NEUROLOGY/CLINICAL POLICY Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department

From the American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Use of Intravenous tPA for Ischemic Stroke: Michael D. Brown, MD, MSc (Subcommittee Chair) John H. Burton, MD Devorah J. Nazarian, MD Susan B. Promes, MD, MBA

Members of the American College of Emergency Physicians Clinical Policies Committee (Oversight Committee): Stephen V. Cantrill, MD (Interim Chair 2014) Susan B. Promes, MD, MBA Michael D. Brown, MD, MSc (Chair 2014-2015) Kaushal Shah, MD Deena Brecher, MSN, RN, APN, ACNS-BC, CEN, CPEN (ENA Richard D. Shih, MD Representative 2014-2015) Scott M. Silvers, MD Deborah B. Diercks, MD, MSc Michael D. Smith, MD, MBA Seth R. Gemme, MD Christian A. Tomaszewski, MD, MS, MBA Charles J. Gerardo, MD, MHS Jonathan H. Valente, MD Steven A. Godwin, MD Stephen P. Wall, MD, MSc, MAEd (Methodologist) Sigrid A. Hahn, MD Stephen J. Wolf, MD Benjamin W. Hatten, MD, MPH Robert E. O’Connor, MD, MPH (Board Liaison 2010-2015) Jason S. Haukoos, MD, MSc (Methodologist) Rhonda R. Whitson, RHIA, Staff Liaison, Clinical Policies Amy Kaji, MD, MPH, PhD (Methodologist) Committee and Subcommittees Bruce M. Lo, MD, CPE, RDMS Approved by the ACEP Board, June 24, 2015 Sharon E. Mace, MD Devorah J. Nazarian, MD Endorsed by the Emergency Nurses Association, July 14, 2015 Mark C. Pierce, MD (EMRA Representative 2014-2015)

Policy statements and clinical policies are the official policies of the American College of Emergency Physicians and, as such, are not subject to the same peer review process as articles appearing in the journal. Policy statements and clinical policies of ACEP do not necessarily reflect the policies and beliefs of Annals of Emergency Medicine and its editors.

0196-0644/$-see front matter Copyright © 2015 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2015.06.031

[Ann Emerg Med. 2015;66:322-333.] evaluation and management of patients with acute ischemic stroke.1 A writing subcommittee conducted a systematic review of the literature to derive evidence-based ABSTRACT recommendations to answer the following clinical questions: This clinical policy from the American College of (1) Is intravenous tissue plasminogen activator safe and Emergency Physicians is the revision of a clinical policy effective for patients with acute ischemic stroke if given approved in 2012 addressing critical questions in the within 3 hours of symptom onset? (2) Is intravenous tissue

322 Annals of Emergency Medicine Volume 66, no. 3 : September 2015 Clinical Policy plasminogen activator safe and effective for patients with searches were conducted on January 27, 2014, and September acute ischemic stroke treated between 3 to 4.5 hours after 3, 2014. Specific key words/phrases and years used in the symptom onset? Evidence was graded and recommendations searches are identified under each critical question. were made according to the strength of the available data. Study Selection: 1,765 references were identified in the updated literature search as potentially relevant to the INTRODUCTION critical questions (992 in the search on January 27, 2014, Stroke is a leading cause of death in the United States, and 773 in the search on September 3, 2014). From these, with approximately 800,000 new strokes documented each 136 articles were selected from the January 27, 2014 year.2,3 Among survivors, stroke often results in disability, search, and 59 articles from the September 3, 2014 search, reducing mobility in half of those aged 65 years or older.2 resulting in a total of 195 new articles for full-text review. In 1996, the Food and Drug Administration approved Additionally, given recent changes to the ACEP clinical policy development process, articles rated as Class I or II in intravenous (IV) tissue plasminogen activator (tPA) as a 1 treatment for acute ischemic stroke. Despite their approval, the 2012 policy were also reviewed and graded by the the use of IV tPA for stroke has been polarizing4 and committee methodologists using current grading forms continues to generate a large volume of published literature. (available at http://acep.org/clinicalpolicies). Finally, The last American College of Emergency Physicians relevant articles from the bibliographies of included studies fi (ACEP) clinical policy addressing the use of IV tPA for and more recent articles identi ed by committee members acute ischemic stroke was approved in 2012.1 Since then, and reviewers were also included. changes to the ACEP clinical policies development This policy is a product of the ACEP clinical policy process have been implemented (ACEP’s clinical policy development process and is based on the existing literature; development process can be found at http://www.acep.org/ when literature was not available, consensus of emergency clinicalpolicies), the grading forms used to rate published physicians was used. Clinical policies are scheduled for research have continued to evolve, and newer research revision every 3 years; however, interim reviews such as this articles have been published. revision are conducted when technology, methodology, or fi The 2012 IV tPA clinical policy recommendation to the practice environment changes signi cantly. ACEP was “offer” tPA to patients presenting with acute ischemic the funding source for this clinical policy. stroke within 3 hours of symptom onset was consistent Assessment of Classes of Evidence with other national guidelines (eg, those of the American All articles used in the formulation of this clinical policy 5 Heart Association and the American College of Chest were graded by at least 2 committee members or 6 Physicians ). Unfortunately, the committee’s intent in methodologists; all Class I and Class II articles were graded using the term “offer” may not have conveyed the by at least 2 methodologists. Each article was assigned a importance of having a discussion with the patient or design class with design 1 representing the strongest study family about the potential benefits and harms of IV tPA; design and subsequent design classes (eg, design 2, design therefore, we have expanded on this concept with 3) representing respectively weaker study designs for recommendations addressing shared decisionmaking. therapeutic, diagnostic, or prognostic clinical reports, or 1 As in the previous ACEP clinical policy, the 2 critical meta-analyses (Appendix A). Articles were then graded on questions addressed in this clinical policy are: (1) Is IV tPA dimensions related to the study’s methodological features, safe and effective for patients with acute ischemic stroke if such as randomization processes, blinding, allocation given within 3 hours of symptom onset? (2) Is IV tPA safe concealment, methods of data collection, outcome and effective for patients with acute ischemic stroke treated measures and their assessment, selection and between 3 to 4.5 hours after symptom onset? misclassification biases, sample size, and generalizability. Using a predetermined process related to the study’s design, METHODOLOGY methodological quality, and applicability to the critical This clinical policy was created after careful review and question, articles received a final Class of Evidence grade critical analyses of the medical literature and was based on a (ie, Class I, Class II, Class III, or Class X) (Appendix B). systematic review of the literature. Searches of MEDLINE, Articles identified with fatal flaws or that were ultimately MEDLINE InProcess and other nonindexed citations portion not applicable to the critical question received a Class of of MEDLINE, and the Cochrane Database were performed. Evidence grade “X” and were not used in formulating All searches were limited to English-language sources, human recommendations for this policy. Grading was done with studies, and adults, from January 2011 to September 2014; respect to the specific critical questions; thus, the level of

Volume 66, no. 3 : September 2015 Annals of Emergency Medicine 323 Clinical Policy evidence for any one study may vary according to the ischemic stroke but rather a focused examination of critical question for which it is being considered. As such, it was issues that have particular relevance to the current practice possible for a single article to receive different Classes of of emergency medicine. Evidence as different critical questions were answered from It is the goal of the Clinical Policies Committee to the same study. Question-specific Classes of Evidence provide an evidence-based recommendation when the grading can be found in the Evidentiary Table (available medical literature provides enough quality information to online at www.annemergmed.com). answer a critical question. When the medical literature does not contain adequate empirical data to answer a critical Translation of Classes of Evidence to Recommendation Levels question, the members of the Clinical Policies Committee Strength of recommendations regarding each critical believe that it is equally important to alert emergency question were made by subcommittee members using physicians to this fact. results from strength of evidence grading, expert opinion, This clinical policy is not intended to represent a and consensus among subcommittee members according to legal standard of care for emergency physicians. the following guidelines: Recommendations offered in this policy are not intended to Level A recommendations. Generally accepted represent the only diagnostic or management options principles for patient care that reflect a high degree of available to the emergency physician. ACEP recognizes the clinical certainty (ie, based on evidence from 1 or more importance of the individual physician’s judgment and Class of Evidence I or multiple Class of Evidence II patient preferences. This guideline defines for the physician studies). those strategies for which medical literature exists to Level B recommendations. Recommendations for provide support for answers to the critical questions patient care that may identify a particular strategy or range addressed in this policy. of strategies that reflect moderate clinical certainty (ie, Scope of Application. This guideline is intended for based on evidence from 1 or more Class of Evidence II physicians working in emergency departments (EDs). studies or strong consensus of Class of Evidence III Inclusion Criteria. This guideline is intended for adult studies). patients aged 18 years and older presenting to the ED with Level C recommendations. Recommendations for acute ischemic stroke. patient care that are based on evidence from Class of Exclusion Criteria. This guideline is not intended to be Evidence III studies or, in the absence of any adequate used for pediatric or pregnant patients. published literature, based on expert consensus. In A summary of potential benefits and harms of instances where consensus recommendations are made, implementing the recommendations is presented in “consensus” is placed in parentheses at the end of the Appendix D. recommendation. There are certain circumstances in which the CRITICAL QUESTIONS recommendations stemming from a body of evidence 1. Is IV tPA safe and effective for patients with acute should not be rated as highly as the individual studies ischemic stroke if given within 3 hours of symptom on which they are based. Factors such as heterogeneity onset? of results, uncertainty about effect magnitude and consequences, and publication bias, among others, might Patient Management Recommendations lead to such a downgrading of recommendations. Level A recommendations. None specified. For this policy, recommendations for question 1 were Level B recommendations. With a goal to improve based on 1 Class I randomized controlled trial, 5 Class II functional outcomes, IV tPA should be offered and may be articles, and 29 Class III studies. For question 2, given to selected patients with acute ischemic stroke within recommendations were based on 1 Class II randomized 3 hours after symptom onset at institutions where systems controlled trial and 42 Class III studies. are in place to safely administer the medication. The When possible, clinically oriented statistics (eg, increased risk of symptomatic intracerebral hemorrhage likelihood ratios, number needed to treat [NNT]) are (sICH) should be considered when deciding whether to presented to help the reader better understand how the administer IV tPA to patients with acute ischemic stroke. results may be applied to the individual patient. For a Level C recommendations. When feasible, shared definition of these statistical concepts, see Appendix C. decisionmaking between the patient (and/or his or her This policy is not intended to be a complete manual on surrogate) and a member of the health care team should the evaluation and management of patients with acute include a discussion of potential benefits and harms prior to

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Table. Modified Rankin Scale.* (Used with permission). the subcommittee reported results using the more inclusive Score Description NINDS definition. 0 No symptoms 1 No significant disability despite symptoms; able to carry out all usual duties and activities Potential Benefits 2 Slight disability; unable to carry out all previous activities but It has been nearly 20 years since the last patient was able to look after own affairs without assistance enrolled in part 2 of the tPA for acute stroke trials 3 Moderate disability; requiring some help but able to walk without fi assistance sponsored by the NINDS. This trial provided the scienti c 4 Moderately severe disability; unable to walk without assistance basis for the Food and Drug Administration’s approval of and unable to attend to own bodily needs without assistance the use of IV tPA in acute stroke.8 The results of the 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention NINDS trial (part 2) (Class I) demonstrated an absolute 6 Dead difference of 13% with respect to excellent functional

Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. outcomes (ie, 39% with mRS score 0 to 1 for tPA versus Scott Med J. 1957;2:200-215. © Copyright 1957 Royal Society of Medicine Press, UK. 26% for control), thus rendering a NNT of 8; 95% *The modified Rankin Scale is a 6-point clinical outcome scale that measures a fi patient’s function and independence. A lower score indicates a better outcome. con dence interval [CI] 4 to 31. Although the enrollment criteria for the NINDS trials (Figure 2) required a measurable deficit on the NIHSS, there was a paucity of patients presenting with mild stroke (NIHSS score 0 to the decision whether to administer IV tPA for acute 4).10 In an effort to address the current state of equipoise ischemic stroke. (Consensus recommendation) for IV tPA in patients presenting with mild (NIHSS score Key words/phrases for literature searches: stroke, 0 to 4) or rapidly improving symptoms, a randomized cerebrovascular accident, thrombolytic, tPA, thrombolytic controlled trial is actively enrolling subjects.11 therapy, drug therapy, emergency department or Data from the NINDS trials continue to be reanalyzed emergency room, emergency service, hospital, and and despite inherent problems with post hoc reanalyses,12 variations and combinations of the key words/phrases. these studies highlight the strengths and limitations of the A study was considered directly applicable if IV tPA was NINDS trials.10,13-19 Although strict randomization was administered within the specified timeframe (ie, within 3 followed in the NINDS trials, there was an imbalance in hours of symptom onset). To be included, articles were baseline stroke severity scores between the intervention and required to report patient-centered outcomes such as sICH, control groups.13,14 A subsequent reanalysis of the original mortality, or a validated measure for functional outcome. NINDS data set showed that a larger proportion of patients In terms of assessing the potential benefits of IV tPA, the with milder strokes with an NIHSS score of 0 to 5 (19% subcommittee focused on the modified Rankin Scale versus 4%) at 91 to 180 minutes were randomized to (mRS) because it is both patient centered and consistently tPA.14 Last, the NINDS trials were designed to enroll half reported1,7 (Table). An “excellent” functional outcome is of their subjects within 90 minutes of symptom onset, typically equated to a score of 0 to 1 on the mRS; a score of which has raised questions about the generalizability of 2 is considered a “good” functional outcome; and a score of their findings.20 3 to 6 is considered “poor” functional outcome. To place The only other randomized controlled trial (Class II) this into context, an mRS score of 2 is defined as a slight that directly addressed the critical question enrolled disability that allows the patient to look after their affairs subjects within 6 hours of stroke symptom onset, using without assistance yet be unable to perform some previous block randomization stratified by 0 to less than 3 hours and activities (eg, drive a car, dance).7 3 to 6 hours.22 This study did not show benefit for tPA The major harm associated with IV tPA therapy in this administered within 6 hours of symptom onset (the clinical setting is sICH, defined as bleeding associated with primary analysis), and the difference in the subgroup “any decline in neurological status” per the National randomized to less than 3 hours (42% with mRS score 0 to Institute of Neurological Disorders and Stroke (NINDS) 2 for tPA versus 38% for placebo) did not reach statistical trials8 and, when it occurs, sICH is ultimately associated significance (odds ratio [OR]¼1.2; 95% CI 0.6 to 2.3). with a substantial increase in the risk of an unfavorable A Class III open-label clinical trial, the Third outcome (mRS score 3 to 6).9 Studies have used various International Stroke Trial (IST-3), by Sandercock et al,23 definitions for sICH, such as those requiring a deterioration enrolled patients within 6 hours of symptom onset. In this of 4 or more points on the National Institutes of Health trial, patients did not meet the standard European Union Stroke Scale (NIHSS)9 (Figure 1). When possible, license–approved protocol for IV tPA; a large percentage of

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Figure 1. National Institutes of Health Stroke Scale.* patients were elderly (53% older than 80 years), had The literature search also identified an updated meta- elevated systolic blood pressure (34% greater than 165 mm analysis (Class II) of randomized controlled trials for IV Hg), or had low baseline NIHSS scores (20% with scores tPA.24 The pooled results of the prespecified subgroup 0 to 5). Because of slow enrollment, the trial was stopped analysis for treatment within 3 hours demonstrated benefit early. Among the prespecified subgroups of subjects in terms of a good functional outcome (mRS score 0 to 2) randomized at less than 3 hours of symptom onset with thrombolysis (OR¼1.53; 95% CI 1.26 to 1.86). (N¼849), the tPA group achieved better functional Although the authors of the meta-analysis concluded that outcomes compared with controls (31% with good the 12 studies analyzed were at low risk of bias, a sensitivity functional outcomes for tPA versus 23% for controls; analysis based on the methodological and quality OR¼1.64; 95% CI 1.03 to 2.62), resulting in a NNT of differences was not performed. The trial contributing the 13 (95% CI 7 to 51). largest proportion of patient data to the pooled estimate of

326 Annals of Emergency Medicine Volume 66, no. 3 : September 2015 Clinical Policy effect (ie, Sandercock et al IST-323) was rated Class III by Emberson et al25 (OR¼1.00; 95% CI 0.81 to 1.24), the subcommittee. Another meta-analysis (Class III) based respectively. According to another Class III meta-analysis on individual patient-level data reported a similar effect size by Wardlaw et al50 that included trials using tPA and for tPA administered within 3 hours of symptom onset other thrombolytic agents, there was again no difference (OR¼1.75; 95% CI 1.35 to 2.27).25 in mortality when given within 3 hours of stroke onset Although efficacy estimates in observational studies are (OR 0.99; 95% CI 0.82 to 1.21). Among the Class III often flawed, these studies may provide information on cohort studies, there was substantial variability in the safety. Among the many registry studies identified in the reported mortality prevalences, ranging from 1% to updated searches, methodological limitations such as 24%.27-31,33-37,40,45,51 selection bias (eg, eligible patients missed or purposely not Appendix D contains information on key risk-benefit enrolled in a registry) and measurement bias (eg, mRS concepts. score assessed by research assistant telephone follow-up 2. Is IV tPA safe and effective for patients with acute rather than an in-person interview by a neurologist) ischemic stroke treated between 3 to 4.5 hours after typically resulted in downgrading to Class III or Class X. symptom onset? The search identified a few randomized controlled trials comparing new interventions to standard IV tPA (serving Patient Management Recommendations as the control group), which provided data on safety and Level A recommendations. None specified. functional outcomes similar to that of prospective cohort Level B recommendations. Despite the known risk of studies. In summary, numerous Class III studies report sICH and the variability in the degree of benefit in functional prevalences of excellent functional outcomes (mRS score outcomes, IV tPA may be offered and may be given to 0 to 1) with administration of IV tPA within 3 hours of carefully selected patients with acute ischemic stroke within 3 26-36 symptom onset ranging from 37% to 53%. However, to 4.5 hours after symptom onset at institutions where registries typically included patients with less severe systems are in place to safely administer the medication. strokes (baseline mean or median NIHSS scores ranging Level C recommendations. When feasible, shared from 11 to 13) compared with those enrolled in the decisionmaking between the patient (and/or his or her NINDS trials. surrogate) and a member of the health care team should include a discussion of potential benefits and harms prior to Potential Harms the decision whether to administer IV tPA for acute 8 The NINDS trial, part 2 (Class I) demonstrated an ischemic stroke. (Consensus recommendation) absolute increase in the prevalence of sICH of 6% (ie, sICH¼7% for tPA versus 1% for control), thus Key words/phrases for literature searches: stroke, indicating a number needed to harm [NNH] of 17; cerebrovascular accident, thrombolytic, tPA, thrombolytic 95% CI 12 to 34. The Class II meta-analysis by therapy, drug therapy, emergency department or Wardlaw et al24 reported a pooled estimate for sICH of emergency room, emergency service, hospital, and 8% for tPA versus 1% for controls (OR¼4.55; 95% CI variations and combinations of the key words/phrases. 2.92 to 7.09); however, the definition for sICH varied among the included individual trials. Among Class III Potential Benefits cohort studies, prevalences of sICH were remarkably The Class II study, European Cooperative Acute Stroke consistent when based on the NINDS definition Study (ECASS III) (Figure 2), by Hacke et al21 (approximately 5% to 7%).33,35-44 As expected, demonstrated improvement in the prevalence of excellent reported rates of sICH are lower in studies that used functional outcomes (mRS score 0 to 1) with IV tPA standard doses of tPA and a definition requiring a administered within 3 to 4.5 hours after symptom onset deterioration of 4 or more points on the NIHSS (range (52% for tPA versus 45% for controls; OR¼1.34; 95% CI of 4% to 6% for sICH).28,30,31,39,45-49 1.02 to 1.76; NNT¼14; 95% CI 7 to 244). Reasons for In the NINDS trials,8 there was no statistically downgrading ECASS III to a Class II level include baseline significant difference in 3-month mortality (17% for tPA differences between groups and changes in the timing of versus21%forcontrol;OR¼0.81; 95% CI 0.54 to 1.21). tPA administration during the course of the study. Similarly, 1 Class II and 1 Class III meta-analyses reported The Class III open-label clinical trial (IST-3) by no difference in mortality for patients treated with IV tPA Sandercock et al23 enrolled patients not meeting the within 3 hours of symptom onset to the end of follow-up: standard European Union–approved protocol for IV tPA Wardlaw et al24 (OR¼0.91; 95% CI 0.73 to 1.13) and as discussed under critical question 1 above. In the 3- to

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Figure 2. NINDS and ECASS III inclusion and exclusion criteria for intravenous tPA for acute ischemic stroke.

4.5-hour subgroup (N¼1,177), there was no statistically Potential Harms significant difference in functional outcomes in those The Class II study by Hacke et al21 reported sICH randomized to the tPA arm (32% with good functional prevalence of 8% for tPA versus 4% for placebo (OR¼2.38; outcome in the tPA group versus 38% in the control 95% CI 1.25 to 4.52; NNH¼23; 95% CI 13 to 78); there group [OR¼0.73; 99% CI 0.50 to 1.07]). The was no difference in mortality between the 2 groups. The investigators reported this outcome using a 99% CI rather Class III individual patient data meta-analysis also reported than a conventional 95% CI; use of a 95% CI would have no difference in mortality for the 3- to 4.5-hour subgroup resulted in a statistically significant association between (hazard ratio¼1.14; 95% CI 0.95 to 1.36).25 Among other patients in the placebo arm and good functional Class III studies,33,36,37,41,44,50,55,56,58,61,66,68-77 the outcomes. An older Class III randomized trial also showed prevalences of sICH associated with IV tPA administration no difference in 90-day functional outcomes between the within 4.5 hours ranged from 3% to 8% when based on the tPA and control groups.52 A Class III meta-analysis by the NINDS definition, whereas the prevalence was lower (2% to Stroke Thrombolysis Trialists’ Collaborative Group25 that 6%) for those studies using an sICH definition requiring a pooled individual patient data from multiple trials change of 4 or more on the NIHSS.39,53,54,57,60,62-65,67,78-84 reported an effect size similar to that of ECASS III (OR¼1.26; 95% CI 1.05 to 1.51) for the 3- to 4.5-hour subgroup. Among the Class III observational studies, there Future Research was wide variability in baseline stroke severity (mean Further research is needed to refine estimates for the NIHSS scores ranged from 5 to 17), making comparisons effectiveness and safety of IV tPA across the entire acute difficult.33,36,37,39,53-67 stroke population (ie, heterogeneity of treatment effect) so

328 Annals of Emergency Medicine Volume 66, no. 3 : September 2015 Clinical Policy that clinicians and patients can have a more informed 9. Gumbinger C, Gruschka P, Bottinger M, et al. Improved prediction of fi poor outcome after thrombolysis using conservative definitions of conversation about who is most likely to bene t from the symptomatic hemorrhage. Stroke. 2012;43:240-242. administration of IV tPA, and clinicians can better identify 10. Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS trial. Ann those individuals at highest risk for sICH and other Emerg Med. 2009;54:329-336. complications.85-89 There is some evidence to suggest that 11. PRISMS trial. ClinicalTrials.gov: NCT02072226. Available at: https:// clinicaltrials.gov/ct2/show/NCT02072226. Accessed November 7, lower weight-based doses of tPA may be effective and result 2014. in fewer adverse outcomes, warranting further studies in this 12. Christakis DA, Zimmerman FJ. Rethinking reanalysis. JAMA. area.26,75,82,90 Advancement in precision medicine (eg, 2013;310:2499-2500. 13. Feng W, Vasquez G, Suri FK, et al. Repeated-measures analysis of the predicting risk based on systems biology) and more accurate National Institute of Neurological Disorders and Stroke rt-PA stroke assessment of patient weight may play a role in deciphering trial. J Stroke Cerebrovasc Dis. 2011;20:241-246. the appropriate treatment of stroke patients. Although trial 14. Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated results on endovascular interventions have been with better outcome. The NINDS rt-PA stroke study. Neurology. 78,91,92 2000;55:1649-1655. mixed, more recent trials focusing on the subgroup of 15. Saver JL, Gornbein J, Starkman S. Graphic reanalysis of the two patients with large vessel occlusion have reported NINDS-tPA trials confirms substantial treatment benefit. Stroke. benefit,83,84,93,94 thus representing an area of research that is 2010;41:2381-2390. 16. Johnston KC, Connors AF Jr, Wagner DP, et al. Risk adjustment effect likely to yield further improvements in acute stroke care. on stroke clinical trials. Stroke. 2004;35:e43-e45. 17. Saver JL, Yafeh B. Confirmation of tPA treatment effect by baseline Relevant industry relationships: There were no severity-adjusted end point reanalysis of the NINDS-tPA stroke trials. Stroke. 2007;38:414-416. relevant industry relationships disclosed by the 18. Kwiatkowski T, Libman R, Tilley BC, et al. The impact of imbalances in subcommittee members. baseline stroke severity on outcome in the National Institute of Relevant industry relationships are those relationships Neurological Disorders and Stroke Recombinant Tissue Plasminogen with companies associated with products or services that Activator Stroke Study. Ann Emerg Med. 2005;45:377-384. fi fi 19. Ingall TJ, O’Fallon WM, Asplund K, et al. Findings from the reanalysis signi cantly impact the speci c aspect of disease of the NINDS tissue plasminogen activator for acute ischemic stroke addressed in the critical question. treatment trial. Stroke . 2004;35:2418-2424. 20. Mazighi M, Chaudhry SA, Ribo M, et al. Impact of onset-to-reperfusion time on stroke mortality: a collaborative pooled analysis. Circulation. 2013;127:1980-1985. REFERENCES 21. Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. 1. Edlow JA, Smith EE, Stead LG, et al; American College of Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic Emergency Physicians and American Academy of Neurology. stroke. N Engl J Med. 2008;359:1317-1329. Clinical policy: use of intravenous tPA for the management of 22. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind acute ischemic stroke in the emergency department. 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Cochrane Database Syst Rev. acute ischaemic stroke: a systematic review and meta-analysis to aid 2014;7:CD000213. decision making in patients over 80 years of age. J Neurol Neurosurg 51. Topakian R, Brainin M, Eckhardt R, et al. Thrombolytic therapy for Psychiatry. 2011;82:712-717. acute stroke in Austria: data from the Safe Implementation of 33. Liao XL, Wang CX, Wang YL, et al; Thrombolysis Implementation and Thrombolysis in Stroke (SITS) register. Eur J Neurol. 2011;18: Monitor of acute ischemic Stroke in China (TIMS-China) Investigators. 306-311. Implementation and outcome of thrombolysis with alteplase 3 to 4.5 52. Clark WM, Wissman S, Albers GW, et al; ATLANTIS Study h after acute stroke in Chinese patients. CNS Neurosci Ther. Investigators. Recombinant tissue-type plasminogen activator 2013;19:43-47. (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The 34. Martins SC, Friedrich MA, Brondani R, et al. Thrombolytic therapy for Atlantis Study: a randomized controlled trial. JAMA. 1999;282: acute stroke in the elderly: an emergent condition in developing 2019-2026. countries. J Stroke Cerebrovasc Dis. 2011;20:459-464. 53. Ebinger M, Scheitz JF, Kufner A, et al. MRI-based intravenous 35. Sung PS, Chen CH, Hsieh HC, et al. Outcome of acute ischemic stroke thrombolysis in stroke patients with unknown time of symptom onset. in very elderly patients: is intravenous thrombolysis beneficial? Eur Eur J Neurol. 2012;19:348-350. Neurol. 2011;66:110-116. 54. Garcia-Bermejo P, Calleja AI, Perez-Fernandez S, et al. Perfusion 36. Park TH, Lee JS, Park SS, et al. Safety and efficacy of intravenous computed tomography–guided intravenous thrombolysis for acute recombinant tissue plasminogen activator administered in the 3- to 4.5- ischemic stroke beyond 4.5 hours: a case-control study. Cerebrovasc hour window in Korea. J Stroke Cerebrovasc Dis. 2014;23:1805-1812. Dis. 2012;34:31-37. 37. Ahmed N, Kellert L, Lees KR, et al. Results of intravenous 55. Paliwal PR, Ahmad A, Shen L, et al. Persistence of hyperdense middle thrombolysis within 4.5 to 6 hours and updated results within 3 to 4.5 cerebral artery sign on follow-up CT scan after intravenous hours of onset of acute ischemic stroke recorded in the Safe thrombolysis is associated with poor outcome. Cerebrovasc Dis. Implementation of Treatment in Stroke International Stroke 2012;33:446-452. Thrombolysis Register (SITS-ISTR). An observational study. JAMA 56. Sairanen T, Soinila S, Nikkanen M, et al. Two years of Finnish Neurol. 2013;70:837-844. telestroke: thrombolysis at spokes equal to that at the hub. 38. Sung SF, Chen SC, Lin HJ, et al. Comparison of risk-scoring systems in Neurology. 2011;76:1145-1152. predicting symptomatic intracerebral hemorrhage after intravenous 57. Sobolewski P, Sledzinska-Dzwigal M, Szczuchniak W, et al. The thrombolysis. Stroke. 2013;44:1561-1566. efficacy and safety of intravenous thrombolysis with alteplase in the 39. Alias M, Staff I, McCullough LD. Early experience with community treatment of ischaemic stroke in a rural hospital. Neurol Neurochir implementation of thrombolysis three to 4.5 hours after acute Pol. 2013;47:310-318. ischemic stroke. Conn Med. 2011;75:531-536. 58. Strbian D, Ringleb P, Michel P, et al. Ultra-early intravenous stroke 40. Chao TH, Lin TC, Shieh Y, et al. Intracerebral hemorrhage after thrombolysis. Do all patients benefit similarly? Stroke. 2013;44: thrombolytic therapy in acute ischemic stroke patients with renal 2913-2916. dysfunction. Eur Neurol. 2013;70:316-321. 59. Turc G, Apoil M, Naggara O, et al. Magnetic resonance 41. Cronin CA, Sheth KN, Zhao X, et al. Adherence to third European imaging–DRAGON score: 3-month outcome prediction after Cooperative Acute Stroke Study 3- to 4.5-hour exclusions and intravenous thrombolysis for anterior circulation stroke. Stroke. association with outcome: data from Get With the Guidelines — 2013;44:1323-1328. Stroke. Stroke. 2014;45:2745-2749. 60. Vujkovic Z, Racic D, Miljkovic S, et al. Hemorrhagic complications of 42. Flint AC, Gupta R, Smith WS, et al; SITS International and VISTA-plus thrombolytic therapy. Med Pregl. 2012;65:9-12. investigators. The THRIVE score predicts symptomatic intracerebral 61. Xian Y, Liang L, Smith EE, et al. Risks of intracranial hemorrhage hemorrhage after intravenous tPA administration in SITS-MOST. Int J among patients with acute ischemic stroke receiving warfarin and Stroke. 2014;9:705-710. treated with intravenous tissue plasminogen activator. JAMA. 43. Mehrpour M, Aghaei M, Motamed MR. Safety and feasibility of 2012;307:2600-2608. intravenous thrombolytic therapy in Iranian patients with acute 62. Zinkstok SM, Roos YB; ARTIS Investigators. Early administration of ischemic stroke. Med J Islam Repub Iran. 2013;27:113-118. aspirin in patients treated with alteplase for acute ischaemic stroke: 44. Saver JL, Fonarow GC, Smith EE, et al. Time to treatment with a randomised controlled trial. Lancet. 2012;380:731-737. intravenous tissue plasminogen activator and outcome from acute 63. Dharmasaroja PA, Dharmasaroja P, Muengtaweepongsa S. Outcomes ischemic stroke. JAMA. 2013;309:2480-2488. of Thai patients with acute ischemic stroke after intravenous 45. Chowdhury M, Birns J, Rudd A, et al. Telemedicine versus face-to- thrombolysis. J Neurol Sci. 2011;300:74-77. face evaluation in the delivery of thrombolysis for acute ischaemic 64. Fischer U, Mono ML, Zwahlen M, et al. Impact of thrombolysis on stroke: a single centre experience. Postgrad Med J. stroke outcome at 12 months in a population: the Bern stroke 2012;88:134-137. project. Stroke. 2012;43:1039-1045.

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65. Al-Khaled M, Matthis C, Eggers J. Predictors of in-hospital 83. Goyal M, Demchuk AM, Menon BK, et al; ESCAPE Trial Investigators. mortality and the risk of symptomatic intracerebral hemorrhage Randomized assessment of rapid endovascular treatment of after thrombolytic therapy with recombinant tissue plasminogen ischemic stroke. N Engl J Med. 2015;372:1019-1030. activator in acute ischemic stroke. J Stroke Cerebrovasc Dis. 84. Campbell BC, Mitchell PJ, Kleinig TJ, et al; EXTEND-IA Investigators. 2014;23:7-11. Endovascular therapy for ischemic stroke with perfusion-imaging 66. Tong X, George MG, Yang Q, et al. Predictors of in-hospital death and selection. N Engl J Med. 2015;372:1009-1018. symptomatic intracranial hemorrhage in patients with acute ischemic 85. Kent DM, Rothwell PM, Ioannidis JP, et al. Assessing and reporting stroke treated with thrombolytic therapy: Paul Coverdell Acute Stroke heterogeneity in treatment effects in clinical trials: a proposal. Trials. Registry 2008-2012. Int J Stroke. 2014;9:728-734. 2010;11:85. 67. Yeo LL, Paliwal P, Teoh HL, et al. Early and continuous neurologic 86. Kent DM, Hayward RA. Limitations of applying summary results of improvements after intravenous thrombolysis are strong predictors of clinical trials to individual patients. The need for risk stratification. favorable long-term outcomes in acute ischemic stroke. J Stroke JAMA. 2007;298:1209-1212. Cerebrovasc Dis. 2013;22:e590-e596. 87. Kent DM, Selker HP, Ruthazer R, et al. The stroke-thrombolytic 68. Dharmasaroja PA, Muengtaweepongsa S, Pattaraarchachai J, et al. predictive instrument: a predictive instrument for intravenous Intracerebral hemorrhage following intravenous thrombolysis in Thai thrombolysis in acute ischemic stroke. Stroke. 2006;37: patients with acute ischemic stroke. J Clin Neurosci. 2012;19: 2957-2962. 799-803. 88. Gonzalez RG, Lev MH, Goldmacher GV, et al. Improved outcome 69. Meurer WJ, Kwok H, Skolarus LE, et al. Does preexisting antiplatelet prediction using CT angiography in addition to standard ischemic treatment influence postthrombolysis intracranial hemorrhage in stroke assessment: results from the STOPStroke study. PLoS One. community-treated ischemic stroke patients? An observational study. 2012;7:e30352. Acad Emerg Med. 2013;20:146-154. 89. Menon BK, Saver JL, Prabhakaran S, et al. Risk score for intracranial 70. Paciaroni M, Agnelli G, Caso V, et al. Intravenous thrombolysis for hemorrhage in patients with acute ischemic stroke treated with acute ischemic stroke associated to extracranial internal carotid intravenous tissue-type plasminogen activator. Stroke. artery occlusion: the ICARO-2 study. Cerebrovasc Dis. 2012;34: 2012;43:2293-2299. 430-435. 90. Chao AC, Liu CK, Chen CH, et al; Taiwan Thrombolytic Therapy for 71. Messe SR, Fonarow GC, Smith EE, et al. Use of tissue-type Acute Ischemic Stroke (TTT-AIS) Study Group. Different doses of plasminogen activator before and after publication of the European recombinant tissue-type plasminogen activator for acute stroke in Cooperative Acute Stroke Study III in Get With the Guidelines—Stroke. Chinese patients. Stroke. 2014;45:2359-2365. Circ Cardiovasc Qual Outcomes. 2012;5:321-326. 91. Singh B, Parsaik AK, Prokop LJ, et al. Endovascular therapy for acute 72. Wong EH, Lau AY, Soo YO, et al. Is stroke thrombolysis safe ischemic stroke: a systematic review and meta-analysis. Mayo Clin and efficacious in Hong Kong? Hong Kong Med J. 2012;18:92-98. Proc. 2013;88:1056-1065. 73. Ebinger M, Winter B, Wendt M, et al. Effect of the use of ambulance- 92. Hill MD, Demchuk AM, Goyal M, et al. Alberta Stroke Program early based thrombolysis on time to thrombolysis in acute ischemic stroke. computed tomography score to select patients for endovascular A randomized clinical trial. JAMA. 2014;311:1622-1631. treatment. Interventional Management of Stroke (IMS)-III Trial. 74. Fonarow GC, Zhao X, Smith EE. Door-to-needle times for tissue Stroke. 2014;45:444-449. plasminogen activator administration and clinical outcomes in acute 93. Berkhemer OA, Fransen PS, Beumer D, et al; The MR CLEAN ischemic stroke before and after a quality improvement initiative. Investigators. A randomized trial of intraarterial treatment for acute JAMA. 2014;311:1632-1640. ischemic stroke. N Engl J Med. 2015;372:11-20. 75. Hsieh CY, Lin HJ, Sung SF, et al. Is renal dysfunction associated with 94. Saver JL, Goyal M, Bonafe A, et al; SWIFT PRIME Investigators. Stent- adverse stroke outcome after thrombolytic therapy? Cerebrovasc Dis. retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. 2014;37:51-56. N Engl J Med. 2015;372:2285-2295. 76. Reiter M, Teuschi Y, Matz K, et al. Diabetes and thrombolysis for acute 95. Flynn D, Knoedler MA, Hess EP, et al. Engaging patients in health stroke: a clear benefit for diabetics. Eur J Neurol. 2014;21:5-10. care decisions in the emergency department through shared 77. Strbian D, Michel P, Seiffge DJ, et al. Symptomatic intracranial decision-making: a systematic review. Acad Emerg Med. 2012;19: hemorrhage after stroke thrombolysis: comparison of prediction 959-967. scores. Stroke. 2014;45:752-758. 96. Legare F, Witteman HO. Shared decision making: examining key 78. Ciccone A, Valvassori L, Nichelatti M, et al; SYNTHESIS Expansion elements and barriers to adoption into routine clinical practice. Investigators. Endovascular treatment for acute ischemic stroke. Health Aff (Millwood). 2013;32:276-284. N Engl J Med. 2013;368:904-913. 97. Hoffmann TC, Montori VM, Del Mar C. The connection between 79. Matijevic V, Poljakovic Z, Malojcic B, et al. Systemic thrombolytic evidence-based medicine and shared decision making. 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Appendix A. Literature classification schema.* Design/Class Therapy† Diagnosis‡ Prognosis§ 1 Randomized, controlled trial or Prospective cohort using a criterion standard Population prospective cohort or meta-analysis of randomized trials or meta-analysis of prospective studies meta-analysis of prospective studies 2 Nonrandomized trial Retrospective observational Retrospective cohort Case control 3 Case series Case series Case series Case report Case report Case report Other (eg, consensus, review) Other (eg, consensus, review) Other (eg, consensus, review)

*Some designs (eg, surveys) will not fit this schema and should be assessed individually. †Objective is to measure therapeutic efficacy comparing interventions. ‡Objective is to determine the sensitivity and specificity of diagnostic tests. §Objective is to predict outcome, including mortality and morbidity.

Appendix B. Approach to downgrading strength of evidence. Design/Class Downgrading 123 None I II III 1 level II III X 2 levels III X X Fatally flawed X X X

Appendix C. Likelihood ratios and number needed to treat.* LR (D) LR (-) 1.0 1.0 Does not change pretest probability 1-5 0.5-1 Minimally changes pretest probability 10 0.1 May be diagnostic if the result is concordant with pretest probability 20 0.05 Usually diagnostic 100 0.01 Almost always diagnostic even in the setting of low or high pretest probability

LR, likelihood ratio. *Number needed to treat (NNT): number of patients who need to be treated to achieve 1 additional good outcome; NNT¼1/absolute risk reductionx100, where absolute risk reduction is the risk difference between 2 events (ie, experimental and control groups).

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Appendix D. Potential benefits and harms of medical interventions98; therefore, it is suggested that implementing the recommendations patient decision aids be used to improve decision quality.95 1. Is IV tPA safe and effective for patients with acute Graphic risk communication tools such as person icon arrays have been developed for IV thrombolysis decisions in ischemic stroke if given within 3 hours of symptom 99,100 onset? acute ischemic stroke. Although these tools rely on group-level data from clinical trials rather than providing Patient Management Recommendations dynamic individualized estimates of risk, they may provide Level A recommendations. None specified. a starting point for shared decisionmaking. Level B recommendations. With a goal to improve 2. Is IV tPA safe and effective for patients with acute functional outcomes, IV tPA should be offered and may be ischemic stroke treated between 3 to 4.5 hours after given to selected patients with acute ischemic stroke within symptom onset? 3 hours after symptom onset at institutions where systems are in place to safely administer the medication. The Patient Management Recommendations increased risk of sICH should be considered when deciding Level A recommendations. None specified. whether to administer IV tPA to patients with acute Level B recommendations. Despite the known risk of ischemic stroke. sICH and the variability in the degree of benefitin Level C recommendations. When feasible, shared functional outcomes, IV tPA may be offered and may be decisionmaking between the patient (and/or his or her given to carefully selected patients with acute ischemic surrogate) and a member of the health care team should stroke within 3 to 4.5 hours after symptom onset at include a discussion of potential benefits and harms prior to institutions where systems are in place to safely administer the decision whether to administer IV tPA for acute the medication. ischemic stroke. (Consensus recommendation) Level C recommendations. When feasible, shared Potential Benefit of Implementing the decisionmaking between the patient (and/or his or her Recommendations: Administration of IV tPA within 3 surrogate) and a member of the health care team should hours of stroke symptom onset increases the probability of include a discussion of potential benefits and harms prior to better long-term functional outcome (NNT¼8; 95% CI 4 the decision whether to administer IV tPA for acute to 31 when based on data from the Class I NINDS8 trial ischemic stroke. (Consensus recommendation) part 2). Potential Benefit of Implementing the Potential Harm of Implementing the Recommendations: Administration of IV tPA for patients Recommendations: Administration of IV tPA within 3 with ischemic stroke within 3 to 4.5 hours of stroke hours of stroke symptom onset increases the risk of early symptom onset may increase the probability of better long- sICH (NNH¼17; 95% CI 12 to 34 when based on data term functional outcome (NNT¼14; 95% CI 7 to 244 from the Class I NINDS8 trial part 2). when based on data from the Class II ECASS III21 trial). When considering administration of IV tPA for a patient Potential Harm of Implementing the with acute ischemic stroke within 3 hours of stroke Recommendations: Administration of IV tPA for patients symptom onset, the physician and patient (and/or the with ischemic stroke within 3 to 4.5 hours of stroke surrogate) should weigh the potential benefit in terms of symptom onset increases the risk of early sICH long-term functional outcome against the increased risk of (NNH¼23; 95% CI 13 to 78 when based on data from sICH while recognizing that IV tPA does not alter 90-day the Class II ECASS III21 trial). mortality. When considering administration of IV tPA for a patient Shared decisionmaking relies on a combination of the with ischemic stroke within 3 to 4.5 hours of stroke best available research evidence, the clinical expertise of the symptom onset, the physician and patient (and/or the providers, and the unique attributes of the patient and the surrogate) should weigh the potential benefit in terms of patient’s family.95-97 Patients tend to overestimate the long-term functional outcome against the increased risk of benefits and underestimate the harms associated with sICH.

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