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Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department

  • This clinical policy is the result of a collaborative project of the American College of Emergency Physicians and the American Academy of Neurology
      [Ann Emerg Med. 2013;61:225-243.]
      Development Panel
      Jonathan A. Edlow, MD (Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA)
      Eric E. Smith, MD, MPH (Department of Clinical Neurosciences, Hotchkiss Brain Institute [E.E.S.], University of Calgary, Foothills Medical Centre, Calgary, Canada)
      Latha Ganti Stead, MD, MS, MBA (Professor of Emergency Medicine and Neurological Surgery; Director, Center for Brain Injury Research and Education, University of Florida, Gainesville, FL)
      Gary Gronseth, MD (Department of Neurology, University of Kansas Medical Center, Kansas City, KS)
      Steven R. Messé, MD (Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA)
      Andy S. Jagoda, MD (Professor and Chair, Department of Emergency Medicine Mount Sinai School of Medicine; Medical Director, Emergency Department, Mount Sinai Hospital, New York, NY)
      Robert L. Wears, MD, MS (Methodologist; Department of Emergency Medicine, University of Florida, Jacksonville, FL)
      Wyatt W. Decker, MD (Vice President and Trustee Mayo Clinic, CEO Mayo Clinic Arizona, Scottsdale, AZ)
      Providing Project Support:
      Rhonda R. Whitson, RHIA, Clinical Practice Manager, American College of Emergency Physicians
      Thomas S. D. Getchius, Associate Director, Clinical Practice, American Academy of Neurology

      Abstract

      This policy was developed by a joint writing panel of the American College of Emergency Physicians and the American Academy of Neurology. The panel reviewed the literature to derive evidence-based recommendations to help clinicians answer the following critical questions:
      (1) Is intravenous tissue plasminogen activator (tPA) safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset? (2) Is intravenous tPA safe and effective for acute ischemic stroke patients treated between 3 to 4.5 hours after symptom onset? Evidence was graded and recommendations were given based on the strength of the available data in the medical literature.

      Introduction

      It is estimated that there are 795,000 new strokes in the United States each year.
      • Lloyd-Jones D.
      • Adams R.J.
      • Brown T.M.
      • et al.
      American Heart Association Statistics Committee and Stroke Statistics Subcommittee
      Heart disease and stroke statistics—2010 update: a report from the American Heart Association.
      Stroke is the third leading cause of death in the United States, causing 1 of every 17 deaths in 2005.
      • Lloyd-Jones D.
      • Adams R.J.
      • Brown T.M.
      • et al.
      American Heart Association Statistics Committee and Stroke Statistics Subcommittee
      Heart disease and stroke statistics—2010 update: a report from the American Heart Association.
      In 1996, the Food and Drug Administration (FDA) approved intravenous (IV) tissue plasminogen activator (tPA) as a treatment for acute ischemic stroke. Since then, the use of IV tPA for stroke has been one of the most contentious medical treatments.

      Methodology

      A joint development panel was appointed by the American College of Emergency Physicians (ACEP) and the American Academy of Neurology (AAN) to produce a clinical evidence–based guideline on the use of tPA for acute ischemic stroke.
      This clinical policy was created after careful review and critical analysis of the medical literature. Multiple searches of MEDLINE and the Cochrane Database for articles published between January 1999 and May 2011 were performed using a combination of key words, including “cerebrovascular accident,” “tissue plasminogen activator,” “tPA,” “thrombolytic therapy,” “stroke,” “intracerebral hemorrhage,” “subarachnoid hemorrhage,” “emergency department,” “emergency service,” “emergency room,” “therapy in emergency department,” and “treatment in emergency department.” The searches were limited to the English language and human studies. Additional articles were reviewed from the bibliographies of studies cited. Panel members supplied articles from their own knowledge and files, and more recent articles identified during the process were also included.
      The reasons for developing ACEP's clinical policies and the approaches used in their development have been enumerated.
      • Schriger D.L.
      • Cantrill S.V.
      • Greene C.S.
      The origins, benefits, harms and implications of emergency medicine clinical policies.
      Expert review comments were received from emergency physicians, neurologists, and individual members of the American Academy of Family Physicians, American College of Physicians, Emergency Nurses Association, American Stroke Association, National Stroke Association, Neurocritical Care Society, and the Society for Academic Emergency Medicine. Their responses were used to further refine and enhance this policy; however, their responses do not imply endorsement of this clinical policy. Comments were also received from internal ACEP and AAN committees and workgroups. ACEP clinical policies are scheduled for revision every 3 years; however, interim reviews are conducted when technology or the practice environment changes significantly. ACEP and AAN are the funding source for this clinical policy.
      The searches resulted in 1,140 articles, of which 303 were selected for additional review and grading. All articles used in the formulation of this clinical policy were independently graded by at least 2 panel members for strength of evidence and classified by the panel members into 3 classes of evidence on the basis of the design of the study, with design 1 representing the strongest evidence and design 3 representing the weakest evidence for therapeutic, diagnostic, and prognostic clinical reports, respectively (Appendix A). Articles were then graded on 6 dimensions thought to be most relevant to the development of a clinical guideline: blinded versus nonblinded outcome assessment, allocation, direct or indirect outcome measures, biases (eg, selection, detection, transfer), external validity (ie, generalizability), and sufficient sample size. Articles received a final grade (Class I, II, III) on the basis of a predetermined formula taking into account design and quality of study (Appendix B). Articles with fatal flaws were given an “X” grade and not used in formulating recommendations in this policy. Evidence grading was done with respect to the specific data being extracted and the specific critical question being reviewed. Thus, the level of evidence for any one study may vary according to the question, and it is possible for a single article to receive different levels of grading as different critical questions are answered. Question-specific level of evidence grading may be found in the Evidentiary Table included at the end of this policy.
      Clinical findings and strength of recommendations regarding patient management were then made according to the following criteria:

       Level A recommendations

      Generally accepted principles for patient management that reflect a high degree of clinical certainty (ie, based on strength of evidence Class I or overwhelming evidence from strength of evidence Class II studies that directly address all of the issues).

       Level B recommendations

      Recommendations for patient management that may identify a particular strategy or range of management strategies that reflect moderate clinical certainty (ie, based on strength of evidence Class II studies that directly address the issue, decision analysis that directly addresses the issue, or strong consensus of strength of evidence Class III studies).

       Level C recommendations

      Other strategies for patient management that are based on Class III studies, or in the absence of any adequate, published literature, based on panel consensus.
      There are certain circumstances in which the recommendations stemming from a body of evidence should not be rated as highly as the individual studies on which they are based. Factors such as heterogeneity of results, uncertainty about effect magnitude and consequences, and publication bias, among others, might lead to such a downgrading of recommendations.
      When possible, clinically oriented statistics (eg, likelihood ratios, number needed to treat) will be presented to help the reader better understand how the results can be applied to the individual patient. For further definition of these statistical concepts, see Appendix C.
      This policy is not intended to be a complete manual on the evaluation and management of adult patients with acute ischemic stroke but rather a focused examination of critical issues that have particular relevance to the current practice of emergency medicine. It is the goal of this panel to provide an evidence-based recommendation when the medical literature provides enough quality information to answer a critical question. When the medical literature does not contain enough quality information to answer a critical question, the members of the panel believe that it is equally important to alert physicians to this fact. Recommendations offered in this policy are not intended to represent the only diagnostic and management options that the physician should consider. ACEP and AAN clearly recognize the importance of the individual physician's judgment. Rather, this guideline defines for the physician those strategies for which medical literature exists to provide support for answers to the critical questions addressed in this policy.

       Scope of Application

      This guideline is intended for physicians working in hospital-based emergency departments (EDs).

       Inclusion Criteria

      This guideline is intended for adult patients presenting to the ED with acute ischemic stroke.

       Exclusion Criteria

      This guideline is not intended to be applied to children younger than 18 years.

      Critical Questions

      • 1
        Is IV tPA safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset?
      • 2
        Is IV tPA safe and effective for acute ischemic stroke patients treated between 3 to 4.5 hours after symptom onset?

       Patient Management Recommendations

       Level A recommendations

      In order to improve functional outcomes, IV tPA should be offered to acute ischemic stroke patients who meet National Institute of Neurological Disorders and Stroke (NINDS) inclusion/exclusion criteria and can be treated within 3 hours after symptom onset.
      The effectiveness of tPA has been less well established in institutions without the systems in place to safely administer the medication.

       Level B recommendations

      In order to improve functional outcomes, IV tPA should be considered in acute ischemic stroke patients who meet European Cooperative Acute Stroke Study (ECASS) III inclusion/exclusion criteria and can be treated between 3 to 4.5 hours after symptom onset.
      The effectiveness of tPA has been less well established in institutions without the systems in place to safely administer the medication.
      Note: Within any time window, once the decision is made to administer IV tPA, the patient should be treated as rapidly as possible. As of this writing, tPA for acute ischemic stroke in the 3- to 4.5-hour window is not FDA approved.

       Level C recommendations

      None specified.
      Most ischemic strokes in adults are caused by thrombotic or embolic occlusions of an artery. With tPA, inactive plasminogen is converted into the active form plasmin, which promotes thrombolysis by cleaving fibrin. In 1995, the NINDS tPA Stroke Study Group published a 2-part randomized controlled trial showing that human recombinant tPA improved outcomes after ischemic stroke.
      National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group
      Tissue plasminogen activator for acute ischemic stroke.
      This publication led to FDA approval in 1996. Reaction to the availability of tPA for acute ischemic stroke has ranged from skepticism
      • Mitka M.
      Tensions remain over tPA for stroke.
      to unbridled enthusiasm.
      • Lyden P.D.
      • Lees K.R.
      • Davis S.M.
      Alteplase for acute stroke revisited: the first 10 years.
      The Class I NINDS tPA study was divided into 2 parts.
      National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group
      Tissue plasminogen activator for acute ischemic stroke.
      Each part was performed in a unique, independently enrolled population of patients with acute ischemic stroke but with different prespecified primary outcomes. In both parts, acute ischemic stroke patients presenting within 3 hours of symptom onset were randomized 1:1 to placebo versus IV treatment with 0.9 mg/kg of the human recombinant tPA alteplase, with 10% of the total dose administered as a bolus and the remaining 90% infused over 60 minutes (maximum dose 90 mg). Randomization was stratified by clinical center and by time from the onset of stroke to treatment (0 to 90 minutes and 91 to 180 minutes). The prespecified primary outcome of NINDS part I (n=291) was early clinical improvement, defined as complete resolution of the stroke symptoms or an improvement in the National Institutes of Health Stroke Scale (NIHSS) (Figure 1) score by 4 or more points at 24 hours. There was no difference in early clinical improvement in the tPA group compared with the placebo group (relative risk 1.2; 95% confidence interval [CI] 0.9 to 1.6; P=.21). The prespecified primary outcome of NINDS part II (n=333) was a favorable outcome at 3 months, determined using 4 assessment scales: the Barthel Index (Figure 2), modified Rankin Scale (Table 1), Glasgow Outcome Scale (Table 2), and NIHSS (Figure 1). To test the primary hypothesis, a global endpoint was derived from the individual scales with the use of scale-specific cut points. The odds ratio (OR) for a favorable outcome in the tPA group, defined as minimal or no disability at 90 days, was 1.7 (95% CI 1.2 to 2.6; P=.008). A favorable outcome for the tPA group was observed on each of the 4 assessment scales (P=.02 to .03), with absolute percentage differences between tPA and placebo ranging from 11% to 13%. For example, a modified Rankin Scale score outcome of 0 or 1, indicating no residual disabling stroke symptoms, was achieved in 39% of tPA-treated patients versus 26% of placebo-treated patients. There was a 12% absolute increase in the number of patients with minimal or no disability in the tPA group, defined by the global statistic. This corresponds to a number needed to treat of 8.3, meaning that 8.3 patients would need to be treated for 1 additional patient to achieve a favorable outcome with essentially no stroke-related disability. A subsequent reanalysis of the trial data suggested that the number needed to treat to produce a 1-point shift in the Rankin Scale, including from states of severe disability to more moderate disability, may be as low as 3.
      • Saver J.L.
      Number needed to treat estimates incorporating effects over the entire range of clinical outcomes: novel derivation method and application to thrombolytic therapy for acute stroke.
      Figure thumbnail gr1
      Figure 1National Institutes of Health Stroke Scale.
      Table 1Modified Rankin Scale.
      The modified Rankin Scale is a 6-point clinical outcome scale that measures a patient's function and independence. A lower score indicates a better outcome.
      (Used with permission).
      Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J. 1957;2:200−215. © Copyright 1957 Royal Society of Medicine Press, UK.
      ScoreDescription
      0No symptoms
      1No significant disability despite symptoms; able to carry out all usual duties and activities
      2Slight disability; unable to carry out all previous activities but able to look after own affairs without assistance
      3Moderate disability; requiring some help but able to walk without assistance
      4Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance
      5Severe disability; bedridden, incontinent, and requiring constant nursing care and attention
      6Dead
      low asterisk The modified Rankin Scale is a 6-point clinical outcome scale that measures a patient's function and independence. A lower score indicates a better outcome.
      Table 2Glasgow Outcome Score.
      The Glasgow Outcome Score is another simple measure of functional outcome.
      (Used with permission).
      Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1:480-484. © Copyright 1975, with permission from Elsevier.
      5Good RecoveryResumption of normal life despite minor deficits.
      4Moderate DisabilityDisabled but independent. Can work in sheltered setting.
      3Severe DisabilityConscious but disabled. Dependent for daily support.
      2Persistent vegetativeMinimal responsiveness
      1Death
      low asterisk The Glasgow Outcome Score is another simple measure of functional outcome.
      Combined analysis of parts I and II of the NINDS study showed a consistent effect of IV tPA on favorable outcome at 90 days.
      National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group
      Tissue plasminogen activator for acute ischemic stroke.
      This beneficial effect was observed in both the 0- to 90-minute and the 91- to 180- minute time strata. Mortality was similar in both groups (17% for tPA versus 21% for placebo; P=.30). There was, however, an increase in symptomatic intracerebral hemorrhage in the tPA-treated group during the first 36 hours (6% versus 0.6% in the placebo group; P<.001). Many of these tPA-related hemorrhages were fatal (45%). Therefore, the improved 90-day outcomes in the tPA group (without an increased overall mortality) occurred despite the excess mortality in patients who had symptomatic intracerebral hemorrhage.
      Secondary subgroup analyses of the combined NINDS part I and part II studies failed to find evidence of a different effect of tPA according to age, sex, stroke severity, and stroke type.
      The NINDS t-PA Stroke Study Group
      Generalized efficacy of t-PA for acute stroke Subgroup analysis of the NINDS t-PA stroke trial.
      In 1995 and 1996, several other large randomized trials of thrombolytic agents in acute ischemic stroke were published, including the Australian Streptokinase trial,
      • Donnan G.A.
      • Davis S.M.
      • Chambers B.R.
      • et al.
      Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group.
      Multicenter Acute Stroke Trial–Italy,
      Multicentre Acute Stroke Trial–Italy (MAST-I) Group
      Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke.
      Multicenter Acute Stroke Trial–Europe,
      The Multicenter Acute Stroke Trial–Europe Study Group
      Thrombolytic therapy with streptokinase in acute ischemic stroke.
      and ECASS I.
      • Hacke W.
      • Kaste M.
      • Fieschi C.
      • et al.
      Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke The European Cooperative Acute Stroke Study (ECASS).
      All of these studies failed to demonstrate a benefit of thrombolysis for stroke, and some were halted early because of excessive mortality in the treatment arm.
      Multicentre Acute Stroke Trial–Italy (MAST-I) Group
      Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke.
      The Multicenter Acute Stroke Trial–Europe Study Group
      Thrombolytic therapy with streptokinase in acute ischemic stroke.
      All of these studies were different from the NINDS study in that they used different thrombolytic agents (streptokinase),
      • Donnan G.A.
      • Davis S.M.
      • Chambers B.R.
      • et al.
      Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group.
      Multicentre Acute Stroke Trial–Italy (MAST-I) Group
      Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke.
      The Multicenter Acute Stroke Trial–Europe Study Group
      Thrombolytic therapy with streptokinase in acute ischemic stroke.
      different time periods for treatment (up to 6 hours), higher doses of tPA (1.1 mg/kg),
      • Hacke W.
      • Kaste M.
      • Fieschi C.
      • et al.
      Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke The European Cooperative Acute Stroke Study (ECASS).
      or allowed other concomitant antithrombotics (aspirin).
      Multicentre Acute Stroke Trial–Italy (MAST-I) Group
      Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke.
      Other randomized trials of IV tPA, using the same dose but with longer time periods, generated mixed outcomes. The Class I ECASS II tested tPA (0.9 mg/kg) versus placebo in acute ischemic stroke of less than 6 hours' duration.
      • Hacke W.
      • Kaste M.
      • Fieschi C.
      • et al.
      Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators.
      The primary endpoint was the proportion of patients with a favorable outcome on the modified Rankin Scale, defined as a score of 0 or 1. There was no difference in this outcome between tPA-treated and placebo controls in the overall cohort (40% versus 37%; P=.28) and in patients treated within 3 hours (42% versus 38%; P=.63), although less than 20% of patients were treated within that time period. Parenchymal hemorrhage on posttreatment computed tomography (CT) was observed in 12% of tPA and 3% of placebo patients (P<.001). The 90-day mortality rate was equal (11%) for both the tPA and placebo groups (P=.99).
      The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trial also tested IV tPA (0.9 mg/kg) versus placebo in patients with stroke symptoms of fewer than 6 hours' duration.
      • Clark W.M.
      • Albers G.W.
      • Madden K.P.
      • et al.
      Thrombolytic Therapy in Acute Ischemic Stroke Study Investigators
      The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study.
      The trial was stopped prematurely after enrolling 142 patients because of increased symptomatic intracerebral hemorrhage in patients enrolled 5 to 6 hours after stroke symptom onset. The trial protocol was modified and a new trial, enrolling patients 0 to 5 hours after stroke onset, was begun (ATLANTIS Part B). In ATLANTIS Part B, 613 patients were randomized 1:1 to 0.9 mg/kg tPA or placebo.
      • Clark W.M.
      • Wissman S.
      • Albers G.W.
      • et al.
      Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke Study Investigators
      Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset The ATLANTIS Study: a randomized controlled trial.
      After 31 patients were enrolled, the time window was changed to 3 to 5 hours after symptom onset because of FDA approval for IV tPA in 1996. The primary outcome was the proportion of patients with an excellent recovery, defined as an NIHSS score of 0 or 1 at 90 days. There was no difference in the primary outcome between tPA-treated patients and placebo controls (34% versus 32%; P=.65). In the tPA-treated group, there was a higher rate of symptomatic intracerebral hemorrhage (7% versus 1%; P<.001) and a trend toward higher mortality (11% versus 6.9%; P=.09).
      • Clark W.M.
      • Wissman S.
      • Albers G.W.
      • et al.
      Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke Study Investigators
      Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset The ATLANTIS Study: a randomized controlled trial.
      The mean time to treatment in this study was 4 hours 28 minutes. Among the 61 patients randomized within 3 hours, of whom 23 were randomized to tPA and 38 were randomized to placebo, more tPA-treated patients achieved the primary outcome (61% of tPA versus 26% of placebo; P=.01) and had symptomatic intracerebral hemorrhage (13% of tPA versus 0% of placebo; P=.05).
      • Albers G.W.
      • Clark W.M.
      • Madden K.P.
      • et al.
      ATLANTIS trial: results for patients treated within 3 hours of stroke onset.
      The NINDS part II study is therefore unique in showing a benefit in the preselected primary outcome for 0.9 mg/kg tPA for patients with ischemic stroke of less than 3 hours' duration.
      National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group
      Tissue plasminogen activator for acute ischemic stroke.
      The reproducibility of the finding is supported by the reanalysis of the NINDS study, which found that 90-day outcomes were again significantly improved, without a difference in mortality rates.
      • Ingall T.J.
      • O'Fallon W.M.
      • Asplund K.
      • et al.
      Findings from the reanalysis of the NINDS tissue plasminogen activator for acute ischemic stroke treatment trial.
      Furthermore, a Class II patient-level meta-analysis that includes data from the NINDS, ECASS, ATLANTIS, and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) studies of patients treated within 3 hours also supports the efficacy of tPA.
      • Lees K.R.
      • Bluhmki E.
      • von Kummer R.
      • et al.
      Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.
      The increased number of patients in this meta-analysis provided a more precise estimate of the potential effect of treatment, and the calculated 95% CIs suggested that tPA's benefit diminished over time but remained significant up to 4.5 hours after onset of symptoms.
      • Lees K.R.
      • Bluhmki E.
      • von Kummer R.
      • et al.
      Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.
      Two independent groups have reanalyzed the NINDS trial data. First, an independent committee was commissioned by the NINDS to verify the validity of the NINDS trial results and to address the concern that an imbalance in stroke severity at baseline may have confounded the analysis of the relationship between IV tPA and the likelihood of a good outcome.
      • Ingall T.J.
      • O'Fallon W.M.
      • Asplund K.
      • et al.
      Findings from the reanalysis of the NINDS tissue plasminogen activator for acute ischemic stroke treatment trial.
      Although the median baseline NIHSS score was not different in the tPA and placebo groups (P=.10), there were more patients in the 91- to 180-minute stratum with baseline NIHSS 0 to 5 who were randomized to tPA rather than placebo (29 patients to tPA versus 7 patients to placebo). The committee found that the relationship between tPA use and good outcome remained robust (OR 2.1; 95% CI 1.5 to 2.9) after adjustment for baseline NIHSS and other factors related to stroke outcome, using data from NINDS part I and part II.
      • Ingall T.J.
      • O'Fallon W.M.
      • Asplund K.
      • et al.
      Findings from the reanalysis of the NINDS tissue plasminogen activator for acute ischemic stroke treatment trial.
      Second, an independent author group reanalyzed the data with graphic analysis but without statistical testing.
      • Hoffman J.R.
      • Schriger D.L.
      A graphic reanalysis of the NINDS trial.
      They concluded that tPA had only a small effect on the change in NIHSS score between baseline and day 90. The NIHSS change was not a primary outcome of the NINDS part II trial, however, and the authors did not dispute that tPA had a statistically significant effect on the primary trial outcome.
      Data have been accumulating addressing the use of IV tPA within 3 to 4.5 hours after onset of symptoms. As noted above, the Class II meta-analysis of studies using 0.9 mg/kg of tPA confirmed a benefit for tPA within 3 hours of onset of symptoms and suggested that the benefit remained significant up to 4.5 hours from symptom onset.
      • Lees K.R.
      • Bluhmki E.
      • von Kummer R.
      • et al.
      Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.
      The benefit of 0.9 mg/kg tPA between 3 to 4.5 hours after symptom onset was directly tested in the Class I ECASS III randomized controlled trial.
      • Hacke W.
      • Kaste M.
      • Bluhmki E.
      • et al.
      ECASS Investigators
      Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.
      The trial used the same dosing regimen and inclusion/exclusion criteria as the NINDS protocol (Figure 3), with additional exclusions: age greater than 80 years, baseline NIHSS score greater than 25, any oral anticoagulant use (regardless of the international normalized ratio), and the combination of a previous stroke and diabetes mellitus. In addition, in contrast to the NINDS protocol, patients were permitted to receive parenteral anticoagulants for prophylaxis of deep venous thrombosis within the first 24 hours after treatment with tPA. The frequency of the primary efficacy outcome in ECASS III (defined as modified Rankin Scale score 0 to 1 at 90 days after treatment) was significantly greater with tPA (291/418; 52.4%) than placebo (182/403; 45.2%) (OR 1.34; 95% CI 1.02 to 1.76; risk ratio 1.16; 95% CI 1.01 to 1.34; P=.04). Mortality rates were equivalent (7.7% for tPA-treated patients versus 8.4% for placebo-treated patients). Symptomatic intracranial hemorrhage, as defined by the criteria used in the NINDS study, was reported in 33 subjects treated with t-PA (7.9%) and in 14 subjects given placebo (3.5%) (OR 2.38; 95% CI 1.25 to 4.52; P=.006). The hemorrhage rates were slightly higher for both placebo and tPA-treated patients compared with that in the NINDS study, which may be attributable to the early use of parenteral deep venous thrombosis prophylaxis allowed in this study. The benefit in ECASS III was more modest than that observed in the NINDS trials, and the number needed to treat to achieve 1 excellent outcome was 14 in this study. This is consistent with the tPA meta-analysis within this timeframe and reinforces the concept that earlier time to treatment has a large impact on likelihood of good outcome within any defined timeframe. Therefore, although the time window for tPA treatment may have been lengthened based on the ECASS III results, the aggregate data strongly suggest that patient outcomes will be optimized by the earliest possible administration of tPA after a safe and thorough clinical and brain imaging evaluation. The notion that there is “plenty of time” to evaluate patients and administer tPA could lead to delays that reduce the effectiveness of the drug.
      • Del Zoppo G.J.
      • Saver J.L.
      • Jauch E.C.
      • et al.
      American Heart Association Stroke Council
      Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association.
      Figure thumbnail gr3
      Figure 3NINDS and ECASS III inclusion and exclusion criteria for intravenous tPA for acute ischemic stroke.
      The substantial increased rate of symptomatic intracerebral hemorrhage among tPA-treated patients has tempered enthusiasm for the rapid adoption of tPA as routine care, in part because of the concern that treatment may be less safe in routine clinical practice than in the highly monitored setting of a clinical trial. As a result, regulatory agencies in the United States, Canada, and the European Union mandated phase IV studies to determine whether outcomes in clinical practice matched those achieved in the trials. Single-center (or in 1 case, single system
      • Wang D.Z.
      • Rose J.A.
      • Honings D.S.
      • et al.
      Treating acute stroke patients with intravenous tPA The OSF Stroke Network experience.
      ) studies from early adopters suggested cause for concern, with major protocol violations occurring in 9% to 67% of treated patients.
      • Wang D.Z.
      • Rose J.A.
      • Honings D.S.
      • et al.
      Treating acute stroke patients with intravenous tPA The OSF Stroke Network experience.
      • Lopez-Yunez A.M.
      • Bruno A.
      • Williams L.S.
      • et al.
      Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage.
      • Katzan I.L.
      • Furlan A.J.
      • Lloyd L.E.
      • et al.
      Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience.
      • Bravata D.M.
      • Kim N.
      • Concato J.
      • et al.
      Thrombolysis for acute stroke in routine clinical practice.
      • Szoeke C.E.
      • Parsons M.W.
      • Butcher K.S.
      • et al.
      Acute stroke thrombolysis with intravenous tissue plasminogen activator in an Australian tertiary hospital.
      • Bray J.E.
      • Coughlan K.
      • Bladin C.
      Thrombolytic therapy for acute ischaemic stroke: successful implementation in an Australian tertiary hospital.
      Most violations were related to time criteria, blood pressure monitoring and control, or provision of antithrombotics or anticoagulants within 24 hours of tPA administration. Some studies found that protocol violations were associated with a higher rate of symptomatic intracerebral hemorrhage
      • Lopez-Yunez A.M.
      • Bruno A.
      • Williams L.S.
      • et al.
      Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage.
      and mortality.
      • Bravata D.M.
      • Kim N.
      • Concato J.
      • et al.
      Thrombolysis for acute stroke in routine clinical practice.
      The first large postmarketing multicenter study, mandated by the FDA, was the Class III Standard Treatment with Alteplase to Reverse Stroke (STARS) study.
      • Albers G.W.
      • Bates V.E.
      • Clark W.M.
      • et al.
      Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study.
      Most of the participating centers had previously enrolled patients in clinical trials of tPA for stroke. The administration of tPA followed the NINDS protocol.
      National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group
      Tissue plasminogen activator for acute ischemic stroke.
      Outcomes were similar to those in the tPA arm of the NINDS trial (see Evidentiary Table). Two larger registries from Canada and Europe found that tPA administered in clinical practice had rates of symptomatic intracerebral hemorrhage of 4% to 5% and rates of disability and mortality similar to that observed in the NINDS trial.
      • Hill M.D.
      • Buchan A.M.
      Canadian Alteplace for Stroke Effectiveness Study (CASES) Investigators
      Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study.
      • Wahlgren N.
      • Ahmed N.
      • Davalos A.
      • et al.
      SITS-MOST Investigators
      Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study.
      The Class II Canadian Alteplase for Stroke Effectiveness Study (CASES)
      • Hill M.D.
      • Buchan A.M.
      Canadian Alteplace for Stroke Effectiveness Study (CASES) Investigators
      Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study.
      tracked outcomes of 1,135 tPA-treated patients, which the authors estimated to represent 84% of all treated patients in Canada during the study period. Using multivariable-adjusted predictive modeling, the authors found no difference between the observed rate of a good outcome and the expected rate based on a model derived from the NINDS data set. The Class II Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) tracked outcomes of 6,442 tPA-treated patients from 285 centers in Europe.
      • Wahlgren N.
      • Ahmed N.
      • Davalos A.
      • et al.
      SITS-MOST Investigators
      Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study.
      The proportion with good outcome was 38.9%, and symptomatic intracerebral hemorrhage, defined according to criteria used in ECASS II,
      • Hacke W.
      • Kaste M.
      • Fieschi C.
      • et al.
      Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators.
      was 4.6%.
      There are fewer data on the use of tPA in clinical practice in the 3- to 4.5-hour time period. The Class III Safe Implementation of Treatments in Stroke–International Stroke Thrombolysis Registry (SITS-ISTR) 3- to 4.5- hour study was a post hoc assessment of data acquired between December 2002 and February 2010 from an ongoing international registry.
      • Ahmed N.
      • Wahlgren N.
      • Grand M.
      • et al.
      SITS-MOST Investigators
      Implementation and outcome of thrombolysis with alteplase 3-4.5 hours after an acute stroke: an updated analysis from SITS-ISTR.
      This study reported outcomes in 2,317 patients treated with tPA between 3 to 4.5 hours after onset. Most patients were treated after publication of the ECASS III trial in October 2008. There were 44.5% with good outcome (modified Rankin Scale score 0 or 1), whereas 7.4% had symptomatic intracranial hemorrhage by the NINDS trial definition and 12.0% died by 3 months. Compared with the ECASS III tPA-treated arm, the proportion with good outcome was somewhat lower and the proportion with mortality was somewhat higher, probably because patients in the SITS-ISTR registry had higher initial stroke severity and more medical comorbidities than the patients enrolled in the ECASS III trial.

       Putting the Evidence Into Clinical Context

      Safe and effective administration of tPA relies on a hospital having a system in place for treating stroke patients. Patients must undergo rapid and accurate diagnosis of acute ischemic stroke, including rapid access to laboratory test results, brain imaging, and accurate image interpretation. Protocols must be in place for drug administration, close clinical monitoring, active blood pressure management, and treatment of hemorrhagic complications (systemic or intracerebral) if they occur. If a given hospital is unable to provide this infrastructure, protocols should be in place for transferring patients to a facility that can. Whatever a hospital's approach is, an ongoing quality assurance program ought to be in place. Physician expertise and written protocols are therefore hypothesized to be important for use of tPA
      • Alberts M.J.
      • Hademenos G.
      • Latchaw R.E.
      • et al.
      Recommendations for the establishment of primary stroke centers Brain Attack Coalition.
      but may be in short supply in smaller centers without an abundance of stroke specialists. The CASES and SITS-MOST studies, which included a broad selection of academic and community hospitals, showed results similar to those observed in the NINDS trial. Additionally, both studies failed to find a difference in outcomes in patients treated at more experienced centers, defined by tPA case volume, compared with less experienced centers. The SITS-MOST findings must be treated with some caution, however, because all centers were required to have a neurologist or other physician with “considerable experience in stroke care.”
      • Wahlgren N.
      • Ahmed N.
      • Davalos A.
      • et al.
      SITS-MOST Investigators
      Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study.
      Adequate physician acute stroke care expertise has not been rigorously defined in the literature, based on either credential or degree of experience, or studied in clinical trials. The definition should not be restricted to neurologists and should include emergency physicians or other physicians with expertise and experience in stroke care, according to recommendations from the Brain Attack Coalition
      • Alberts M.J.
      • Hademenos G.
      • Latchaw R.E.
      • et al.
      Recommendations for the establishment of primary stroke centers Brain Attack Coalition.
      and the Canadian Stroke Consortium.
      • Norris J.W.
      • Buchan A.
      • Cote R.
      • et al.
      Canadian guidelines for intravenous thrombolytic treatment in acute stroke A consensus statement of the Canadian Stroke Consortium.
      For centers without on-site acute stroke specialists, telestroke technology offers a means to obtain remote consultation about the administration of IV tPA. In a study by Fisher,
      • Fisher M.
      Developing and implementing future stroke therapies: the potential of telemedicine.
      the formation of “telestroke” networks allowed inexperienced centers to obtain expert medical and radiologic consultation by remote video linkage. Accumulating data show that this model of stroke care produces results similar to those obtained by on-site consultation with stroke experts.
      • LaMonte M.P.
      • Bahouth M.N.
      • Hu P.
      • et al.
      Telemedicine for acute stroke: triumphs and pitfalls.
      • Wang S.
      • Gross H.
      • Lee S.B.
      • et al.
      Remote evaluation of acute ischemic stroke in rural community hospitals in Georgia.
      • Schwamm L.H.
      • Rosenthal E.S.
      • Hirshberg A.
      • et al.
      Virtual TeleStroke support for the emergency department evaluation of acute stroke.
      A Class III study from a network of hospitals in Bavaria, Germany, found that 115 patients treated with tPA at remote sites using telestroke had similar inhospital rates of symptomatic hemorrhage (7.8%) and mortality (3.5%) compared with locally treated patients at the academic stroke centers.
      • Audebert H.J.
      • Kukla C.
      • Vatankhah B.
      • et al.
      Comparison of tissue plasminogen activator administration management between telestroke network hospitals and academic stroke centers: the Telemedical Pilot Project for Integrative Stroke Care in Bavaria/Germany.
      A randomized controlled trial showed that more accurate decisions are made when video consultation, rather than telephone consultation, is used.
      • Meyer B.C.
      • Raman R.
      • Hemmen T.
      • et al.
      Efficacy of site-independent telemedicine in the STRokE DOC trial: a randomized, blinded, prospective study.
      The American Heart Association published recommendations on the use of telemedicine for acute stroke care.
      • Schwamm L.H.
      • Audebert H.J.
      • Amarenco P.
      • et al.
      American Heart Association Stroke Council, Council on Epidemiology and Prevention, Interdisciplinary Council on Peripheral Vascular Disease, Council on Cardiovascular Radiology and Intervention
      Recommendations for the implementation of telemedicine within stroke systems of care: a policy statement from the American Heart Association.
      There has been clinical concern about treatment of patient groups who would meet NINDS criteria but have a poor prognosis for good outcome, irrespective of tPA use, including those with advanced age, severe clinical deficits, and CT hypodensity in a large portion of the middle cerebral artery territory or hemisphere. The SITS-MOST and SITS-ISTR treatment protocol excluded patients older than 80 years, with NIHSS score greater than or equal to 25, or with “severe stroke” on CT.
      • Wahlgren N.
      • Ahmed N.
      • Davalos A.
      • et al.
      SITS-MOST Investigators
      Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study.
      • Ahmed N.
      • Wahlgren N.
      • Grand M.
      • et al.
      SITS-MOST Investigators
      Implementation and outcome of thrombolysis with alteplase 3-4.5 hours after an acute stroke: an updated analysis from SITS-ISTR.
      The Canadian guidelines list CT evidence of infarction involving more than one third of the middle cerebral artery territory as an exclusion criterion.
      • Norris J.W.
      • Buchan A.
      • Cote R.
      • et al.
      Canadian guidelines for intravenous thrombolytic treatment in acute stroke A consensus statement of the Canadian Stroke Consortium.
      The American Heart Association/American Stroke Association guidelines include that CT does not show a “hypodensity greater than one third of the cerebral hemisphere” and a “caution” for the presence of major deficits,
      • Adams Jr, H.P.
      • del Zoppo G.
      • Alberts M.J.
      • et al.
      Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists.
      and the American College of Chest Physicians guidelines recommend against treatment when clearly identifiable hypodensity is present in greater than one third of the middle cerebral artery territory while not disallowing treatment in the presence of early ischemic changes such as subtle loss of gray-white differentiation or sulcal effacement without hypodensity.
      • Albers G.W.
      • Amarenco P.
      • Easton J.D.
      • et al.
      Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
      Patients with these characteristics have been excluded, underrepresented, or not reported on in the major observational studies; therefore, data on outcomes in these patient subgroups in clinical practice are lacking.
      The exception is advanced age, for which several studies report generally worse outcomes compared with younger subjects but no increased risk of symptomatic intracerebral hemorrhage.
      • Sylaja P.N.
      • Cote R.
      • Buchan A.M.
      • et al.
      Canadian Alteplase for Stroke Effectiveness Study (CASES) Investigators
      Thrombolysis in patients older than 80 years with acute ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study.
      • Engelter S.T.
      • Reichhart M.
      • Sekoranja L.
      • et al.
      Thrombolysis in stroke patients aged 80 years and older: Swiss survey of IV thrombolysis.
      • Tanne D.
      • Gorman M.J.
      • Bates V.E.
      • et al.
      Intravenous tissue plasminogen activator for acute ischemic stroke in patients aged 80 years and older: the tPA stroke survey experience.
      This is not a surprising finding, given that age is a well-established risk factor for poor outcome regardless of intervention. Although it is appropriate to exercise caution when considering treatment for these subgroups with poor prognosis, a post hoc analysis of the 1995 NINDS trial failed to show evidence of a differential effect of tPA according to patient subgroups, including those with advanced age, severe clinical deficits, and more extensive CT changes.
      The NINDS t-PA Stroke Study Group
      Generalized efficacy of t-PA for acute stroke Subgroup analysis of the NINDS t-PA Stroke Trial.

       Addendum

      After this document was completed, the International Stroke Trial 3 (IST-3) was electronically published in Lancet.

      Sandercock P, Wardlaw JM, Lindley RI, et al, for the IST-3 Collaborative Group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h or acute ischaemic stroke (the third International Stroke Trial [IST-3]): a randomized controlled trial. Lancet. doi:10.1016/S0140-6736(12)60768-5.

      IST-3 was designed to evaluate the effects of tPA on patients with ischemic stroke up to 6 hours from symptom onset in whom benefit was deemed to be uncertain (the vast majority of whom had contraindications to tPA defined by NINDS criteria in the 0- to 3-hour window or ECASS-3 criteria in the 3- to 4.5-hour window). IST-3 looked at a different cohort of patients than those on which this policy focuses. The published trial data were carefully reviewed by the writing panel, and it was determined that the study's methodology was such that the findings did not affect the recommendations made in this practice guideline.

       Disclosures

      Dr. Edlow serves on the Executive Committee of the Foundation for Education and Research in Neurologic Emergencies, coedited the textbook of Neurological Emergencies for Oxford University Press, and serves on the editorial board of the Journal of Internal and Emergency Medicine and the International Journal of Emergency Medicine. He also reviews medical malpractice cases for both plaintiff and defense.
      Dr. Smith served on a scientific advisory board for Genentech in 2010, received speaker honoraria from the Canadian Conference on Dementia, serves as an assistant editor for Stroke, has served on speakers' bureaus for QuantiaMD and BMJ Best Practice, is on the Data and Safety Monitoring Board for the MR Witness trial funded by the National Institutes of Health (NIH)/NINDS, and receives research support from the NIH/ NINDS, Canadian Institutes for Health Research, Canadian Stroke Network, the Alberta Heritage Fund for Medical Research, and the Heart and Stroke Foundation of Canada.
      Dr. Stead is editor-in-chief of the International Journal of Emergency Medicine.
      Dr. Gronseth serves as an editorial advisory board member of Neurology Now, serves on a speakers' bureau for Boehringer Ingelheim, and receives honoraria from Boehringer Ingelheim and the American Academy of Neurology.
      Dr. Messé receives publishing royalties from Up-To-Date, formerly served on the speakers' bureau for Boehringer Ingelheim (ended 4/2011), and receives research support from Gore, the NIH (NIDDK, U01-DK060990, Endpoint Adjudication Committee), National Heart, Lung, and Blood Institute (NHLBI) (1R01HL084375-01A2, subinvestigator, neurologic assessments), NINDS (U01NS40406-04, local principal investigator), and NIH (HHSN268200800003C, backup medical monitor).
      Dr. Jagoda serves on the executive board for the Brain Attack Coalition and for the Foundation for Education and Research in Neurologic Emergencies, serves on the advisory board for the Brain Trauma Foundation, and is a consultant for Banyan Biomarkers, Cyvek, Pfizer, and GORE. He is also editor-in-chief of Emergency Medicine Practice and serves on the editorial boards for Pediatric Emergency Medicine Practice, Emergency Medicine Practice Guidelines, EM Critical Care, Annals of Emergency Medicine, ACEP News, and Australasian Journal of Emergency Medicine.
      Dr. Wears serves on the board of directors of the Emergency Medicine Patient Safety Foundation, on the editorial board for Annals of Emergency Medicine, and on the editorial board for Human Factors and International Journal of Risk and Safety in Medicine.
      Dr. Decker serves as trustee and Vice President, Mayo Clinic, CEO for Mayo Clinic in Scottsdale, AZ.

      Supplementary data.

      Evidentiary Table
      Appendix ALiterature classification schema.
      Some designs (eg, surveys) will not fit this schema and should be assessed individually.
      Design/ClassTherapy
      Objective is to measure therapeutic efficacy comparing interventions.
      Diagnosis
      Objective is to determine the sensitivity and specificity of diagnostic tests.
      Prognosis
      Objective is to predict outcome including mortality and morbidity.
      1Randomized, controlled trial or meta-analysis of randomized trialsProspective cohort using a criterion standard or meta-analysis of prospective studiesPopulation prospective cohort or meta-analysis of prospective studies
      2Nonrandomized trialRetrospective observational
      • Retrospective cohort
      • Case control
      3
      • Case series
      • Case report
      • Other (eg, consensus, review)
      • Case series
      • Case report
      • Other (eg, consensus, review)
      • Case series
      • Case report
      • Other (eg, consensus, review)
      low asterisk 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 BApproach to downgrading strength of evidence.
      Design/Class
      Downgrading123
      NoneIIIIII
      1 levelIIIIIX
      2 levelsIIIXX
      Fatally flawedXXX
      Appendix CLikelihood ratios and number needed to treat.
      Number needed to treat (NNT): the number of patients who need to be treated to achieve 1 additional good outcome; NNT=1/absolute risk reductionx100, where absolute risk reduction is the risk difference between 2 event rates (ie, experimental and control groups).
      LR (+)LR (−)
      1.01.0Useless
      1-50.5-1Rarely of value, only minimally changes pretest probability
      100.1Worthwhile test, may be diagnostic if the result is concordant with pretest probability
      200.05Strong test, usually diagnostic
      1000.01Very accurate test, almost always diagnostic even in the setting of low or high pretest probability
      LR, likelihood ratio.
      low asterisk Number needed to treat (NNT): the number of patients who need to be treated to achieve 1 additional good outcome; NNT=1/absolute risk reductionx100, where absolute risk reduction is the risk difference between 2 event rates (ie, experimental and control groups).

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