Acute ischemic stroke is a leading cause of morbidity and mortality in the United States, and a majority of acute ischemic stroke patients are evaluated for the first time by a clinician in the emergency department. Intravenous tissue plasminogen activator and mechanical thrombectomy are powerful tools for the treatment of acute ischemic stroke. Treatment algorithms for acute ischemic stroke are evolving rapidly, and strokes in select patients can now be treated up to 24 hours after last known well time. However, even in the setting of extended treatment times, the treatment effects of both intravenous tissue plasminogen activator and mechanical thrombectomy are time dependent. The emergency clinician must remain current with the newest treatment algorithms in order to provide expeditious and high-quality care to stroke patients.
Stroke currently ranks fifth among all causes of death in the United States, where a stroke occurs on average every 40 seconds, with an incidence of approximately 795,000 acute strokes every year.1 Of these, the majority are ischemic strokes (87%), with the remainder comprised of hemorrhagic strokes and subarachnoid hemorrhages.1 The incidence of stroke has decreased over time,2 likely due to strong national efforts to improve control of vascular risk factors in outpatient settings. Despite this, the prevalence is expected to increase by 3.4 million individuals by the year 2030, based on projections from data obtained through the National Health and Nutrition Examination Survey (NHANES) and the United States Census Bureau.3 One likely explanation for this observation is the aging population in the United States, as stroke risk increases with age. This rise in stroke prevalence results in a tremendous financial burden, and it is projected that between 2012 and 2030, total direct medical stroke-related costs will more than double, from $71.55 billion to $184.13 billion.3
In 1995, intravenous tissue plasminogen activator (IV tPA) was approved by the United States Food and Drug Administration (FDA) for the treatment of acute ischemic stroke (AIS), after the National Institute of Neurological Disorders and Stroke (NINDS) demonstrated significant improvement in clinical outcomes with IV tPA.4 More recently, endovascular stroke treatment with mechanical thrombectomy has proven to be a powerful and effective therapy as well, allowing select patients to be treated in an extended time window beyond 0 to 3 hours after last known well time.5-11 Despite this extended time window, the effects of both IV tPA and mechanical thrombectomy remain time dependent. A meta-analysis evaluating 9 randomized phase III trials comparing IV tPA to placebo found that earlier treatment with IV tPA increased the odds of a good clinical outcome (defined in the study as no significant disability at 3-6 months, as indicated by a modified Rankin Score of 0 or 1).12 Similarly, a meta-analysis evaluating 5 randomized phase III trials comparing mechanical thrombectomy and medical therapy to medical therapy alone found that earlier treatment with mechanical thrombectomy was associated with lower degrees of poststroke disability.13
In the majority of cases, the initial evaluation of a patient with AIS will occur in the emergency department (ED). In 2015, 640,000 ED visits had stroke as the principal diagnosis.1 Given the time-dependent nature of the treatments that have been proven to improve outcomes significantly in patients presenting with AIS, it is important for emergency clinicians to be able to evaluate these patients rapidly for appropriate treatment.
A literature search was performed in PubMed, using the search terms stroke, acute ischemic stroke, intravenous tissue plasminogen activator, tPA, mechanical thrombectomy, endovascular stroke treatment, perfusion imaging, NIHSS, and modified Rankin Scale. Given the narrow focus of this article on management of AIS after 3 hours from last known well time, articles published after 1995 were primarily reviewed. The Cochrane Database of Systematic Reviews yielded 71 reviews from the search term acute ischemic stroke. The 2018 American Heart Association/American Stroke Association (AHA/ASA) Guidelines for the Early Management of Patients With Acute Ischemic Stroke14 as well as the 2019 AHA/ASA update15 to the 2018 guidelines were reviewed. Both guidelines provided rigorous, evidence-based recommendations. The AHA/ASA Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke16 was also reviewed.
Guidelines for the treatment of AIS are typically derived from multicenter randomized controlled trials. In many cases, subsequent pooled analysis of multiple randomized trials has been performed. Though there is strong evidence supporting the treatment of AIS in specific patient populations enrolled in those particular trials, evidence is lacking for the patient populations not included. For example, mechanical thrombectomy trials after 6 hours only included patients with a causative occlusion of the intracranial internal carotid artery or the M1 segment of the middle cerebral artery; there are only observational or case report studies evaluating the utility of mechanical thrombectomy in more-distal occlusions. In this review, AHA/ASA recommendations are noted when indicated, as are areas of uncertainty in the literature.
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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 is included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.
4. * 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; 624 patients) DOI: 10.1056/NEJM199512143332401
5. * 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. (Randomized trial; 500 patients) DOI: 10.1056/NEJMoa1411587
10. * Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selec-tion by perfusion imaging. N Engl J Med. 2018;378(8):708-718. (Multicenter, randomized, open-label trial, with blinded outcome assessment; 182 patients, 92 to the endovascular-therapy group and 90 to the medical-therapy group).) DOI: 10.1056/NEJMoa1713973
11. * 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. (Randomized controlled trial; 206 patients) DOI: 10.1056/NEJMoa1706442
15. * Powers WJ, Rabinstein AA, Ackerson T, et al. 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(12):e344-e418. (Guidelines) DOI: 10.1161/STR.0000000000000211
24. * 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 trial; 821 patients) DOI: 10.1056/NEJMoa0804656
25. * 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. (Multicenter randomized controlled trial; 503 patients) DOI: 10.1056/NEJMoa1804355
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Keywords: acute ischemic stroke, AIS, intravenous tissue plasminogen activator, tPA, mechanical thrombectomy, endovascular stroke treatment, perfusion imaging, NIHSS, modified Rankin scale, mRS, cerebral bloodflow, CBF, computed tomography, CT, magnetic resonance imaging, MRI, National Institute of Neurological Disorders and Stroke, NINDS, blood pressure, glucose, coagulopathy, European Cooperative Acute Stroke Study III, ECASS III, National Institutes of Health Stroke Scale, NIHSS, Alberta Stroke Program Early CT Score, ASPECTS, computed tomographic angiography, CTA, magnetic resonance angiography, MRA, large-vessel occlusion, diffusion-weighted imaging, DWI, computed tomographic perfusion, CTP, DAWN, DEFUSE 3, WAKE-UP, wake-up stroke, fluid-attenuated inversion recovery, FLAIR, neurology, intensive care unit, ICU
James Pham Ho, MD
Rhonda Cadena, MD; Holly K. Ledyard, MD, MS
June 15, 2021
June 15, 2024
4 AMA PRA Category 1 Credits.™ Specialty CME Credits: Included as part of the 4 credits, this CME activity is eligible for 4 Stroke CME and 1 Pharmacology CME credits, subject to your state and institutional approval.