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

Hedley Emsley, Peter Sandercock, Joanna M. Wardlaw, Richard I. Lindley, Martin Dennis, Geoff Cohen, Gordon Murray, Karen Innes, Graham Venables, Anna Czlonkowska, Adam Kobayashi, Stefano Ricci, Veronica Murray, Eivind Berge, Karsten Bruins Slot, Graeme J. Hankey, Manuel Correia, Andre Peeters, Karl Matz, Phillippe LyrerGord Gubitz, Stephen J. Phillips, Antonio Arauz, Colin Baigent, David Chadwick, Pippa Tyrrell, Gordon Lowe, Rory Collins, Philip Bath, Jan Van Gijn, Richard Gray, Robert Hart, Salim Yusuf, Alison Clark, David Perry, Vera Soosay, David Buchanan, Sheila Grant, Eleni Sakka, Jonathan Drever, Pauli Walker, Indee Herath, Ann Leigh Brown, Paul Chmielnik, Christopher Armit, Andrea Walton, Mischa Hautvast, Steff Lewis, Graeme Heron, Sylvia Odusanya, Pam Linksted, Ingrid Kane, Will Whiteley, Robin Sellar, Philip White, Peter Keston, Andrew Farrell, Zoe Morris, Hector Miranda, Lisa Blackwell

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    Background Thrombolysis is of net benefi t 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 benefi t 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 defi ned 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-signifi cant absolute increase of 14/1000, 95% CI-20 to 48). An ordinal analysis showed a signifi cant 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. Benefi t 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.
    Original languageEnglish
    Pages (from-to)2352-2363
    Number of pages11
    JournalThe Lancet
    Issue number9834
    Publication statusPublished - Jun 2012


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