Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke
Werner Hacke, M.D., Markku Kaste, M.D., Erich Bluhmki, Ph.D., Miroslav Brozman, M.D., Antoni Dávalos, M.D., Donata Guidetti, M.D., Vincent Larrue, M.D., Kennedy R. Lees, M.D., Zakaria Medeghri, M.D., Thomas Machnig, M.D., Dietmar Schneider, M.D., Rüdiger von Kummer, M.D., Nils Wahlgren, M.D., Danilo Toni, M.D., for the ECASS Investigators
Background Intravenous thrombolysis with alteplase is the onlyapproved treatment for acute ischemic stroke, but its efficacyand safety when administered more than 3 hours after the onsetof symptoms have not been established. We tested the efficacyand safety of alteplase administered between 3 and 4.5 hoursafter the onset of a stroke.
Methods After exclusion of patients with a brain hemorrhageor major infarction, as detected on a computed tomographic scan,we randomly assigned patients with acute ischemic stroke ina 1:1 double-blind fashion to receive treatment with intravenousalteplase (0.9 mg per kilogram of body weight) or placebo. Theprimary end point was disability at 90 days, dichotomized asa favorable outcome (a score of 0 or 1 on the modified Rankinscale, which has a range of 0 to 6, with 0 indicating no symptomsat all and 6 indicating death) or an unfavorable outcome (ascore of 2 to 6 on the modified Rankin scale). The secondaryend point was a global outcome analysis of four neurologic anddisability scores combined. Safety end points included death,symptomatic intracranial hemorrhage, and other serious adverseevents.
Results We enrolled a total of 821 patients in the study andrandomly assigned 418 to the alteplase group and 403 to theplacebo group. The median time for the administration of alteplasewas 3 hours 59 minutes. More patients had a favorable outcomewith alteplase than with placebo (52.4% vs. 45.2%; odds ratio,1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). Inthe global analysis, the outcome was also improved with alteplaseas compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to1.65; P<0.05). The incidence of intracranial hemorrhage washigher with alteplase than with placebo (for any intracranialhemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranialhemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differsignificantly between the alteplase and placebo groups (7.7%and 8.4%, respectively; P=0.68). There was no significant differencein the rate of other serious adverse events.
Conclusions As compared with placebo, intravenous alteplaseadministered between 3 and 4.5 hours after the onset of symptomssignificantly improved clinical outcomes in patients with acuteischemic stroke; alteplase was more frequently associated withsymptomatic intracranial hemorrhage. (ClinicalTrials.gov number,NCT00153036
[ClinicalTrials.gov]
.)
Source Information
From the Department of Neurology, Universität Heidelberg, Heidelberg, Germany (W.H.); the Department of Neurology, Helsinki University Central Hospital, Helsinki (M.K.); the Department of Statistics, Boehringer Ingelheim, Biberach, Germany (E.B.); the Neurology Clinic, University Hospital Nitra, Nitra, Slovakia (M.B.); the Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (A.D.); the Department of Neurology, Hospital of Piacenza, Piacenza, Italy (D.G.); the Department of Neurology, University of Toulouse, Toulouse, France (V.L.); the Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom (K.R.L.); Boehringer Ingelheim, Reims, France (Z.M.); Boehringer Ingelheim, Ingelheim, Germany (T.M.); the Department of Neurology, Universität Leipzig, Leipzig, Germany (D.S.); the Department of Neuroradiology, Technische Universität Dresden, Dresden, Germany (R.K.); the Department of Neurology, Karolinska Institutet, Stockholm (N.W.); and the Department of Neurological Sciences, University La Sapienza, Rome (D.T.).
Address reprint requests to Dr. Hacke at the Department of Neurology, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany, or at werner.hacke{at}med.uni-heidelberg.de.
Thrombolysis 3 to 4.5 Hours after Acute Ischemic Stroke
Torbey M. T., Jauch E., Liebeskind D. S., the Acute Stroke Advisory Board of the National Stroke Association , Fitzpatrick A. E., Noone I., O'Shea D. D., Schwamm L. H., Fonarow G. C., Morris D. C., Hacke W., Kaste M., Toni D.
Extract |
Full Text |
PDF
N Engl J Med 2008;
359:2839-2841, Dec 25, 2008.
Correspondence
This article has been cited by other articles:
Donnan, G. A., Davis, S. M.
(2009). IV and IA Thrombolytic Stroke Strategies Are Complementary. Stroke
40: 2615-2615
[Full Text]
Ahmed, N., Wahlgren, N., Brainin, M., Castillo, J., Ford, G. A., Kaste, M., Lees, K. R., Toni, D., for the SITS Investigators,
(2009). Relationship of Blood Pressure, Antihypertensive Therapy, and Outcome in Ischemic Stroke Treated With Intravenous Thrombolysis: Retrospective Analysis From Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR). Stroke
40: 2442-2449
[Abstract][Full Text]
Liu, W., Hendren, J., Qin, X.-J., Liu, K. J.
(2009). Normobaric Hyperoxia Reduces the Neurovascular Complications Associated With Delayed Tissue Plasminogen Activator Treatment in a Rat Model of Focal Cerebral Ischemia. Stroke
40: 2526-2531
[Abstract][Full Text]
Lansberg, M. G., Bluhmki, E., Thijs, V. N.
(2009). Efficacy and Safety of Tissue Plasminogen Activator 3 to 4.5 Hours After Acute Ischemic Stroke: A Metaanalysis. Stroke
40: 2438-2441
[Abstract][Full Text]
Saver, J. L., Albers, G. W., Dunn, B., Johnston, K. C., Fisher, M., for the STAIR VI Consortium,
(2009). Stroke Therapy Academic Industry Roundtable (STAIR) Recommendations for Extended Window Acute Stroke Therapy Trials. Stroke
40: 2594-2600
[Abstract][Full Text]
Saver, J. L., Gornbein, J., Grotta, J., Liebeskind, D., Lutsep, H., Schwamm, L., Scott, P., Starkman, S.
(2009). Number Needed to Treat to Benefit and to Harm for Intravenous Tissue Plasminogen Activator Therapy in the 3- to 4.5-Hour Window: Joint Outcome Table Analysis of the ECASS 3 Trial. Stroke
40: 2433-2437
[Abstract][Full Text]
Kohrmann, M., Schellinger, P. D.
(2009). Acute Stroke Triage to Intravenous Thrombolysis and Other Therapies with Advanced CT or MR Imaging: Pro MR Imaging. Radiology
251: 627-633
[Full Text]
Lansberg, M. G., Schrooten, M., Bluhmki, E., Thijs, V. N., Saver, J. L.
(2009). Treatment Time-Specific Number Needed to Treat Estimates for Tissue Plasminogen Activator Therapy in Acute Stroke Based on Shifts Over the Entire Range of the Modified Rankin Scale. Stroke
40: 2079-2084
[Abstract][Full Text]
Putaala, J., Metso, T. M., Metso, A. J., Makela, E., Haapaniemi, E., Salonen, O., Kaste, M., Tatlisumak, T.
(2009). Thrombolysis in Young Adults With Ischemic Stroke. Stroke
40: 2085-2091
[Abstract][Full Text]
von Kummer, R.
(2009). After European Cooperative Acute Stroke Study 3: Mission Accomplished?. Stroke
40: 2268-2270
[Full Text]
Ingall, T. J.
(2009). Intravenous Thrombolysis for Acute Ischemic Stroke: Time Is Prime. Stroke
40: 2264-2265
[Full Text]
Davis, S. M., Donnan, G. A.
(2009). 4.5 Hours: The New Time Window for Tissue Plasminogen Activator in Stroke. Stroke
40: 2266-2267
[Full Text]
Fowler, R. A., Adhikari, N. K. J., Scales, D. C., Lee, W. L., Rubenfeld, G. D.
(2009). Update in Critical Care 2008. Am. J. Respir. Crit. Care Med.
179: 743-758
[Full Text]
Nogueira, R.G., Yoo, A.J., Buonanno, F.S., Hirsch, J.A.
(2009). Endovascular Approaches to Acute Stroke, Part 2: A Comprehensive Review of Studies and Trials. Am. J. Neuroradiol.
30: 859-875
[Abstract][Full Text]
Tyrrell, P, Swain, S, Rudd, A, Acute Stroke & TIA Guideline Development Group,
(2009). NICE guideline on acute stroke and TIA: commentary. Heart
95: 843-845
[Full Text]
Werring, D J, Brown, M M
(2009). New NICE guideline on acute stroke and TIA: need for major changes in delivery of stroke treatment. Heart
95: 841-843
[Full Text]
Earnshaw, S. R., Jackson, D., Farkouh, R., Schwamm, L.
(2009). Cost-Effectiveness of Patient Selection Using Penumbral-Based MRI for Intravenous Thrombolysis. Stroke
40: 1710-1720
[Abstract][Full Text]
Higgins, P., Lees, K. R.
(2009). Advances in Emerging Therapies. Stroke
40: e292-e294
[Full Text]
Mayer, S. A., Schwab, S.
(2009). Advances in Critical Care and Emergency Medicine. Stroke
40: e298-e300
[Full Text]
Luft, A. R.
(2009). Stroke: A Practical Approach. JAMA
301: 1717-1718
[Full Text]
Nogueira, R.G., Schwamm, L.H., Hirsch, J.A.
(2009). Endovascular Approaches to Acute Stroke, Part 1: Drugs, Devices, and Data. Am. J. Neuroradiol.
30: 649-661
[Abstract][Full Text]
Mateen, F. J., Nasser, M., Spencer, B. R., Freeman, W. D., Shuaib, A., Demaerschalk, B. M., Wijdicks, E. F. M.
(2009). Outcomes of Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke in Patients Aged 90 Years or Older. Mayo Clin Proc.
84: 334-338
[Abstract][Full Text]
Zivin, J. A., Albers, G. W., Bornstein, N., Chippendale, T., Dahlof, B., Devlin, T., Fisher, M., Hacke, W., Holt, W., Ilic, S., Kasner, S., Lew, R., Nash, M., Perez, J., Rymer, M., Schellinger, P., Schneider, D., Schwab, S., Veltkamp, R., Walker, M., Streeter, J., for the NEST-2 Investigators,
(2009). Effectiveness and Safety of Transcranial Laser Therapy for Acute Ischemic Stroke. Stroke
40: 1359-1364
[Abstract][Full Text]
Donnan, G. A., Davis, S. M.
(2009). The Ethics of Thrombolytic Trials Beyond 3 (or 4.5) Hours: Randomized Controlled Trials Are Required to Change Clinical Practice. Stroke
40: 1545-1545
[Full Text]
Ozdemir, O., Beletsky, V., Chan, R., Hachinski, V.
(2009). Thrombolysis, Fluctuations, and Protocol Expansions--Reply. Arch Neurol
66: 418-419
[Full Text]
(2009). Thrombolytic therapy with alteplase for ischaemic stroke. DTB
47: 14-18
[Abstract][Full Text]
Torbey, M. T., Jauch, E., Liebeskind, D. S., the Acute Stroke Advisory Board of the National St, , Fitzpatrick, A. E., Noone, I., O'Shea, D. D., Schwamm, L. H., Fonarow, G. C., Morris, D. C., Hacke, W., Kaste, M., Toni, D.
(2008). Thrombolysis 3 to 4.5 Hours after Acute Ischemic Stroke. NEJM
359: 2839-2841
[Full Text]
Alberts, M. J., Felberg, R. A., Guterman, L. R., Levine, S. R., for Writing Group 4,
(2008). Atherosclerotic Peripheral Vascular Disease Symposium II: Stroke Intervention: State of the Art. Circulation
118: 2845-2851
[Full Text]
Lindsay, P. BScN PhD, Bayley, M. MD, Hellings, C. BScH, Hill, M. MSc MD, Woodbury, E. BCom MHA, Phillips, S. MBBS, (Canadian Stroke Strategy Best Practices and Stand,
(2008). Canadian best practice recommendations for stroke care (updated 2008). CMAJ
179: S1-S25
[Full Text]
Lindsay, P. BScN PhD, Bayley, M. MD, Hellings, C. BA, Hill, M. MSc MD, Woodbury, E. BCom MHA, Phillips, S. MBBS, (Groupe de redaction Pratiques optimales et normes,
(2008). Recommandations canadiennes pour les pratiques optimales de soins de l'AVC (mise a jour de 2008). CMAJ
179: SF1-SF29
[Full Text]
Bayley, M. MD, Lindsay, P. BScN PhD, Hellings, C. BScH, Woodbury, E. BCom MHA, Phillips, S. MBBS, on behalf of the Canadian Stroke Strategy (a joint,
(2008). Balancing evidence and opinion in stroke care: the 2008 best practice recommendations. CMAJ
179: 1247-1249
[Full Text]
(2008). All you need to read in the other general journals. BMJ
337: a1854-a1854
[Full Text]
Lyden, P.
(2008). Thrombolytic Therapy for Acute Stroke -- Not a Moment to Lose. NEJM
359: 1393-1395
[Full Text]
(2008). Thrombolysis for Stroke Within 4.5 Hours Is Safe and Effective. JWatch Emergency Med.
2008: 1-1
[Full Text]
(2008). Extending the Time Frame for Alteplase: The ECASS III Trial. Journal Watch Cardiology
2008: 1-1
[Full Text]
Previous
