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Lancet. 2010 May 15;375(9727):1695-703. doi: 10.1016/S0140-6736(10)60491-6.

Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.

Collaborators (752)

Klingelhöfer J, Krauseneck P, Schneider D, Hielscher, Büttner T, Hennen G, Marx P, Lücking CH, Felgenhaner K, Hacke W, Müllges W, Krieter G, Schwartz A, Krämer G, Diener HC, Busse O, Wiersbitzky M, Ferbert A, Druschky KF, Lechner H, Ladurner G, Schmutzhard W, Rogousslavsky J, Vignolo A, Regesta G, Re G, Pecorari L, Lagi A, Argentino C, Ferrari G, Mamoli A, Mironi F, Erilä T, Sivenius I, Murros K, Liukkonen H, Hedman Ch, Muuronen A, Sotaniemi K, Thomassen L, Rosjo O, Brautaset N, Indredavik B, Sandset PM, Petersson J, Radberg H, Térent A, Carlström Ch, Kjällman L, Overgaard K, Boysen G, Enevoldsen E, Munck O, St Jensen T, Campbell M, Hawkins SA, Franke CL, Vos J, Frenken WG, Op de Coul AA, Verslegers W, Cras P, Laloux P, Blecic, Marchau M, Féve J-, Rancurel G, Weber M, Mahagne MH, Larrue, Trouillas, Blard JM, Caussanel, Chollet, Orgogozo JM, Arnoud, Cunha L, Castillo J, Tejedor D, Chomorro A, Sancho H, Davalos A, Hacke W, Fieschi C, Kaste M, Verstraete M, Lesaffre E, Feuerer W, Overgaard K, Sanset PM, Wahlgren NG, Boysen G, Hijdra AH, Bes A, Toni D, Hennerici M, von Kummer R, Bozzao L, Manelfe C, Peock K, del Zoppo G, Zeumer H, Lenzi GL, Mau J, Crimmins D, Donnan G, Davis S, Gerraty R, Hankey G, Niederkorn K, Brainin M, Deisenhammer E, Baumhackl U, Ladurner G, Grisold W, Podreka I, Alf C, Sluga E, Brücke B, Kristoferitsch W, Cras P, Magnussen I, Vorstrup S, Olesen J, Muuronen A, Kaste M, Rissanen A, Sivenius J, Hedman C, Numminen H, Liukkonen J, Sotaniemi K, Kolvisto K, Erila T, Caussanel JP, Dumas R, Trouillas P, Blard JM, Weber M, Feve JR, Mahagne MH, Amarenco P, Rancurel G, Zuber M, Chollet F, Larrue V, Saudeau D, Krauseneck P, Villringer A, Buttner T, Heiss WD, Gond M, Reichmann H, Klotz J, Prange H, Wiersbitzky M, Hacke W, Steiner T, Ferbert A, Schneider D, Kaps M, Lowitzsch K, Tettenborn B, Busse O, Hamann G, Klingelhofer J, Bogdahn U, Mullgers W, Bottacchi E, Cappelletti C, Lagi A, Regesta G, Solime F, Toso V, Ricevuti G, Argentino C, Ferrari G, Stam J, de Keijzer JH, Koudstaal P, de Kort PL, Hammond-Tooke GD, Timmings P, Thomassen I, Rosjo O, Rygh J, Indredavik B, Cunha I, Correia C, Castillo J, Rubio F, Chamorro A, Sabin JA, Vilata JL, Zarranz JJ, Davalos A, Diez-Tejedor E, Egido A, Mora JV, Delgado G, Gil-Peralta A, Lainez JM, Mostacero E, Radberg J, Prantare H, Carlstrom C, Costulas V, Wahlgren NG, Malm J, Terent A, Lyrer P, Bogousslavsky J, Hawkins S, Campbell MJ, Ford GA, Mendelow AD, Hacke W, Davalos A, Donnan G, Fieschi C, Kaste M, von Kummer R, Larrue V, Meier D, Poeck K, Asplund K, Lenzi GL, Marler J, Martinez-Vila E, Mau J, Zeumer H, del Zoppo GJ, Hacke W, Dávalos A, Kaste M, von Kummer R, Larrue V, Toni D, Wahlgren N, Lees KR, Heiss WD, Lesaffre E, Orgogozo JM, von Kummer R, Bastianello S, Wardlaw JM, Peyrieux JC, Sauce C, Medeghri Z, Mazenc R, Sauce C, Machnig T, Bluhmki E, Aichner F, Alf C, Baumhackl U, Brainin M, Eggers C, Gruber F, Ladurner G, Niederkorn K, Noistering G, Willeit J, Vanhooren G, Blecic S, Bruneel B, Caekebeke J, Laloux P, Simons PJ, Thijs V, Bar M, Dvorakova H, Vaclavik D, Boysen G, Andersen G, Iversen HK, Traberg-Kristensen B, Kaste M, Marttila R, Sivenius J, Trouillas P, Amarenco P, Bouillat J, Ducrocq X, Giroud M, Jaillard A, Larrieu JM, Larrue V, Leys D, Magne C, Mahagne MH, Milhaud D, Sablot D, Saudeau D, Busse O, Berrouschot J, Faiss JH, Glahn J, Görtler M, Grau A, Grond M, Haberl R, Hamann G, Hennerici M, Koch H, Krauseneck P, Marx J, Meves S, Meyding-Lamadé U, Ringleb P, Schneider D, Schwarz A, Sobesky J, Urban P, Karageorgiou K, Komnos A, Csányi A, Csiba L, Valikovics A, Toni D, Agnelli G, Billo G, Bovi P, Comi G, Gigli G, Guidetti D, Inzitari D, Marcello N, Marini C, Orlandi G, Pratesi M, Rasura M, Semplicini A, Serrati C, Tassinari T, Brouwers PJ, Stam J, Naess H, Indredavik B, Kloster R, Czlonkowska A, Kuczyńska-Zardzewialy A, Nyka W, Opala G, Romanowicz S, Cunha L, Correia C, Cruz V, Pinho e Melo T, Brozman M, Dvorak M, Garay R, Krastev G, Kurca E, Alvarez-Sabin J, Chamorro A, Guerrero Mdel M, Herrero JA, Gil-Peralta A, Leira R, Martí-Vilalta JL, Vallejo JM, Millán M, Molina C, Mostacero E, Segura T, Serena J, Mora JV, Danielsson E, Cederin B, von Zweigberg E, Wahlgren NG, Welin L, Lyrer P, Bogousslavsky J, Hungerbühler HJ, Weder B, Ford GA, Jenkinson D, MacLeod MJ, MacWalter RS, Markus HS, Muir KW, Sharma AK, Walters MR, Warburton EA, Albakri E, Albers G, Alberts M, Atkinson R, Bell R, Jefferson T, Black S, Blumenfeld A, Brooks W, Brott T, Bruno A, Buchan A, Bumgartner J, Carpenter D, Castellani D, Chaturvedi S, Clark W, Coccia C, Cohen S, Comber J, Coull B, Culebras A, Curfman T, Curtin J, Dayno J, DeMatteis J, Desai H, Dietrich D, Dissin J, Driscoll P, Duke R, Edelsohn L, Feinberg W, Ford S, Gasecki A, Gilbert G, Gray L, Grayum B, Grindal A, Grotta J, Hachinski V, Hakim A, Hassan R, Hess D, Hidalgo A, Homer D, Horowitz D, Horowitz S, Hsu C, Hughes R, Hurtig H, Huang TL, Jacoby M, Jhamandas J, Karlsberg R, Kelley R, Koller R, Kirshner H, Krieger D, LaFranchise F, LaMonte M, Lebrun LH, Levine S, Lyden P, Madden K, Mallenbaum S, Mandelbaum M, Mattio T, Mirsen T, Morris D, Munschauer F 3rd, Murthy K, Newman G, Pelligrino R, Pettigrew C, Raps E, Rosa L 3rd, Rowe V, Sauter M, Scott P, Sergay S, Sheppard G, Shuaib A, Silliman S, Simard D, Simon R, Sloan M, Smith W, Smith R, Steel JG, Stobbe G, Strunk B, Tabbaa M, Tarrel R, Taylor L, Tolge C, Turel A, Verro P, Wilterdink J, Wissman S, Wohlberg C, Brott T, Broderick J, Kothari R, O'Donoghue M, Barsan W, Tomsick T, Spilker J, Miller R, Sauerbeck L, Farrell J, Kelly J, Perkins T, Miller R, McDonald T, Rorick M, Hickey C, Armitage J, Perry C, Thalinger K, Rhude R, Armitage J, Schill J, Becker PS, Heath RS, Adams D, Reed R, Klei M, Hughes A, Rhude R, Anthony J, Baudendistel D, Zadicoff C, Miller R, Rymer M, Bettinger I, Laubinger P, Schmerler M, Meirose G, Lyden P, Rapp K, Babcock T, Daum P, Persona D, Brody M, Jackson C, Lewis S, Liss J, Mahdavi Z, Rothrock J, Tom T, Zweifler R, Dunford J, Zivin J, Kobayashi R, Kunin J, Licht J, Rowen R, Stein D, Grisolia J, Martin F, Chaplin E, Kaplitz N, Nelson J, Neuren A, Silver D, Chippendale T, Diamond E, Lobatz M, Murphy D, Rosenberg D, Ruel T, Sadoff M, Schim J, Schleimer J, Atkinson R, Wentworth D, Cummings R, Frink R, Heublein P, Grotta JC, DeGraba T, Fisher M, Ramirez A, Hanson S, Morgenstern L, Sills C, Pasteur W, Yatsu F, Andrews K, Villar-Cordova C, Pepe P, Bratina P, Greenberg L, Rozek S, Simmons K, Kwiatkowski TG, Horowitz SH, Libman R, Kanner R, Silverman R, LaMantia J, Mealie C, Duarte R, Donnarumma R, Okola M, Cullin V, Mitchell E, Levine SR, Lewandowski CA, Tokarski G, Ramadan NM, Mitsias P, Gorman M, Zarowitz B, Kokkinos J, Dayno J, Verro P, Gymnopoulos C, Dafer R, D'Olhaberriague L, Sawaya K, Daley S, Mitchell M, Frankel M, Mackay B, Barch C, Braimah J, Faherty B, MacDonald J, Sailor S, Cook A, Karp H, Nguyen B, Washington J, Weissman J, Williams M, Williamson T, Kozinn M, Hellwick L, Haley EC Jr, Bleck TP, Cail WS, Lindbeck GH, Granner MA, Wolf SS, Gwynn MW, Mettetal RW Jr, Chang CW, Solenski NJ, Brock DG, Ford GF, Kongable GL, Parks KN, Wilkinson SS, Davis MK, Sheppard GL, Zontine DW, Gustin KH, Crowe NM, Massey SL, Meyer M, Gaines K, Payne A, Bales C, Malcolm J, Barlow R, Wilson M, Cape C, Bertorini T, Misulis K, Paulsen W, Shepard D, Tilley BC, Welch KM, Fagan SC, Lu M, Patel S, Masha E, Verter J, Boura J, Main J, Gordon L, Maddy N, Chociemski T, Windham J, Zadeh HS, Alves W, Keller MF, Wenzel JR, Raman N, Cantwell L, Warren A, Smith K, Bailey E, Welch C, Tilley BC, Marler JR, Welch KM, Brott T, Lyden P, Grotta JC, Kwiatkowski TG, Levine SR, Frankel M, Haley EC Jr, Meyer M, Tilley BC, Marler JR, Froehlich J, Breed J, Easton JD, Hallenbeck JF, Lan G, Marsh JD, Walker MD, Marler JR, Davis SM, Donnan GA, Parsons MW, Levi C, Butcher K, Peeters A, Barber PA, Bladin C, Chalk JB, Fink JN, Kimber TE, Schultz D, Hand PJ, Frayne J, Hankey G, Muir K, Gerraty R, Tress BM, Byrnes G, Attia J, D'Este C, McNeil J, Burns R, Johnston C, Stark R, Tress BM, Desmond PM, Butcher KS, Christensen S, Ebinger M, Butcher KS, De Silva DA, Jackson D, Levi C, Parsons MW, Davis SM, Donnan GA, Bladin C, Chalk JB, Kimber T, Schultz D, Frayne J, Williams M, Hankey G, Gerraty R, Peeteis A, Barber PA, Fink J, Muir K.

Abstract

BACKGROUND:

Early administration of intravenous recombinant tissue plasminogen activator (rt-PA) after ischaemic stroke improves outcome. Previous analysis of combined data from individual patients suggested potential benefit beyond 3 h from stroke onset. We re-examined the effect of time to treatment with intravenous rt-PA (alteplase) on therapeutic benefit and clinical risk by adding recent trial data to the analysis.

METHODS:

We added data from ECASS III (821 patients) and EPITHET (100 patients) to a pool of common data elements from six other trials of alteplase for acute stroke (2775 patients). We used multivariate logistic regression to assess the relation of stroke onset to start of treatment (OTT) with treatment on favourable 3-month outcome (defined as modified Rankin score 0-1), mortality, and occurrence and outcome of clinically relevant parenchymal haemorrhage. The presence of an arterial occlusion was inferred from the patient's symptoms and absence of haemorrhage or other causes of ischaemic stroke. Vascular imaging was not a requirement in the trials. All patients with confirmed OTT within 360 min were included in the analysis.

FINDINGS:

Treatment was started within 360 min of stroke onset in 3670 patients randomly allocated to alteplase (n=1850) or to placebo (n=1820). Odds of a favourable 3-month outcome increased as OTT decreased (p=0.0269) and no benefit of alteplase treatment was seen after around 270 min. Adjusted odds of a favourable 3-month outcome were 2.55 (95% CI 1.44-4.52) for 0-90 min, 1.64 (1.12-2.40) for 91-180 min, 1.34 (1.06-1.68) for 181-270 min, and 1.22 (0.92-1.61) for 271-360 min in favour of the alteplase group. Large parenchymal haemorrhage was seen in 96 (5.2%) of 1850 patients assigned to alteplase and 18 (1.0%) of 1820 controls, with no clear relation to OTT (p=0.4140). Adjusted odds of mortality increased with OTT (p=0.0444) and were 0.78 (0.41-1.48) for 0-90 min, 1.13 (0.70-1.82) for 91-180 min, 1.22 (0.87-1.71) for 181-270 min, and 1.49 (1.00-2.21) for 271-360 min.

INTERPRETATION:

Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous alteplase when treated up to 4.5 h. To increase benefit to a maximum, every effort should be taken to shorten delay in initiation of treatment. Beyond 4.5 h, risk might outweigh benefit.

FUNDING:

None.

Copyright 2010 Elsevier Ltd. All rights reserved.

[PubMed - indexed for MEDLINE]
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