AHA/ASA Scientific Statement 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 The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Endorsed by the American Association of Neurological Surgeons and Congress of Neurological Surgeons Bart M. Demaerschalk, MD, MSc, FRCPC, FAHA, Chair; Dawn O. Kleindorfer, MD, FAHA, Vice-Chair; Opeolu M. Adeoye, MD, MS, FAHA; Andrew M. Demchuk, MD; Jennifer E. Fugate, DO; James C. Grotta, MD; Alexander A. Khalessi, MD, MS, FAHA; Elad I. Levy, MD, MBA, FAHA; Yuko Y. Palesch, PhD; Shyam Prabhakaran, MD, MS, FAHA; Gustavo Saposnik, MD, MSc, FAHA; Jeffrey L. Saver, MD, FAHA; Eric E. Smith, MD, MPH, FAHA; on behalf of the American Heart Association Stroke Council and Council on Epidemiology and Prevention Purpose—To critically review and evaluate the science behind individual eligibility criteria (indication/inclusion and contraindications/exclusion criteria) for intravenous recombinant tissue-type plasminogen activator (alteplase) treatment in acute ischemic stroke. This will allow us to better inform stroke providers of quantitative and qualitative risks associated with alteplase administration under selected commonly and uncommonly encountered clinical circumstances and to identify future research priorities concerning these eligibility criteria, which could potentially expand the safe and judicious use of alteplase and improve outcomes after stroke. Methods—Writing group members were nominated by the committee chair on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council’s Scientific Statement Oversight Committee and the American Heart Association’s Manuscript Oversight Committee. The writers used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge and, when appropriate, formulated recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on and approved the final version of this document. The document underwent extensive American Heart Association internal peer review, Stroke The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on September 24, 2015, and the American Heart Association Executive Committee on October 5, 2015. A copy of the document is available at http://my.americanheart.org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com. The online-only Data Supplement, which contains literature search strategies and Figures A, B, and C, is available with this article at http://circ. ahajournals.org/lookup/suppl/doi:10.1161/STR.0000000000000086/-/DC1. The American Heart Association requests that this document be cited as follows: Demaerschalk BM, Kleindorfer DO, Adeoye OM, Demchuk AM, Fugate JE, Grotta JC, Khalessi AA, Levy EI, Palesch YY, Prabhakaran S, Saposnik G, Saver JL, Smith EE; on behalf of the American Heart Association Stroke Council and Council on Epidemiology and Prevention. 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. Stroke. 2016;47:581–641. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the “Policies and Development” link. 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 http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Permissions Request Form” appears on the right side of the page. © 2015 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STR.0000000000000086 Downloaded from http://stroke.ahajournals.org/581 by guest on June 6, 2016 582 Stroke February 2016 Council Leadership review, and Scientific Statements Oversight Committee review before consideration and approval by the American Heart Association Science Advisory and Coordinating Committee. Results—After a review of the current literature, it was clearly evident that the levels of evidence supporting individual exclusion criteria for intravenous alteplase vary widely. Several exclusionary criteria have already undergone extensive scientific study such as the clear benefit of alteplase treatment in elderly stroke patients, those with severe stroke, those with diabetes mellitus and hyperglycemia, and those with minor early ischemic changes evident on computed tomography. Some exclusions such as recent intracranial surgery are likely based on common sense and sound judgment and are unlikely to ever be subjected to a randomized, clinical trial to evaluate safety. Most other contraindications or warnings range somewhere in between. However, the differential impact of each exclusion criterion varies not only with the evidence base behind it but also with the frequency of the exclusion within the stroke population, the probability of coexistence of multiple exclusion factors in a single patient, and the variation in practice among treating clinicians. (Stroke. 2016;47:581-641. DOI: 10.1161/STR.0000000000000086.) Key Words: AHA Scientific Statements ◼ brain ischemia ◼ cerebral infarction ◼ fibrinolytic agents◼ stroke ◼ thrombolytic therapy ◼ tissue plasminogen activator or our exclusion criteria, we elected to focus only on stroke actually receive this medication across the United FAmerican Heart Association (AHA)/American Stroke States. Although some hospital and quality registry estimates Association (ASA) guidelines and exclusions, warnings, of alteplase treatment rates can range as high as 20% to 30%,7,8 risks, and contraindications based on the US Food and Drug national estimates of use have ranged only from 3% to 5% Administration (FDA) package insert, specifically for the only since 2004.9,10 Although these rates of treatment are quite low, tissue-type plasminogen activator licensed for use in acute they are improving slowly over time. This low use is likely ischemic stroke, alteplase. We did not include international attributable to a number of reasons, including the paucity of guidelines or other international governmental restrictions community public education about recognition and response on the use of alteplase because it was beyond the scope of to acute stroke symptoms and signs, the slow adoption of the this document. However, we included data from international medication in the medical community, and the complexity of studies in our review of the literature for each exclusion. large system changes at the hospital level that are necessary Literature search strategies are published as an online-only for this medication to be provided in a safe and timely man- Data Supplement. ner.11 However, although these issues are all extremely impor- We have also intentionally focused on alteplase rather than tant, we believe that one of the most likely reasons for low on any or all types of thrombolytic agents. We have concen- rates of alteplase treatment is the low eligibility rate for this trated on intravenous use of alteplase rather than on any inter- medication. ventional or intra-arterial strategies for recanalization. The Estimates of eligibility for alteplase within a population of controversies and approvals for these different approaches ischemic stroke patients range from 6% to 8% of all strokes, are many and currently are not as generalizable as the FDA- with slightly higher estimates in cross-sectional studies.12–15 approved intravenous administration of alteplase. The most common exclusion for alteplase is dominated by Recommendations were formulated with the use of stan- delays in presentation to medical attention. Within a popula- dard AHA criteria (Tables 1 and 2). All members of the writing tion, only 22% to 31% of patients with ischemic stroke present group had the opportunity to comment on the recommenda- to an emergency department within 3 hours from symptom tions and approved the final version of this document. The onset. In addition, arrival times to presentation are not linearly document underwent extensive AHA internal peer review, distributed. Most patients arrive either <2 or >8 hours from Stroke Council Leadership review, and