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Lancet. 2012 Jun 23;379(9834):2352-63. doi: 10.1016/S0140-6736(12)60768-5. Epub 2012 May 23.

The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.

Collaborators (1301)

Baigent C, Chadwick D, Tyrrell P, Lowe G, Goodare H, Farrall A, von Kummer R, Cala L, von Heijne A, Morris Z, Adami A, Potter G, Brady N, Collins R, Bath P, van Gijn J, Gray R, Hart R, Yusuf S, Muir K, Brainin M, Engelter S, Terent A, Norrving B, Wester P, Clark A, Perry D, Soosay V, Buchanan D, Grant S, Sakka E, Drever J, Walker P, Herath I, Brown AL, Chmielnik P, Armit C, Walton A, Hautvast M, Lewis S, Heron G, Odusanya S, Linksted P, Kane I, Whiteley W, Sellar R, White P, Keston P, Farrell A, Morris Z, Miranda H, Blackwell L, Celani MG, Righetti E, Cenciarelli S, Mazzoli T, Cantisani TA, Bembenek J, Isaakson E, Freys G, Venables G, Blank C, Bowler H, Doyle C, Endean K, Harkness K, Parker E, Randall M, Roffe C, Ahmad N, Arora A, Brammer S, Chembala J, Davies B, Ellis S, Epstein E, Finney K, Jackson C, Jadun C, Kinston R, Maguire H, Memon I, Natarajan I, Poulson M, Sanyal R, Sills S, Vreeburg A, Ward E, Sandercock P, Al-Shahi Salman R, Davenport R, Dennis M, Hand P, Hart S, Kane I, Keir S, MacLeod M, McKinlay L, Milligan H, Sandeman E, Stone J, Sudlow C, Taylor P, Wardlaw J, Warlow C, Whiteley W, Williams A, Brown M, Athwal B, Bassan V, Bhupathiraju N, Bowler J, Davie C, Doig D, Erande R, Gilbert S, Ginsberg L, Greenwood R, Gregoire S, Harding N, Losseff N, Luder R, Passeron N, Perry R, Rayson P, Simister R, Stone S, Werring D, Barrett J, Aitken H, Cherian S, Davis R, Downham S, Godd L, Gott V, Jose D, Little V, Lowe D, Luxford L, McGrory M, Owings P, Price N, Richards J, Sangster G, Sherlock J, Vargese S, Wakefield I, Weir P, Guyler P, Attygale T, Chandler S, Coward L, Feasey S, Khuoge C, Loganathan T, Martin S, O'Brien A, Sinha D, Thompson V, Tysoe S, Walsh R, Metcalf K, Cochius J, Fulcher R, Gange N, Green C, Jagger J, Lee M, Myint P, Potter J, Ravenhill G, Shields S, Shinh N, Staunton T, Thomas E, Woodward W, Worth P, Wyatt N, Sunman W, Bath P, Berman P, Clarke J, Gaynor C, Hammonds F, Harwood R, Mitchell K, Munshi S, Pacey S, Shetty A, Sprigg N, Stear H, Subramanian G, Wills A, Rudd A, Audebert H, Bhalla A, Birns J, Chowdhury R, Cluckie G, Davies I, Gibbs C, Holmes P, Mitchell N, Schiavone F, White E, Yeung M, Mehrzad A, Baliga V, Brown E, Burnside L, Esisi B, Kent J, Orr P, Stead D, Wayman E, Durairaj R, Cullen C, Kumar R, Martin H, McDowell D, Sharma A, Sutton V, White R, Hughes T, Ali K, Anderson J, Baker K, Bethune K, Bethune K, Booth M, Cossburn M, Halpin S, Hourihan M, Marsh E, Peall K, Powell R, Shetty H, Wardle M, Williams M, Muhiddin K, Beavan J, Clarke M, Donneley R, Elliott S, Fox P, Gorman P, Harper M, Mangoyana M, Memon I, Mills L, Wright L, Warburton L, Baron J, Barry P, Day D, Harold T, Martin P, Mitchell J, O'Brien E, Rycarte J, Turnham M, Cloud G, Choy L, Clarke B, Griffin C, Halse O, Jones I, Kennedy F, Khan U, Lewis R, Loosemore A, Lovelock C, Markus H, Moynihan B, O'Reilly J, Paul O, Pereira A, Punter M, Rich P, Rolfe D, Schiavone F, James M, Bell J, Bowring A, Boxall L, Cageao J, Eastwood H, Elyas S, Hall F, Harries S, Hemsley A, Jackson S, Keenan S, Mudd P, Sekhar A, Strain D, Sword J, Wedge N, MacLeod M, Bruce M, Joyson A, Kemp M, McMullan K, Reid J, Robb O, Webster J, Wilkinson S, Sharma P, Bentley P, Jenkins H, Kar A, Sachs T, Cohen D, Bathula R, Devine J, Mpelembue M, Hargroves D, Balogun I, Cowie L, Maidment A, Rand D, Rowe J, Rudenko H, Smithard D, Wray L, Paterson J, Brown J, Hampton J, Jamieson S, Rose R, Volans A, Chatterjee K, Abbott G, Brookes R, Castle C, Kelly C, Leason S, Nallasivan A, Sen A, Collas D, Cottle M, Damani N, Jacob P, Oza D, Werring D, Kenton A, Dab N, Aldridge L, Allroggen H, Brown Y, Cross R, Galvin L, Ghosh K, Grubneac A, Lindahl A, Mehta H, Pritchard M, Randall C, Ray P, Shehu A, Thelwell S, Jenkinson D, Bell J, Black T, David O, Kwan J, Orpen A, Ovington C, Tiwari D, ud Din Babar Z, Hassan A, Bailey A, Bamford J, Bedford C, Bellfield R, Cooper J, Dunsmure L, Greig J, Keeling M, Mandizvidza L, Rankine J, Roberts E, Wanklyn P, Webb T, Williamson S, Coyle J, Crane S, Croser C, Duffey P, Evans R, Iverson E, Keeling M, Kitching G, Porte M, Rhymes C, Barer D, Armstrong M, Bokhari M, Cassidy T, McClelland B, Gunathilagan G, Dolke P, Jain S, Jones S, Maidment A, Rosser L, Thomas G, White C, Sanmuganathan P, Scholtz C, Stratford E, O'Donnell M, Goddard H, Hoadley G, Howard J, Leach S, McIlmoyle J, Stewart A, Strain A, Huwez F, Croot P, Gadi N, Mguni N, Umasankar U, Mead G, Chapman B, Coull A, Hart S, Kinnear A, Morrow B, Morrow C, Ames D, Ball J, Bannerjee S, Chataway J, Rashed K, Buckley C, Donaldson D, Hayward D, Lawson C, Sekaran L, Bharaj K, Justin F, Jutlla G, Phiri D, Sethuraman S, Tate M, Sandler D, Carr P, Jones G, Lyons J, Warren K, Kalra L, Davis A, Jarosz J, Manawadu D, Sztriha L, Chadha D, Holford A, Willcoxson P, Shaw L, Button D, Cunningham A, Dow L, Dutson J, Hall T, Hardy C, Jakeman N, Kaye P, Madigan B, O'Brien K, Pressdee D, Price M, Robinson L, Taylor C, Williamson D, Sandler D, Carr P, Lyons J, McCormack J, Stretton C, Earnshaw P, Brown E, Bruce S, Church C, Desai S, Esisi B, Myint M, Watt N, Price C, Elliott S, Graham H, Lakey R, Mitchelson K, Murphy P, Ball L, Caine S, Dovey J, Hughes J, Steele A, Dizayee K, Brown A, Chattopadhyay T, Cheetham J, Cochrane H, Datta A, Datta-chaudhuri M, Fox C, Kilroy D, Krishnamoorthy S, Levy F, Metha S, Ngoma P, Venkatesh B, Ali K, Gautam R, Henderson N, Jones M, Murphy S, Spurling G, Wiggam I, Boyd C, Fullerton K, Gray P, Kinnaird M, MacNair S, Morgan C, Reid M, Tauro S, Loharuka S, Balmforth D, Cox P, Fletcher G, Ledger A, Manoj A, Wilkinson M, Nicholl D, Clegg S, Hurdowar S, Kausar S, Law K, Singal A, Sturman S, Gompertz P, Evanson J, Farrell A, Petrou A, Saastamoinen K, Sachs T, Salek-Haddadi A, Yadava R, O'Connell J, Brew H, Butler S, Crawford S, Gray C, Gulliver D, Majmudar N, O'Brien R, Wani M, Dacey L, Davies L, Evans R, Harris D, Jones T, Storton S, Punekar S, Ashton A, Duberley S, Emsley H, Gilmour C, Gregary B, Hough L, Philip S, Wuppalapati S, Fotherby K, Bourke P, D'Costa D, Kauldhar K, Leung D, Lodwick R, McBride S, Morgan D, Qaiyum M, Sahota G, Srinvasan M, Kane I, Chuter N, Garrad L, Hookway M, Ivatts S, Kennedy G, Darawil K, Al Dhahirl L, Andole S, Baig M, Dugh P, Dunne K, Hariuki H, Khan M, Rathnayaka S, Power M, Dynan K, Finnerty J, Heaney A, Leonard C, McKnight K, Turkington J, Wroath B, Dewan B, Cotton S, Gardiner M, Saunders T, Vincent B, Sims D, Guest P, Jones E, McCormack J, Nicholl D, Savanhu J, Tongue R, Willmot M, Eveson D, Dawson S, Dickens M, Fotherby M, Hunt R, Khan S, Kumar T, Marsh R, Mistri A, Robinson T, Thompson J, Aghoram P, Daniel T, Gatehouse M, Hussein S, Jackson A, Shanganya T, Strachan E, Tan G, Richard B, Elaine S, Hanson S, Mosely S, Reed H, Williams M, Saksena R, Cook S, Demuran D, Keating M, Needle R, Paramsothy V, Sebastian A, Sivakumar R, Wright A, Grue R, Barberan E, Dickson C, Douglas C, Jellicoe J, Marsden T, Priestley J, Quick E, Sherrington C, Singh A, Smith C, Stevens J, Tyrell P, Wainwright J, Ardron M, Birchall J, Shekhar R, Barsted C, Coleman S, Fletcher S, Graham J, Buchan A, Hinkle J, Kennedy J, Manoj A, Westwood M, Mohd Nor A, Allder S, Hyams B, Pace A, Orugun E, Brewer C, Huntley L, Jolly R, Summers C, Sharobeem K, Khaira J, Leahy J, Linehan E, Moore G, Rizkalla J, Wilkinson J, Kelly D, Hilaire C, Otaiku O, Connell L, Delaney-Sagar G, James G, Lomax L, Matthew D, Simpson J, Whittle H, Sanmuganathan S, Burrows S, Mahmood A, Durward G, Barker S, Cantle J, Crawford P, Evans S, Pressly V, Weir N, Cvoro V, McCormick K, Czlonkowska A, Bembenek J, Bilik M, Chabik G, Czepiel W, Dzierka J, Gluszkiewicz M, Grabska K, Janus-Laszuk B, Jedrzejewska J, Kobayashi A, Litwin T, Oskedra A, Piorkowska A, Skowronska M, Sliwinska A, Stepien U, Sobolewski P, Gajewska A, Grzesik M, Hatalska-Zerebiec R, Labudzka I, Loch B, Medrykowska A, Sledzinska M, Sobota A, Szczuchniak W, Wolak G, Zdyb I, Nyka W, Gasecki D, Chwojnick K, Gojska A, Karaszewski B, Kozera G, Kwarciany M, Nowak M, Swierkocka-Miastkowska M, Szczyrba S, Wisniewska M, Wnorowska E, Richter P, Bochynska A, Chahwan M, Graban A, Rola R, Stepien A, Brodacki B, Grotowska M, Kotowicz J, Staszewski J, Swistak J, Zaloga S, Stoiñski J, Czajkowaka-Fornal K, Czubak P, Kaczor A, Kraska J, Nowakowska-Sledz E, Ozdoba-Rot J, Zawadzka E, Fudala M, Adamczyk D, Brola W, Guldzinska I, Kaluzny K, Kucharska-Lipowska M, Mosiolek M, Polewczyk M, Ziomek M, Opala G, Arkuszewski M, Kudlacik M, Malgorzata P, Swiat M, Fiszer U, Lenska-Mieciek M, Cenciarelli S, Barilaro A, Condurso R, Coppola F, Dioguardi S, Gallinella E, Mattioni A, Menichetti C, Ricci S, Casoni F, Bacchelli M, Cavazzuti M, Malagoli M, Zini A, Benemio G, Celani M, Allegrucci R, Bondo V, Cupella S, Guerra L, Guerrieri S, Ottaviani C, Righetti E, Rossi C, Sacchi N, Scucchi M, Stefanini V, Mazzoli T, Bigaroni S, Greco L, Paris R, Parise P, Ricci S, Ciccone A, Basso L, Causarano R, Doneda P, Ferrante E, Gatti A, Guccione A, Gullo A, Imbesi F, Jan S, Marazzi R, Moro E, Motto C, Parodi D, Protti A, Riva M, Rosiello A, Santilli I, Sterzi R, Tiraboschi P, Venturelli G, Iemolo F, Campagna R, Campagnolo G, Carnemolla A, D'Apico N, D'Asta G, Giannarita S, Giordano A, Sanzar E, Bottacchi E, Cordera S, Corso G, Di Giovanni M, Giardini G, Lia C, Meloni T, Pesenti Campagnoni M, Tosi P, Adami A, Rossato G, Zuppini T, Procaccianti G, Sacquegna T, Gandolfo C, Balestrino M, Bruno C, Castellan L, Del Sette M, Ferrari A, Finocchi C, Reale N, Rizzi D, Del Sette M, Benedetti L, Capellini C, Carabelli E, Cibei E, Godani M, Guariglia G, Landini E, Mannironi A, Nucciarone B, Parodi S, Tonelli S, Traverso E, Zito D, Brustenghi P, Corea F, Flamini O, Lolli S, Pelliccia G, Ricci R, Stefanucci S, Zampolini M, Consoli D, Galati F, Postorino P, Rinaldi G, Carapelle E, Grilli G, Guido M, Specchio L, Checcarelli N, Borin G, Chiveri L, Clerici R, Corengia E, Gandola L, Garavaglia P, Guidotti M, Martegani A, Mauri M, Muscia F, Raudino F, Chiodo Grandi F, Bratina A, Carraro N, Gaio M, Granato A, Koscica N, Naccarato M, Sarra V, Schincariol P, Vilotti C, Zugna Z, Idone D, Bonato C, De Angelis E, Forgione A, Gambera M, Recchia F, Tamburin S, Tinazzi Martini P, Zanette G, Grasselli S, Agnelli G, Andrea A, Billecia A, Caso V, Casso V, Fabiola R, Fanelli P, Paciaroni M, Sergio B, Vemti M, Silvestri M, Altarini L, Bonfante A, Bonornetti M, Costa B, D'Attoma N, Deluca N, Frattini F, Niego R, Rafaele D, Ravenna V, Turazzini M, Cammarata S, Lundström E, Jonsson L, Söderström U, Terént A, Murray V, Alvelius A, Arbin von M, Dalenbring I, Doverhall A, Franzén-Dahlin A, Greilert N, Hallberg M, Heijne von A, Isaksson E, Kumpulainen H, Laska A, Lundström A, Martin C, Muhrbeck J, Näslund E, Ringart N, Rooth E, Undén R, Waldenström P, Esbjornsson M, Petranek E, Cederin B, Bertholds E, Elgåsen A, Johansson T, Witteborn B, Kwiatkowska M, Gustafsson E, Noren T, Saaf J, Teichert J, Bertilsson M, Nilsson S, Oestberg S, Welin L, Fredricson K, Pehn L, Hambraeus J, Lonn I, Capio S, Hojeberg B, Adolfsson A, Anzen M, Wallen T, Schloenzig R, Söderström P, Wennerberg A, Buchwald F, Abul-Kasim K, Berkeskold A, Petersson J, Poromaa E, Wester P, Backlund R, Sjöström A, Hedström B, Campbell E, Johnsson K, Karlsson B, Lekokotla N, Lundahl C, Risedal A, Sandgren P, Svensson A, Bysell S, Smedberg E, Vestberg Bysell A, Sjögren V, Högvall B, Andsberg G, Cronberg T, Lindgren A, Wannberg H, Ax F, Nyren L, Sanner J, Andersson H, Andler F, Holmgård S, Johansson R, Magnussan I, Nilsson K, Rådberg J, Indredavik B, Ellekjær H, Østvik A, Rohweder G, Steckhan D, Storvold J, Berge E, Rønning Y, Aakvik R, Bruins Slot K, Knutsen G, Moxness M, Pettersen R, Wyller T, Wahl C, Iversen O, Johnsen S, Norderhus B, Steffensen L, Stensland E, Asak T, Aaseth J, Rotnes T, Sparby J, Wetterhus S, Hallan H, Aardal A, Graven T, Hansbakk Skjetne H, Klykken B, Lindqvist K, Tommy A, Engstad T, Antonsen M, Bajic R, Fønnebø W, Hykkerud S, Lyngmo I, Nyrnes A, Rogne S, Sparr S, Kildahl-Andersen O, Pedersen K, Ulrichsen H, Skogen O, Alnes I, Hukari R, Seljeseth Y, Vadset P, Knutsen G, Fure B, Ihle-Hansen H, Johnsen N, Kornberg L, Schuler S, Heibert M, Lillebø M, Aasen O, Eskeland I, Hamre T, Hareide S, Helset H, Kolnes K, Lødemel B, Ose Velle H, Reite S, Velle E, Grimley R, Ahern E, Cocks C, Courtney M, Devin R, Endacott J, Fawcett C, Harrington V, Johnston C, Koltermann M, Murray S, Ng K, Styles G, Tampiyappa A, Levi C, Chung K, Dark L, Evans M, Gawarikar Y, Kerr E, Loiselle A, Miteff F, Moore A, O'Brien W, Parsons M, Quain D, Royan A, Russell M, Spratt N, Sturm J, Crimmins D, Griffiths D, Kavelieros P, Kinsella J, Malhotra A, O'Brien B, Schutz A, Webb M, Whyte S, Zenteno V, Lindley R, Bleasel A, Cordato N, Duggins A, Fung V, Gomes L, Ingham N, Ip J, Landau P, Morris J, Vucic S, Hankey G, Claxton A, Lillywhite N, Lueck C, Andrews C, Danta G, Das C, Harvey I, Hughes A, McColl C, Oon A, Tuck R, Read S, Badve M, Broad M, Cadigan G, Cavanagh H, Chalk J, Copsinis D, Etherington K, Henderson R, Hull R, O'Sullivan J, Pandian J, Ross-Lee L, Roxas M, Sheikh N, Skinner G, Wong A, Dewey H, Brodtmann A, Donnan G, Hughes A, Karonen M, Ma H, Mulcahy T, Petrolo S, Walker L, Young D, Zavala J, Thieben M, Harris C, Krause M, Lane S, Park H, Shaffi M, Wood J, Bladin C, Buckland A, Coughlan M, Coulton B, Gilligan A, Lee P, Mullen S, Ross Z, Sien Loh P, Szoeke C, Silva M, Afonso F, Gabriel J, Guimarães P, Velon A, Castelo-Branco M, Alvarez F, Branco V, Coxo C, Goulao P, Leal D, Morgado S, Oliveira R, Paiva F, Rodrigues A, Simoes M, Lopes G, Almeida T, Cardoso M, Chaves J, Correia C, Correia M, Damásio J, Felgueiras R, Pereira J, Tuna A, Ferreira C, Lourenco E, Machado A, Mare R, Rocha J, Peeters A, Matz K, Brainin M, Funk G, Reiner-Deitemyer V, Ferrari J, Flamm-Horak A, Gruber G, Rattinger R, Muellbacher W, Doppelbauer D, Kalchmayr R, Schima W, Wieser T, Zart M, Lyrer P, Bonati L, Engelter S, Fluri F, Muller S, Radue E, Tiemessen A, Walz L, Weisskopf F, Wetzel S, Luft A, Fetz D, Hertler B, Pangalu A, Gubitz G, Boulton P, Jarrett J, Moeller J, Phillips S, Arauz A, Bermudez L, Calleja J, Garcia R.

Erratum in

  • Lancet. 2012 Aug 25;380(9843):730.

Abstract

BACKGROUND:

Thrombolysis is of net benefit in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4·5 h of onset. The third International Stroke Trial (IST-3) sought to determine whether a wider range of patients might benefit up to 6 h from stroke onset.

METHODS:

In this international, multicentre, randomised, open-treatment trial, patients were allocated to 0·9 mg/kg intravenous recombinant tissue plasminogen activator (rt-PA) or to control. The primary analysis was of the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0-2 at 6 months. The study is registered, ISRCTN25765518.

FINDINGS:

3035 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0-2; adjusted odds ratio [OR] 1·13, 95% CI 0·95-1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI -20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10-1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07-11·8; absolute excess 58/1000, 95% CI 44-72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22-2·08, p=0·001; absolute increase 37/1000, 95% CI 17-57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group).

INTERPRETATION:

For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients.

FUNDING:

UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, Arbetsmarknadens Partners Forsakringsbolag (AFA) Insurances Sweden, Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, the Australian Heart Foundation, Australian National Health and Medical Research Council (NHMRC), Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita, Regione dell'Umbria, Italy, and Danube University.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Comment in

PMID:
22632908
[PubMed - indexed for MEDLINE]
PMCID:
PMC3386495
Free PMC Article

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