Published online before print May 28, 2009, doi: 10.1161/STROKEAHA.109.192535
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(Stroke. 2009;40:2945.)
© 2009 American Heart Association, Inc.
AHA/ASA Science Advisory |
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
Key Words: AHA Scientific Statements • stroke • tissue plasminogen activator • hemorrhage • intracerebral hemorrhage
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Introduction |
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 Top Introduction RecommendationsReferences |
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Current guidelines for the management of patients with acute ischemic stroke published by the American Heart Association Stroke Council include specific recommendations for the administration of intravenous recombinant tissue plasminogen activator (rtPA).1 Despite its effectiveness in improving neurological outcomes, the majority of patients with ischemic stroke are not treated with rtPA, largely because they arrive after the currently approved 3-hour time limit for administration of the medication. One of the potential approaches to increase treatment opportunities has been the designation of a longer time window for treatment.2–4
A recent prospective study, the European Cooperative Acute Stroke Study (ECASS)-3, has provided new data on rtPA (alteplase) treatment in the 3-to-4.5–hour window.5 The circumstances surrounding this study are important.
In 2002, the European Medicines Evaluation Agency granted license for the use of rtPA for the treatment of ischemic stroke patients within 3 hours of symptom onset on condition of (1) the completion of a prospective registry of patient treatment experience with rtPA given within the 3-hour window from symptom onset (Safe Implementation of Thrombolysis in Stroke–Monitoring Study, or SITS-MOST)6 and (2) the completion of a prospective, randomized, placebo-controlled trial of rtPA administered between 3 and 4.5 hours after stroke onset, ECASS-3.5 SITS-MOST, which used a specified protocol, reported that the frequency of symptomatic intracerebral hemorrhage (per the SITS-MOST definition) at 24 hours after rtPA was 1.7% (95% confidence interval [CI] 1.4% to 2.0%; Figure 3 in Wahlgren et al6). The frequency of symptomatic intracerebral hemorrhage per the Cochrane/National Institute of Neurological Disorders and Stroke (NINDS) definition at 24 hours after rtPA was 7.3% (95% CI 6.7% to 7.9%). By comparison, this frequency was slightly less than 8.6% in data taken from a pool of randomized, controlled trials (Figure 2 in Wahlgren et al6). For efficacy, the frequency of scores of 0, 1, and 2 on the combined modified Rankin scale at 90 days was 54.8% (95% CI 53.5% to 56.0%) among rtPA patients, which was comparable to the pooled sample.6 These findings appear to confirm the potential safety of rtPA within the 3-hour window in European centers.
In addition, the Safe Implementation of Thrombolysis in Stroke–International Stroke Treatment Registry 3-to-4.5–hour study (SITS-ISTR 3-to-4.5 hour), a post hoc sampling of limited data acquired between December 2002 and November 2007 from the ongoing international registry (SITS-ISTR), compared 11 865 patients treated with rtPA within 3 hours of symptom onset with 664 patients who received treatment within 3 to 4.5 hours.7 Most (72%) of the patients treated after 3 hours were treated between 3 and 3.5 hours. Although there were several weaknesses in that study, no differences between the 3-to-4.5–hour cohort and the <3-hour cohort were apparent with respect to symptomatic intracerebral hemorrhage, mortality, or modified Rankin Scale score of 0 to 2 at 90 days.7 SITS-ISTR is an ongoing registry that includes experience from SITS-MOST, non-European centers, and active studies.
In 2008, ECASS-3, a multicenter, prospective, randomized, placebo-controlled trial that enrolled patients to best medical treatment together with either rtPA (n=418) or placebo (n=403) between 3 and 4.5 hours after symptom onset, was completed.5 The dosing regimen was 0.9 mg/kg (maximum of 90 mg), with 10% given as an initial bolus and the remainder infused over 1 hour, exactly what is stated in the current guidelines.1 Initially, the trial restricted enrollment to patients treated within 4 hours of stroke onset, then increased the permitted time window to 4.5 hours (median treatment interval 
4 hours). The trial excluded persons older than 80 years, those with a baseline National Institutes of Health Stroke Scale score >25, those taking oral anticoagulants, and those who had the combination of a previous stroke and diabetes mellitus. Otherwise, the exclusion and inclusion criteria for the trial were similar to those contained in the American Heart Association Stroke Council guidelines for treating persons within 3 hours of stroke onset.1 Ancillary medical care was similar to that included in the current guidelines except that patients were permitted to receive parenteral anticoagulants for prophylaxis of deep vein thrombosis within 24 hours after treatment with rtPA.
Symptomatic intracranial hemorrhage (according to the ECASS-3 definition) was diagnosed in 10 subjects treated with rtPA (2.4%) and 1 subject who had been given placebo (0.2%; odds ratio [OR] 9.85, 95% CI 1.26 to 77.32, P=0.008).5 Symptomatic intracranial hemorrhage, as defined by the criteria used in the NINDS study, was diagnosed in 33 subjects treated with rtPA (7.9%) and 14 subjects given placebo (3.5%; OR 2.38, 95% CI 1.25 to 4.52, P=0.006). The increased incidence of symptomatic intracranial hemorrhage with the use of thrombolytic agents is consistent with the experience with rtPA in other clinical trials that tested the agent.3,5,8–13 In ECASS-3, the incidence of intracerebral hemorrhage was not increased greatly despite the parenteral administration of anticoagulants for prevention of deep vein thrombosis within the first 24 hours after rtPA treatment.
The frequency of the primary efficacy outcome in ECASS-3 (defined as modified Rankin Scale score of 0 to 1 at 90 days after treatment) was significantly greater with rtPA (52.4%) than with placebo (45.2%; OR 1.34, 95% CI 1.02 to 1.76; risk ratio 1.16, 95% CI 1.01 to 1.34; P=0.04). The point estimate for the degree of benefit seen in ECASS-3 (OR for global favorable outcome 1.28, 95% CI 1.00 to 1.65) was less than the point estimate of benefit found in the pool of patients enrolled from 0 to 3 hours after stroke symptoms in the NINDS study (OR 1.9, 95% CI 1.2 to 2.9)5,8 and was similar to that in a single pooled analysis of the results of subjects enrolled in the 3-to-4.5–hour window in previous trials of rtPA (OR 1.4).8–13 However, the overlap in CIs limits conclusions about these observations. Global favorable outcome was assessed as a modified Rankin Scale score of 0 to 1, a Barthel Index score 
95, a National Institutes of Health Stroke Scale score of 0 or 1, and a Glasgow Outcome Scale score of 1. In ECASS-3, mortality in the 2 treatment groups did not differ significantly, although it was nominally higher among the subjects treated with placebo.5
The ECASS-3 trial represents an important advance in the treatment of acute ischemic stroke. The results, which are consistent with the results in this time window from previous studies and pooled analyses of previous trials,3,4,11 provide level B evidence that intravenous rtPA can be given safely to carefully selected patients treated 3 to 4.5 hours after stroke and that intravenous rtPA given in this time period can improve outcomes after stroke in a selected group of patients. Confirmation of the ECASS-3 outcome is encouraged.
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Recommendations |
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TopIntroductionRecommendationsReferences |
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Patients who are eligible for treatment with rtPA within 3 hours of onset of stroke should be treated as recommended in the 2007 guidelines.1 Although a longer time window for treatment with rtPA has been tested formally, delays in evaluation and initiation of therapy should be avoided, because the opportunity for improvement is greater with earlier treatment.
rtPA should be administered to eligible patients who can be treated in the time period of 3 to 4.5 hours after stroke (Class I Recommendation, Level of Evidence B). The eligibility criteria for treatment in this time period are similar to those for persons treated at earlier time periods, with any one of the following additional exclusion criteria: Patients older than 80 years, those taking oral anticoagulants with an international normalized ratio 
1.7, those with a baseline National Institutes of Health Stroke Scale score >25, or those with both a history of stroke and diabetes. Therefore, for the 3-to-4.5–hour window, all patients receiving an oral anticoagulant are excluded regardless of their international normalized ratio. The relative utility of rtPA in this time window compared with other methods of thrombus dissolution or removal has not been established. The efficacy of intravenous treatment with rtPA within 3 to 4.5 hours after stroke in patients with these exclusion criteria is not well established (Class IIb Recommendation, Level of Evidence C) and requires further study.
Ancillary care for patients receiving rtPA at 3 to 4.5 hours after ischemic stroke should be similar to that included in the 2007 American Heart Association Stroke Council Guidelines.1
These recommendations, which are based on peer-reviewed publications, should be reevaluated after the results of regulatory agency review of detailed, nonpublicly available data are known. The recommendations use the American Heart Association’s classification of recommendations and levels of evidence shown in the Table.
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In 2003, the ACC/AHA Task Force on Practice Guidelines developed a list of suggested phrases to use when writing recommendations. All guideline recommendations have been written in full sentences that express a complete thought, such that a recommendation, even if separated and presented apart from the rest of the document (including headings above sets of recommendations), would still convey the full intent of the recommendation. It is hoped that this will increase readers’ comprehension of the guidelines and will allow queries at the individual recommendation level.
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Acknowledgments |
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Disclosures
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Footnotes |
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The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This advisory was approved by the American Heart Association Science Advisory and Coordinating Committee on April 22, 2009. A copy of the advisory is available at http://www.americanheart.org/presenter.jhtml?identifier=3003999 by selecting either the "topic list" link or the "chronological list" link (No. LS-2097). To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com.
The American Heart Association requests that this document be cited as follows: del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr; on behalf of the 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. Stroke. 2009;40:2945–2948.
Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development, visit http://www.americanheart.org/presenter.jhtml?identifier=3023366.
Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.americanheart.org/presenter.jhtml?identifier=4431. A link to the "Permission Request Form" appears on the right side of the page.
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References |
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TopIntroductionRecommendationsReferences |
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1. Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF. 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 [published corrections appear in Stroke. 2007;38:e38 and Stroke. 2007;38:e96]. Stroke. 2007; 38: 1655–1711.
2. del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, Alberts MJ, Zivin JA, Wechsler L, Busse O, Greenlee R Jr, Brass L, Mohr JP, Feldmann E, Hacke W, Kase CS, Biller J, Gresss D, Otis SM. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol. 1992; 32: 78–86.[CrossRef][Medline] [Order article via Infotrieve]
3. Mori E, Yoneda Y, Tabuchi M, Yoshida T, Ohkawa S, Ohsumi Y, Kitano K, Tsutsumi A, Yamadori A. Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology. 1992; 42: 976–982.
4. Yamaguchi T, Hayakawa T, Kikuchi H; for the Japanese Thrombolysis Study Group. Intravenous tissue plasminogen activator in acute thromboembolic stroke: a placebo-controlled, double blind trial. In: del Zoppo GJ, Mori E, Hacke W, eds. Thrombolytic Therapy in Acute Ischemic Stroke II. Heidelberg, Germany: Springer-Verlag; 1993: 59–65.
5. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008; 359: 1317–1329.
6. Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Kuelkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G; 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 [published correction appears in Lancet. 2007;369:826]. Lancet. 2007; 369: 275–282.[CrossRef][Medline] [Order article via Infotrieve]
7. Wahlgren N, Ahmed N, Dávalos A, Hacke W, Millán M, Muir K, Roine RO, Toni D, Lees KR; SITS Investigators. Thrombolysis with alteplase 3–4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet. 2008; 372: 1303–1309.[CrossRef][Medline] [Order article via Infotrieve]
8. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581–1587.
9. Clark WM, Albers GW, Madden KP, Hamilton S; 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. Stroke. 2000; 31: 811–816.
10. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset: the ATLANTIS Study: a randomized controlled trial: Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999; 282: 2019–2026.
11. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363: 768–774.[CrossRef][Medline] [Order article via Infotrieve]
12. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, Hennerichi M. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA. 1995; 274: 1017–1025.
13. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P; Second European-Australasian Acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998; 352: 1245–1251.[CrossRef][Medline] [Order article via Infotrieve]
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