold of 10 would provide the optimal balance between sensitivity (73%) and specificity (74%). To maximize sensitivity (at the cost of lower specificity), a threshold of 6 would have 87% sensitivity and 52% specificity. However, even this low threshold misses some cases with LVO, whereas the low specificity indicates that false- positives will be common. The sensitivity of CTA and MRA compared with the gold standard of catheter angiography ranges from 87% to 100%, with CTA having greater accuracy than MRA.95,96 Pivotal trials of mechanical thrombectomy all required noninvasive CTA or MRA diagnosis of LVO as an inclusion criterion. See Tables XVII and XXII in online Data Supplement 1. In patients with suspected intracranial LVO and no history of renal impairment, who otherwise meet criteria for mechanical thrombectomy, it is reasonable to proceed with CTA if indicated before obtaining a serum creatinine concentration. IIa B-NR New recommendation. Analyses from a number of observational studies suggest that the risk of contrast-induced nephropathy secondary to CTA imaging is relatively low, particularly in patients without a history of renal impairment. Moreover, waiting for these laboratory results may lead to delays in mechanical thrombectomy.97 102 See Table XXIII in online Data Supplement 1. In patients who are potential candidates for mechanical thrombectomy, imaging of the extracranial carotid and vertebral arteries, in addition to the intracranial circulation, may be reasonable to provide useful information on patient eligibility and endovascular procedural planning. IIb C-EO New recommendation. Knowledge of vessel anatomy and presence of extracranial vessel dissections, stenoses, and occlusions may assist in planning endovascular procedures or identifying patients ineligible for treatment because of vessel tortuosity or inability to access the intracranial vasculature. 2.2.2. IV Alteplase Eligibility (Continued) COR LOE New, Revised, or Unchanged It may be reasonable to incorporate collateral flow status into clinical decision-making in some candidates to determine eligibility for mechanical thrombectomy. IIb C-LD Recommendation revised from 2015 Endovascular. Several studies, including secondary analyses from MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for AIS in the Netherlands) and IMS (Interventional Management of Stroke) III, provide data supporting the role of collateral assessments in identifying patients likely or unlikely to benefit from mechanical thrombectomy.103,104 The ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times), using multiphase CTA to select patients with moderate to good collateral circulation for mechanical thrombectomy up to 12 hours from onset, was stopped early for efficacy.105 Acquisition of advanced imaging should not delay door to groin puncture times. See Tables XXIV and XXV in online Data Supplement 1. 2.2.4. Mechanical Thrombectomy Eligibility Multimodal Imaging COR LOE New, Revised, or Unchanged When selecting patients with AIS within 6 to 24 hours of last known normal who have LVO in the anterior circulation, obtaining CTP or DW-MRI, with or without MRI perfusion, is recommended to aid in patient selection for mechanical thrombectomy, but only when patients meet other eligibility criteria from one of the RCTs that showed benefit from mechanical thrombectomy in this extended time window. I A New recommendation. The DAWN trial (Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) used clinical-core mismatch (a combination of age-adjusted NIHSS score and age-adjusted core infarct size on CTP or DW-MRI) as an eligibility criterion to select patients with large anterior circulation vessel occlusion for mechanical thrombectomy between 6 and 24 hours from last known normal. This trial demonstrated an overall benefit in functional outcome at 90 days in the treatment group (mRS score 0 2, 49% versus 13%; adjusted difference, 33% [95% CI, 21 44]; posterior probability of superiority >0.999).51 The DEFUSE 3 trial (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) used perfusion-core mismatch and maximum core size as imaging criteria to select patients with large anterior circulation occlusion 6 to 16 hours from last seen well for mechanical thrombectomy. This trial showed a benefit in functional outcome at 90 days in the treated group (mRS score 0 2, Benefit was independently demonstrated for the subgroup of patients who met DAWN eligibility criteria and for the subgroup who did not. DAWN and DEFUSE 3 are the only RCTs showing benefit of mechanical thrombectomy >6 hours from onset. Therefore, only the eligibility criteria from one or the other of these trials should be used for patient selection. Although future RCTs may demonstrate that additional eligibility criteria can be used to select patients who benefit from mechanical thrombectomy, at this time, the DAWN or DEFUSE 3 eligibility should be strictly adhered to in clinical practice.51,52 See Table XVII in online Data Supplement 1. When evaluating patients with AIS within 6 hours of last known normal with LVO and an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 6, selection for mechanical thrombectomy based on CT and CTA or MRI and MRA is recommended in preference to performance of additional imaging such as perfusion studies. I B-NR New recommendation. 