A Transformational Era in Stroke Care
The 2018 guidelines for treatment of acute ischemic stroke reflect great advances in patient care.
The goal of the 2018 American Heart Association (AHA)/American Stroke Association (ASA) Acute Stroke Guidelines is to provide a comprehensive set of recommendations for health professionals who care for patients with acute ischemic stroke. There have been major changes in the treatment of patients with acute ischemic stroke since the previous guidelines were published in 2013, primarily around advances in endovascular therapy for treatment of acute stroke. The guidelines address prehospital care, emergency evaluation, treatment with intravenous (IV) and intra-arterial (IA) therapies, in-hospital management, and secondary prevention measures. There has been extensive conversation within the stroke community regarding the guideline format and content that has led to the ongoing revision of the guidelines.
The guidelines provide recommendations to promote prehospital stroke management and systems of care and increase use of acute stroke therapies (Box 1). Prehospital stroke screening and implementation of a stroke protocol by emergency medical services (EMS) is recommended. Although since an AHA update on endovascular therapy in 2015, prehospital stroke identification has focused on screening for large vessel occlusion (LVO), there is still not enough evidence for recommendation of a specific LVO screening tool. The recommendation remains to rapidly transport patients to the closest facility that is able to administer IV thrombolytics, but uncertainty still exists regarding the optimal triage and bypass algorithm for patients with potential LVO, which will likely be region-specific.
Emergency Department Care and Stroke Specialty Guidance
The guidelines recommend deploying an organized team using a standardized protocol for emergent evaluation of suspected stroke with a primary goal of being able to administer IV tissue plasminogen activator (t-PA) as quickly and safely as possible and preferably with a door-to-needle time ≤ 45 minutes in ≥50% of patients who need treatment. The 2018 guidelines comment on the use of FDA-approved teleradiology when in-house radiologists are not available and discuss how remote solutions can help improve care when on-site expertise is unavailable. Telemedicine consultations result in significantly more accurate decision making about eligibility for IV thrombolytics for patients with signs and symptoms of acute stroke in the emergency department (ED)compared to telephone-only consultations.1 There are also data to show that telestroke consultation and guidance for administration of IV t-PA guided for patients with acute ischemic stroke may be as safe and as beneficial as that of an in-person neurologist at stroke centers.2 These data are from a systematic review and meta-analysis that revealed symptomatic intracerebral hemorrhage rates were similar with no difference in mortality or functional independence 3 months after an acute stroke when comparing cases guided by telestroke services versus those managed within a stroke center. Telestroke networks also have the benefit of helping to triage patients with acute ischemic stroke who may be eligible for transfer in order to be considered for acute mechanical thrombectomy. Key points of the initial evaluation are shown in Box 2.
Administration of Thrombolytics
The recommended thrombolytic is IV t-PA for selected patients with ischemic stroke who present within 3 hours of symptom onset or since they were last known to be well (Box 3). In selected patients without contraindications, this window can be extended from 3 to 4.5 hours. Benefits of IV t-PA are not specific to age or to stroke severity. Patients taking warfarin with an international normalized ratio (INR) <1.7 and those with a combined history of diabetes and stroke should be considered for IV t-PA. The guidelines specifically comment on other patient factors that should not be considered as reasons for exclusion from IV t-PA treatment, including mild but disabling stroke symptoms, extracranial cervical arterial dissections, small number (≤10) of cortical microbleeds, and small or moderate-sized (≤10 mm) unruptured unsecured intracranial aneurysms. The guidelines clarify that IV t-PA is potentially harmful in patients with intra-axial intracranial neoplasms and maintains the prior warning of potential harm to patients with history of intracranial hemorrhage.
It is critical not to delay initiation of IV t-PA. Diagnostic testing other than the head computed tomogram (HCT) should be individualized, and only assessment of glucose levels must precede IV t-PA. Other tests such as INR, prothrombin time (PTT), or platelet count results are only necessary if there is suspicion of coagulopathy. Baseline electrocardiogram (EKG) and cardiac troponin levels are recommended but should not delay treatment. The utility of chest radiographs is uncertain. In a cohort study comparing patients with acute ischemic stroke who did or did not have a chest x-ray, treatment was delayed in patients who had a chest x-ray without any change in the occurrence of cardiopulmonary events.3 If the patient is unable to consent and a surrogate is unavailable, it is justifiable to proceed with IV t-PA in an otherwise eligible patient. The use of sonothrombolysis as adjuvant therapy with IV thrombolysis is not recommended, as it has not shown clinical benefit.4
The guidelines make new recommendations for patient eligibility for IV t-PA and subsequent management as well as systems that allow brain imaging studies within 20 minutes of arrival in the ED in at least 50% of patients who may be candidates for IV t-PA and mechanical thrombectomy. Because the benefit of IV t-PA and thrombectomy is time-dependent, reducing time from arrival to imaging can improve door-to-treatment time. The primary goal of an immediate HCT is to exclude intracranial hemorrhage. Routine use of MRI to exclude cerebral microbleeds is not recommended. Blood pressure prior to administration of IV t-PA should be <185/110 and <180/105 for 24 hours after administration based on data suggesting a higher hemorrhage risk with higher blood pressures and blood pressure variability. The exact blood pressure that increases this risk is unknown,5 as is the optimal blood pressure that should be maintained for best outcomes in patients with ischemic stroke.
Multiple randomized trials have shown benefit from thrombectomy, consistent across age groups, at up to 24 hours after symptom onset and key points are in Box 4.6,7 After IV t-PA is administered, the patient should proceed to thrombectomy immediately without observation for clinical effect of t-PA. Benefits of thrombectomy are time-dependent and treatment delays may worsen outcomes. Stent retrievers are the preferred devices for mechanical thrombectomy, and the thrombolysis in cerebral infarction (TICI) scale is used to determine the degree of perfusion seen, with TICI 3 defined as complete perfusion. The goal of thrombectomy is to achieve TICI 2b/3 reperfusion as early as possible, because better outcomes are associated with faster times to reperfusion.8 The optimal blood pressure with intra-arterial therapy is unknown. Randomized controlled trials largely excluded patients with blood pressure of greater than 185/110. Therefore, it is reasonable to use <185/110 as a guideline.
Large Vessel Occlusion
Although there is need and urgency to identify patients with LVO that means many patients have additional vascular or perfusion imaging (eg, CT-angiogram [CTA] or CT-perfusion [CTP]) upon arrival to the hospital, this also should not delay IV t-PA treatment. For patients who present after the 3- to 4.5-hour treatment window for t-PA, use of imaging to select acute stroke cases for IV thrombolytic treatment is not recommended. For patients who otherwise meet criteria for endovascular treatment, it is reasonable to proceed with CTA to assess for LVO. A CTA is necessary because clinical prediction of LVO is imprecise. Creatinine levels do not need be obtained prior to CTA.
Although the National Institute of Health Stroke Scale (NIHSS) is the best instrument to help assess for LVO, even a cut-off of 6 on the NIHSS can miss cases of LVO.9 Advanced imaging can help select patients for thrombectomy within 6 to 24 hours before symptom onset or when the patients were last known to be well. Otherwise, selection criteria for mechanical thrombectomy in patients who present less than 6 hours from their last normal has not changed.
For 2 recent randomized controlled trials, DEFUSE 3a and DAWNb, CT perfusion/MR perfusion or diffusion-weighted imaging (DWI) was used to select patients with salvageable brain tissue despite a prolonged time since they were last known to be well. Ideal patients in this cohort have small infarct cores with large areas of penumbra (Figure) and are thought to have a significant amount of salvageable brain tissue. Patients in these trials were randomized to thrombectomy versus no-thrombectomy, and both trials showed a large benefit for thrombectomy.
The guidelines offer updates regarding antiplatelet management in acute ischemic stroke. Aspirin is not recommended as a substitute for acute stroke treatment in patients who are otherwise eligible for IV t-PA or mechanical thrombectomy. In patients presenting with minor stroke, 21 days of treatment with the dual antiplatelet therapy (aspirin and clopidogrel) begun within 24 hours of symptom onset can be beneficial for early secondary stroke prevention for up to 90 days.10 In a recent randomized trial performed in 10 countries including the US, patients with a minor stroke or high-risk transient ischemic attack (TIA) who were treated with combination therapy of clopidogrel and aspirin had a reduced rate of major ischemic events compared to those who received aspirin alone.11 In a secondary analysis by time period, the benefit of clopidogrel plus aspirin was greater in the first 7 days and in the first 30 days than at 90 days. Ticagrelor is not recommended over aspirin in the acute treatment of patients with minor stroke, although it may be a reasonable alternative in stroke patients who have a contraindication to aspirin.12
Treatment of Acute Complications
The updated guidelines also addressed the treatment of acute complications in patients with acute ischemic stroke including cerebral and cerebellar edema. Decompressive suboccipital craniectomy with dural expansion should be performed in patients with cerebellar infarction causing neurological deterioration from brainstem compression despite maximal medical therapy.13 Patients with large territorial supratentorial infarctions are at high risk for complicating brain edema and increased intracranial pressure. Timely decompressive surgery has been shown to reduce mortality.14 There is evidence that persistent morbidity is common, and individual discussions about end-of-life care and the degree of treatment performed in the face of severe neurological injury must be considered.
In summary, there have been extensive updates to the most recent edition of the acute ischemic stroke guidelines. The guidelines try to be as comprehensive as possible commenting about all aspects of acute ischemic stroke care, while adding sections that address paradigm-shifting endovascular therapies. Endovascular therapy has revolutionized stroke care, with improving outcomes and decreasing disability in patients who previously were left neurologically devastated from strokes.
1. Demaerschalk BM, Raman R, Ernstrom K, Meyer BC. Efficacy of telemedicine for stroke: pooled analysis of the Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC) and STRokE DOC Arizona telestroke trials. Telemed J E Health. 2012;18:230-237.
2. Kepplinger J, Barlinn K, Deckert S, et al. Safety and efficacy of thrombolysis in telestroke: a systematic review and meta-analysis. Neurology. 2016;87:1344-1351.
3. Saber H, Silver B, Santillan A, et al. Role of emergent chest radiography in evaluation of hyperacute stroke. Neurology. 2016;87:782-785.
4. 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;48:335-341.
5. Butcher K, Christensen S, Parsons M, et al. Postthrombolysis blood pressure elevation is associated with hemorrhagic transformation. Stroke. 2010;41:72-77.
6. 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;378:11-21.
7. Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke with perfusion imaging selection at 6-16 hours. N Engl J Med. 2018;378:708-718.
8. Smith EE, Kent DM, Bulsara KR, et al. Accuracy of prediction instruments for diagnosing large vessel occlusion in individuals with suspected stroke: a systematic review for the 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;49e111-e112.
9. Marks MP, Lansberg MG, Mlynash M, et al. Correlation of AOL recanalization, TIMI reperfusion and TICI reperfusion with infarct growth and clinical outcome. J Neurointerv Surg. 2014;6:724-728.
10. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11-19.
11. Johnston SC, Easton JD, Farrant M, Barsan W. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018:Published online May 18. doi: 10.1056/NEJMoa1800410
12. Johnston SC, Amarenco P. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med. 2016;375:1395.
13. Raco A, Caroli E, Isdori A, Salvati M. Management of acute cerebellar infarction: one institution’s experience. Neurosurgery. 2003;53:1061-1605.
14. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomized controlled trials. Lancet Neurol. 2007;6:215-222.
a Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (NCT 02586415)
b DAWN, Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo (NCT 02142283)
Donna K. George, MD
Assistant Professor of Clinical Neurology
Associate Director of Vascular Neurology Fellowship
Department of Neurology
University of Pennsylvania
The author has no relevant financial relationships to disclose.